Data-Driven Prediction of Formation Mechanisms of Lithium Ethylene Monocarbonate with an Automated Reaction Network.

Interfacial reactions are notoriously difficult to characterize, and robust prediction of the chemical evolution and associated functionality of the resulting surface film is one of the grand challenges of materials chemistry. The solid-electrolyte interphase (SEI), critical to Li-ion batteries (LIBs), exemplifies such a surface film, and despite decades of work, considerable controversy remains regarding the major components of the SEI as well as their formation mechanisms. Here we use a reaction network to investigate whether lithium ethylene monocarbonate (LEMC) or lithium ethylene dicarbonate (LEDC) is the major organic component of the LIB SEI. Our data-driven, automated methodology is based on a systematic generation of relevant species using a general fragmentation/recombination procedure which provides the basis for a vast thermodynamic reaction landscape, calculated with density functional theory. The shortest pathfinding algorithms are employed to explore the reaction landscape and obtain previously proposed formation mechanisms of LEMC as well as several new reaction pathways and intermediates. For example, we identify two novel LEMC formation mechanisms: one which involves LiH generation and another that involves breaking the (CH2)O-C(═O)OLi bond in LEDC. Most importantly, we find that all identified paths, which are also kinetically favorable under the explored conditions, require water as a reactant. This condition severely limits the amount of LEMC that can form, as compared with LEDC, a conclusion that has direct impact on the SEI formation in Li-ion energy storage systems. Finally, the data-driven framework presented here is generally applicable to any electrochemical system and expected to improve our understanding of surface passivation.

Surgeon Quality and Patient Survival After Resection for Non-Small-Cell Lung Cancer.

PURPOSE: The quality and outcomes of curative-intent lung cancer surgery vary in populations. Surgeons are key drivers of surgical quality. We examined the association between surgeon-level intermediate outcomes differences, patient survival differences, and potential mitigation by processes of care. PATIENTS AND METHODS: Using a baseline population-based surgical resection cohort, we derived surgeon-level cut points for rates of positive margins, nonexamination of lymph nodes, nonexamination of mediastinal lymph nodes, and wedge resections. Applying the baseline cut points to a subsequent cohort from the same population-based data set, we assign surgeons into three performance categories in reference to each metric: 1 (<25th percentile), 2 (25th-75th percentile), and 3 (>75th percentile). The sum of performance scores created three surgeon quality tiers: 1 (4-6, low), 2 (7-9, intermediate), and 3 (10-12, high). We used chi-squared, Wilcoxon-Mann-Whitney, and Kruskal-Wallis tests to compare patient characteristics between the baseline and subsequent cohorts and across surgeon tiers. We applied Cox proportional hazards models to examine the association between patient survival and surgeon performance tier, sequentially adjusting for clinical stage, patient characteristics, and four specific processes. RESULTS: From 2009 to 2021, 39 surgeons performed 4,082 resections across the baseline and subsequent cohorts. Among 31 subsequent cohort surgeons, five were tier 1, five were tier 2, and 21 were tier 3. Tier 1 and 2 surgeons had significantly worse outcomes than tier 3 surgeons (hazard ratio [HR], 1.37; 95% CI, 1.10 to 1.72 and 1.19; 95% CI, 1.00 to 1.43, respectively). Adjustment for specific processes mitigated the surgeon-tiered survival differences, with adjusted HRs of 1.02 (95% CI, 0.8 to 1.3) and 0.93 (95% CI, 0.7 to 1.25), respectively. CONCLUSION: Readily accessible intermediate outcomes metrics can be used to stratify surgeon performance for targeted process improvement, potentially reducing patient survival disparities.

Mitochondrial permeability transition in the diabetic heart: contributions of thiol redox state and mitochondrial calcium to augmented reperfusion injury.

Mitochondria from diabetic hearts are sensitized to mitochondrial permeability transition pore (PTP) opening, which may be responsible for the increased propensity for cardiac injury in diabetic hearts. The purpose of this study was to determine if redox-dependent PTP opening contributes to augmented injury in diabetic hearts, and if compounds targeted at mitochondrial PTP, ROS, and calcium influx protected diabetic hearts from injury. Hearts from control or streptozotocin-induced diabetic rats were excised for either whole-heart or isolated mitochondria experiments. Myocardial glutathione content was oxidized in diabetic hearts when compared to control, and this translated to increased oxidation of the adenine nucleotide translocase in diabetic hearts. Diabetic mitochondria displayed significantly greater sensitivity to PTP opening than non-diabetic counterparts, which was reversed with the thiol-reducing agent dithiothreitol. The thiol-oxidant diamide increased calcium sensitivity in control, but not diabetic mitochondria. Diabetic animals treated with the mitochondria-targeted ROS suppressing peptide MTP-131 also showed improved resistance to PTP opening. In separate experiments hearts underwent ex vivo ischemia/reperfusion (IR). Diabetic hearts were more susceptible to IR injury, with infarct sizes of 60 ± 4% of the area-at-risk (vs. 46 ± 2% in non-diabetics; P<0.05). Administration of the PTP blocker NIM811 (5 µM), MTP-131 (1 nM) or the mitochondrial calcium uniporter blocker minocycline (1 µM) at the onset of reperfusion reduced infarct sizes in both control and diabetic hearts. These findings suggest that augmented susceptibility to injury in the diabetic heart is mediated by redox-dependent shifts in PTP opening, and that three novel mitochondria-targeted agents administered at reperfusion may be suitable adjuvant reperfusion therapies to attenuate injury in diabetic patients.

A chemically consistent graph architecture for massive reaction networks applied to solid-electrolyte interphase formation.

Modeling reactivity with chemical reaction networks could yield fundamental mechanistic understanding that would expedite the development of processes and technologies for energy storage, medicine, catalysis, and more. Thus far, reaction networks have been limited in size by chemically inconsistent graph representations of multi-reactant reactions (e.g. A + B → C) that cannot enforce stoichiometric constraints, precluding the use of optimized shortest-path algorithms. Here, we report a chemically consistent graph architecture that overcomes these limitations using a novel multi-reactant representation and iterative cost-solving procedure. Our approach enables the identification of all low-cost pathways to desired products in massive reaction networks containing reactions of any stoichiometry, allowing for the investigation of vastly more complex systems than previously possible. Leveraging our architecture, we construct the first ever electrochemical reaction network from first-principles thermodynamic calculations to describe the formation of the Li-ion solid electrolyte interphase (SEI), which is critical for passivation of the negative electrode. Using this network comprised of nearly 6000 species and 4.5 million reactions, we interrogate the formation of a key SEI component, lithium ethylene dicarbonate. We automatically identify previously proposed mechanisms as well as multiple novel pathways containing counter-intuitive reactions that have not, to our knowledge, been reported in the literature. We envision that our framework and data-driven methodology will facilitate efforts to engineer the composition-related properties of the SEI - or of any complex chemical process - through selective control of reactivity.

Quantum chemical calculations of lithium-ion battery electrolyte and interphase species.

Lithium-ion batteries (LIBs) represent the state of the art in high-density energy storage. To further advance LIB technology, a fundamental understanding of the underlying chemical processes is required. In particular, the decomposition of electrolyte species and associated formation of the solid electrolyte interphase (SEI) is critical for LIB performance. However, SEI formation is poorly understood, in part due to insufficient exploration of the vast reactive space. The Lithium-Ion Battery Electrolyte (LIBE) dataset reported here aims to provide accurate first-principles data to improve the understanding of SEI species and associated reactions. The dataset was generated by fragmenting a set of principal molecules, including solvents, salts, and SEI products, and then selectively recombining a subset of the fragments. All candidate molecules were analyzed at the ωB97X-V/def2-TZVPPD/SMD level of theory at various charges and spin multiplicities. In total, LIBE contains structural, thermodynamic, and vibrational information on over 17,000 unique species. In addition to studies of reactivity in LIBs, this dataset may prove useful for machine learning of molecular and reaction properties.

Prestorage leukoreduction ameliorates the effects of aging on banked blood.

BACKGROUND: Previous studies have demonstrated that the transfusion of older blood is independently associated with higher rates of infectious complications, multiple organ failure, and mortality. Putative mechanisms implicate leukocytes in stored blood that generate immunomodulatory mediators as the stored blood ages. The purpose of this retrospective cohort study was to describe the effect of prestorage leukoreduction (PS-LR) on the detrimental clinical effects of increasing age on blood products used in trauma patients. METHODS: All patients receiving >or=6 units of packed red cells and surviving >or=48 hours since May 1999 when institutional universal PS-LR was begun were identified. Transfusion requirements, demographic data, and causes of death were collected. Blood bank records were reviewed to determine the age of each unit of blood transfused. Multivariate logistic regression was used to determine the relationship between the age of PS-LR transfused blood and mortality after adjusting for total transfusion requirement, patient age, Injury Severity Score, head Abbreviated Injury Score, mechanism of injury, and gender. A subgroup analysis was performed excluding those patients in whom care was withdrawn at 48 hours to 72 hours postinjury for brain death or neurologic devastation. RESULTS: A total of 399 patients, receiving 6,603 units of blood, met inclusion criteria. Mortality analysis showed that increasing Injury Severity Score, patient age, head Abbreviated Injury Score, and number of units of packed red cells transfused were all independently associated with an increased risk of death. When mean age of blood was analyzed as a continuous variable, a significant reduction in the risk of death with increasing mean age of transfused PS-LR blood was noted (odds ratio [OR], 0.959; 95% confidence interval [CI], 0.924-0.996). Both of these findings persisted when the mean age of blood was dichotomized at 14 days (OR, 0.426; 95% CI, 0.182-0.998) and 21 days (OR, 0.439; 95% CI, 0.225-0.857). The area under the curve for the receiver operating characteristics of our mortality model was 0.90. After excluding 13 patients in whom care was withdrawn 48 hours to 72 hours postinjury for brain death or neurologic devastation, the mortality analysis still showed that increasing injury severity, number of units of packed red cells transfused, and age were all independently associated with an increased risk of death. The protective effect of receiving older blood seen in the all-cause mortality analysis disappeared because no association was found between odds of dying and increasing age of packed red blood cells units transfused. This was true whether the mean age of transfused blood was dichotomized at 14 days (OR, 0.93; CI, 0.30-2.83) or at 21 days (OR, 0.54; CI, 0.25-1.16). CONCLUSION: Our data suggest that the deleterious effects of aging on banked blood are ameliorated by PS-LR. We are currently conducting a prospective observational study in an effort to duplicate the findings of this retrospective investigation.

Hydrogen sulfide mediates the vasoactivity of garlic.

The consumption of garlic is inversely correlated with the progression of cardiovascular disease, although the responsible mechanisms remain unclear. Here we show that human RBCs convert garlic-derived organic polysulfides into hydrogen sulfide (H(2)S), an endogenous cardioprotective vascular cell signaling molecule. This H(2)S production, measured in real time by a novel polarographic H(2)S sensor, is supported by glucose-maintained cytosolic glutathione levels and is to a large extent reliant on reduced thiols in or on the RBC membrane. H(2)S production from organic polysulfides is facilitated by allyl substituents and by increasing numbers of tethering sulfur atoms. Allyl-substituted polysulfides undergo nucleophilic substitution at the alpha carbon of the allyl substituent, thereby forming a hydropolysulfide (RS(n)H), a key intermediate during the formation of H(2)S. Organic polysulfides (R-S(n)-R'; n > 2) also undergo nucleophilic substitution at a sulfur atom, yielding RS(n)H and H(2)S. Intact aorta rings, under physiologically relevant oxygen levels, also metabolize garlic-derived organic polysulfides to liberate H(2)S. The vasoactivity of garlic compounds is synchronous with H(2)S production, and their potency to mediate relaxation increases with H(2)S yield, strongly supporting our hypothesis that H(2)S mediates the vasoactivity of garlic. Our results also suggest that the capacity to produce H(2)S can be used to standardize garlic dietary supplements.

The cardiolipin-binding peptide elamipretide mitigates fragmentation of cristae networks following cardiac ischemia reperfusion in rats.

Mitochondrial dysfunction contributes to cardiac pathologies. Barriers to new therapies include an incomplete understanding of underlying molecular culprits and a lack of effective mitochondria-targeted medicines. Here, we test the hypothesis that the cardiolipin-binding peptide elamipretide, a clinical-stage compound under investigation for diseases of mitochondrial dysfunction, mitigates impairments in mitochondrial structure-function observed after rat cardiac ischemia-reperfusion. Respirometry with permeabilized ventricular fibers indicates that ischemia-reperfusion induced decrements in the activity of complexes I, II, and IV are alleviated with elamipretide. Serial block face scanning electron microscopy used to create 3D reconstructions of cristae ultrastructure reveals that disease-induced fragmentation of cristae networks are improved with elamipretide. Mass spectrometry shows elamipretide did not protect against the reduction of cardiolipin concentration after ischemia-reperfusion. Finally, elamipretide improves biophysical properties of biomimetic membranes by aggregating cardiolipin. The data suggest mitochondrial structure-function are interdependent and demonstrate elamipretide targets mitochondrial membranes to sustain cristae networks and improve bioenergetic function.

Robotic Transhiatal Esophagectomy in a Community Hospital: Evolution of Technique.

Esophageal cancer is an uncommon but highly lethal disease. Surgical resection is the gold standard of treatment for early-stage disease. Traditional surgical approach entailed significant convalescence, hospital stay, and morbidity and mortality. Transhiatal esophagectomy (THE) involves blind dissection of the esophagus with minimal mediastinal lymphadenectomy. Integration of robotic surgery is an alternate platform for minimally invasive approach while maintaining safety and following oncologic principles. We review our technique for minimally invasive THE using robotic technology, demonstrating the safety and efficacy of robotic technology surgery. We present a retrospective review of a single surgeon's data of patients treated with robotic-assisted THE, with a chart review to evaluate pathology, adequacy of surgical resection, nodal harvest, and perioperative course. Robotic THE (rTHE) shows promise as a valid option for esophageal resection, including premalignant and advanced stages of cancer. Adequate transhiatal mediastinal nodal resection can be performed with the robot.

Stage of the estrous cycle does not influence myocardial ischemia-reperfusion injury in rats (Rattus norvegicus).

Even though cardiovascular disease is the leading cause of death for men and women, the vast majority of animal studies use male animals. Because female reproductive hormones have been associated with cardioprotective states, many investigators avoid using female animals because these hormones are cyclical and may introduce experimental variability. In addition, no studies have investigated the specific effects of the estrous cycle on cardiac ischemic injury. This study was conducted to determine whether the estrous cycle stage influences the susceptibility to ischemic injury in rat hearts. Estrous cycle stage was determined by using vaginal smear cytology, after which hearts underwent either in vivo (surgical) or ex vivo (isolated) ischemia-reperfusion injury. For in vivo studies, the left anterior coronary artery was ligated for 25 min of ischemia and subsequently released for 120 min of reperfusion. Infarct sizes were 42% ± 6%; 49% ± 4%; 40% ± 9%; 47% ± 9% of the zone-at-risk for rats in proestrus, estrus, metestrus, and diestrus, respectively. For ex vivo studies, isolated, perfused hearts underwent global ischemia and reperfusion for 25 and 120 min, respectively. Similar to our in vivo studies, the ex vivo rat model showed no significant differences in susceptibility to infarction or extent of cardiac arrhythmia according to estrous stage. To our knowledge, these studies provide the first direct evidence that the stage of estrous cycle does not significantly alter cardiac ischemia-reperfusion injury in rats.

Redox-dependent increases in glutathione reductase and exercise preconditioning: role of NADPH oxidase and mitochondria.

AIMS: We have previously shown that exercise leads to sustainable cardioprotection through a mechanism involving improved glutathione replenishment. This study was conducted to determine if redox-dependent modifications in glutathione reductase (GR) were involved in exercise cardioprotection. Furthermore, we sought to determine if reactive oxygen species generated by NADPH oxidase and/or mitochondria during exercise were triggering events for GR modulations. METHODS AND RESULTS: Rats were exercised for 10 consecutive days, after which isolated hearts were exposed to ischaemia/reperfusion (25 min/120 min). Exercise protected against infarction and arrhythmia, and preserved coronary flow. The GR inhibitor BCNU abolished the beneficial effects. GR activity was increased following exercise in a redox-dependent manner, with no change in GR protein levels. Because fluorescent labelling of GR protein thiols showed lower amounts of reduced thiols after exercise, we sought to determine the source of intracellular reactive oxygen species that may be activating GR. Subsets of animals were exercised immediately after treatment with either NADPH-oxidase inhibitors apocynin or Vas2870, or with mitoTEMPO or Bendavia, which reduce mitochondrial reactive oxygen species levels. The cardioprotective effects of exercise were abolished if animals exercised in the presence of NADPH oxidase inhibitors, in clear contrast to the mitochondrial reagents. These changes correlated with thiol-dependent modifications of GR. CONCLUSION: Adaptive cardioprotective signalling is triggered by reactive oxygen species from NADPH oxidase, and leads to improved glutathione replenishment through redox-dependent modifications in GR.

Inhibition of transfer to secondary receptors by heparan sulfate-binding drug or antibody induces noninfectious uptake of human papillomavirus.

Infection with various human papillomaviruses (HPVs) induces cervical cancers. Cell surface heparan sulfates (HS) have been shown to serve as primary attachment receptors, and molecules with structural similarity to cell surface HS, like heparin, function as competitive inhibitors of HPV infection. Here we demonstrate that the N,N'-bisheteryl derivative of dispirotripiperazine, DSTP27, efficiently blocks papillomavirus infection by binding to HS moieties, with 50% inhibitory doses of up to 0.4 mug/ml. In contrast to short-term inhibitory effects of heparin, pretreatment of cells with DSTP27 significantly reduced HPV infection for more than 30 h. Using DSTP27 and heparinase, we furthermore demonstrate that HS moieties, rather than laminin 5, present in the extracellular matrix (ECM) secreted by keratinocytes are essential for infectious transfer of ECM-bound virions to cells. Prior binding to ECM components, especially HS, partially alleviated the requirement for cell surface HS. DSTP27 blocks infection by cell-bound virions by feeding into a noninfectious entry pathway. Under these conditions, virus colocalized with HS moieties in endocytic vesicles. Similarly, postattachment treatment of cells with heparinase, cytochalasin D, or neutralizing antibodies resulted in uptake of virions without infection, indicating that deviation into a noninfectious entry pathway is a major mode of postattachment neutralization. In untreated cells, initial colocalization of virions with HS on the cell surface and in endocytic vesicles was lost with time. Our data suggest that initial attachment of HPV to HS proteoglycans (HSPGs) must be followed by secondary interaction with additional HS side chains and transfer to a non-HSPG receptor for successful infection.

Hydrogen sulfide mediates vasoactivity in an O2-dependent manner.

Hydrogen sulfide (H(2)S) has recently been shown to have a signaling role in vascular cells. Similar to nitric oxide (NO), H(2)S is enzymatically produced by amino acid metabolism and can cause posttranslational modification of proteins, particularly at thiol residues. Molecular targets for H(2)S include ATP-sensitive K(+) channels, and H(2)S may interact with NO and heme proteins such as cyclooxygenase. It is well known that the reactions of NO in the vasculature are O(2) dependent, but this has not been addressed in most studies designed to elucidate the role of H(2)S in vascular function. This is important, since H(2)S reactions can be dramatically altered by the high concentrations of O(2) used in cell culture and organ bath experiments. To test the hypothesis that the effects of H(2)S on the vasculature are O(2) dependent, we have measured real-time levels of H(2)S and O(2) in respirometry and vessel tension experiments, as well as the associated vascular responses. A novel polarographic H(2)S sensor developed in our laboratory was used to measure H(2)S levels. Here we report that, in rat aorta, H(2)S concentrations that mediate rapid contraction at high O(2) levels cause rapid relaxation at lower physiological O(2) levels. At high O(2), the vasoconstrictive effect of H(2)S suggests that it may not be H(2)S per se but, rather, a putative vasoactive oxidation product that mediates constriction. These data are interpreted in terms of the potential for H(2)S to modulate vascular tone in vivo.