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BACKGROUND: Surgery is the primary treatment for non-small cell lung cancer (NSCLC), but microscopic residual disease may be unavoidable. Preclinical studies have shown that volatile anesthetics might suppress host immunity and promote a pro-malignant environment that supports cancer cell proliferation, migration, and angiogenesis, whereas propofol may preserve cell-mediated immunity and inhibit tumor angiogenesis. However, clinical evidence that propofol-based total intravenous anesthesia (TIVA) can reduce tumor recurrence after curative resection remains inconsistent due to the retrospective observational nature of previous studies. Therefore, we will test the hypothesis that the recurrence-free survival (RFS) after curative resection of NSCLC is higher in patients who received TIVA than volatile anesthetics (GAS) in this multicenter randomized trial. METHODS: This double-blind, randomized trial will enroll patients at 22 international sites, subject to study registration, institutional review board approval, and patient written informed consent. Eligible patients are adult patients undergoing lung resection surgery with curative intent for NSCLC. Exclusion criteria will be contraindications to study drugs, American Society of Anesthesiologists physical status IV or higher, or preexisting distant metastasis or malignant tumor in other organs. At each study site, enrolled subjects will be randomly allocated into the TIVA and GAS groups with a 1:1 ratio. This pragmatic trial does not standardize any aspect of patient care. However, potential confounders will be balanced between the study arms. The primary outcome will be RFS. Secondary outcomes will be overall survival and complications within postoperative 7 days. Enrollment of 5384 patients will provide 80% power to detect a 3% treatment effect (hazard ratio of 0.83) at alpha 0.05 for RFS at 3 years. DISCUSSION: Confirmation of the study hypothesis would demonstrate that a relatively minor and low-cost alteration in anesthetic management has the potential to reduce cancer recurrence risk in NSCLC, an ultimately fatal complication. Rejection of the hypothesis would end the ongoing debate about the relationship between cancer recurrence and anesthetic management. TRIAL REGISTRATION: The study protocol was prospectively registered at the Clinical trials ( https://clinicaltrials.gov , NCT06330038, principal investigator: Hyun Joo Ahn; date of first public release: March 25, 2024) before the recruitment of the first participant.
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Mammalian cardiomyocytes have limited regenerative ability. Cardiac disease, such as congenital heart disease and myocardial infarction, causes an initial loss of cardiomyocytes through regulated cell death (RCD). Understanding the mechanisms that govern RCD in the injured myocardium is crucial for developing therapeutics to promote heart regeneration. We previously reported that ferroptosis, a non-apoptotic and iron-dependent form of RCD, is the main contributor to cardiomyocyte death in the injured heart. To investigate the mechanisms underlying the preference for ferroptosis in cardiomyocytes, we examined the effects of anti-ferroptotic reagents in infarcted mouse hearts. The results revealed that the anti-ferroptotic reagent did not improve neonatal heart regeneration, and further compromised the cardiac function of juvenile hearts. On the other hand, ferroptotic cardiomyocytes played a supportive role during wound healing by releasing pro-angiogenic factors. The inhibition of ferroptosis in the regenerating mouse heart altered the immune and angiogenic responses. Our study provides insights into the preference for ferroptosis over other types of RCD in stressed cardiomyocytes, and guidance for designing anti-cell-death therapies for treating heart disease.
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Bacterial enhancer-binding proteins (bEBPs) acquire a transcriptionally active state via phosphorylation. However, transcriptional activation by the dephosphorylated form of bEBP has been observed in DctD, which belongs to Group I bEBP. The formation of a complex between dephosphorylated DctD (d-DctD) and dephosphorylated IIAGlc (d-IIAGlc) is a prerequisite for the transcriptional activity of d-DctD. In the present study, characteristics of the transcriptionally active complex composed of d-IIAGlc and phosphorylation-deficient DctD (DctDD57Q) of Vibrio vulnificus were investigated in its multimeric conformation and DNA-binding ability. DctDD57Q formed a homodimer that could not bind to the DNA. In contrast, when DctDD57Q formed a complex with d-IIAGlc in a 1:1 molar ratio, it produced two conformations: dimer and dodecamer of the complex. Only the dodecameric complex exhibited ATP-hydrolyzing activity and DNA-binding affinity. For successful DNA-binding and transcriptional activation by the dodecameric d-IIAGlc/DctDD57Q complex, extended upstream activator sequences were required, which encompass the nucleotide sequences homologous to the known DctD-binding site and additional nucleotides downstream. This is the first report to demonstrate the molecular characteristics of a dephosphorylated bEBP complexed with another protein to form a transcriptionally active dodecameric complex, which has an affinity for a specific DNA-binding sequence.IMPORTANCEResponse regulators belonging to the bacterial two-component regulatory system activate the transcription initiation of their regulons when they are phosphorylated by cognate sensor kinases and oligomerized to the appropriate multimeric states. Recently, it has been shown that a dephosphorylated response regulator, DctD, could activate transcription in a phosphorylation-independent manner in Vibrio vulnificus. The dephosphorylated DctD activated transcription as efficiently as phosphorylated DctD when it formed a complex with dephosphorylated form of IIAGlc, a component of the glucose-phosphotransferase system. Functional mimicry of this complex with the typical form of transcriptionally active phosphorylated DctD led us to study the molecular characteristics of this heterodimeric complex. Through systematic analyses, it was surprisingly determined that a multimer constituted with 12 complexes gained the ability to hydrolyze ATP and recognize specific upstream activator sequences containing a typical inverted-repeat sequence flanked by distinct nucleotides.
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Proteínas de Bactérias , Regulação Bacteriana da Expressão Gênica , Vibrio vulnificus , Trifosfato de Adenosina/metabolismo , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/genética , Proteínas de Bactérias/química , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/química , Fosforilação , Ligação Proteica , Multimerização Proteica , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/química , Transcrição Gênica , Ativação Transcricional , Vibrio vulnificus/genética , Vibrio vulnificus/metabolismo , Vibrio vulnificus/químicaRESUMO
Chest pain is the most common symptom of coronary artery disease (CAD) and diabetes mellitus (DM) is a well-known single strongest risk factor for cardiovascular diseases. Thus, the impact of CAD nor DM on long-term clinical effects is reported widely, but the prognostic factors of non-DM patients presenting with chest pain without significant CAD are limited. A total of 1,046 patients with chest pain without DM and significant CAD who underwent coronary angiography (CAG) and acetylcholine (ACH) provocation tests were finally enrolled. Propensity score matching and multivariate Cox-proportional hazard ratio analysis were performed to adjust for baseline potential confounders. Major adverse cardiac and cerebrovascular events (MACCE) were defined as the composite of total death, myocardial infarction (MI), revascularization, stroke, and recurrent angina. This study aimed to evaluate the long-term prognostic factors for MACCE in patients with chest pain without DM and CAD up to 5 years. Coronary artery spasm (CAS) was the most common cause of chest pain. However, long-term MACCE of CAS was not worse than those of patients with chest pain without CAS when patients with CAS had subsequent optimal antianginal medication therapy. However, a recurrent chest pain remains a problem even with continuous antianginal medication therapy. Up to 5 years, the incidence of MACCE was in 7.3%, including recurrent angina 6.9%. Dyslipidemia (HR: 2.010, 95% CI 1.166-3.466, P = 0.012), mild-moderate (30-70%) coronary stenosis (HR: 2.369, 95% CI 1.118-5.018, P = 0.024), the use of aspirin (HR: 2.885, 95% CI 1.588-5.238, P < 0.001), and the use of nitrates (HR: 1.938, 95% CI 1.094-3.433, P = 0.023) were independent risk factors for MACCE. Among the patients with chest pain without DM and significant CAD, the incidence of MACE were rare, but recurrent angina was still a challenging problem who had treated with antianginal medications.
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Fármacos Cardiovasculares , Doença da Artéria Coronariana , Estenose Coronária , Vasoespasmo Coronário , Diabetes Mellitus , Humanos , Prognóstico , Doença da Artéria Coronariana/complicações , Angina Pectoris/diagnóstico , Angina Pectoris/epidemiologia , Angina Pectoris/etiologia , Vasoespasmo Coronário/complicações , Vasoespasmo Coronário/diagnóstico , Vasoespasmo Coronário/epidemiologia , Estenose Coronária/diagnóstico , Estenose Coronária/diagnóstico por imagem , Dor no Peito/diagnóstico , Dor no Peito/epidemiologia , Dor no Peito/etiologia , Diabetes Mellitus/epidemiologia , Fatores de Risco , Angiografia Coronária/efeitos adversosRESUMO
The discovery of superconductivity in infinite-layer nickelates established another category of unconventional superconductors that shares structural and electronic similarities with cuprates. However, key issues of the superconducting pairing symmetry, gap amplitude and superconducting fluctuations are yet to be addressed. Here we utilize static and ultrafast terahertz spectroscopy to address these. We demonstrate that the equilibrium terahertz conductivity and non-equilibrium terahertz responses of an optimally Sr-doped nickelate film (superconducting transition temperature of Tc = 17 K) are in line with the electrodynamics of d-wave superconductivity in the dirty limit. The gap-to-Tc ratio (2Δ/kBTc) is found to be 3.4, indicating that the superconductivity falls in the weak coupling regime. In addition, we observed substantial superconducting fluctuations near Tc that do not extend into the deep normal state as the optimally hole-doped cuprates do. Our results support a d-wave system that closely resembles the electron-doped cuprates.
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The mid-wave infrared (MWIR), ranging from 2 to 5 micrometers, is of substantial interest for chemical sensing, imaging, and spectroscopy. Black phosphorus (bP)-based MWIR light emitters and detectors have been shown to outperform the state-of-the-art for commercial devices due to the low Auger recombination coefficient of bP. However, the scalability of these devices remains a challenge. Here, we report a bP ink formula that preserves the exceptional MWIR optoelectronic properties of bP to deposit centimeter-scale, uniform, and pinhole free films with a photoluminescence quantum yield higher than competing III-V and II-VI semiconductors with similar bandgaps at high excitation regime. As a proof of concept, we use bP ink as a "phosphor" on a red commercial light-emitting diode to demonstrate bright MWIR light emission. We also show that these films can be integrated into heterostructure device architectures with electron and hole selective contacts for direct-injected light emission and detection in MWIR.
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Formation of charged trions is detrimental to the luminescence quantum efficiency of colloidal quantum dot (QD) thin films as they predominantly undergo nonradiative recombination. In this regard, control of charged trion formation is of interest for both fundamental characterization of the quasi-particles and performance optimization. Using CdSe/CdS QDs as a prototypical material system, here we demonstrate a metal-oxide-semiconductor capacitor based on QD thin films for studying the background charge effect on the luminescence efficiency and lifetime. The concentration ratio of the charged and neutral quasiparticles in the QDs is reversibly controlled by applying a gate voltage, while simultaneous steady-state and time-resolved photoluminescence measurements are performed. Notably, the photoluminescence intensity is modulated by up to 2 orders of magnitude with a corresponding change in the effective lifetime. In addition, chip-scale modulation of brightness is demonstrated, where the photoluminescence is effectively turned on and off by the gate, highlighting potential applications in voltage-controlled electrochromics.
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Optical encryption technologies based on room-temperature light-emitting materials are of considerable interest. Herein, we present three-dimensional (3D) printable dual-light-emitting materials for high-performance optical pattern encryption. These are based on fluorescent perovskite nanocrystals (NCs) embedded in metal-organic frameworks (MOFs) designed for phosphorescent host-guest interactions. Notably, perovskite-containing MOFs emit a highly efficient blue phosphorescence, and perovskite NCs embedded in the MOFs emit characteristic green or red fluorescence under ultraviolet (UV) irradiation. Such dual-light-emitting MOFs with independent fluorescence and phosphorescence emissions are employed in pochoir pattern encryption, wherein actual information with transient phosphorescence is efficiently concealed behind fake information with fluorescence under UV exposure. Moreover, a 3D cubic skeleton is developed with the dual-light-emitting MOF powder dispersed in 3D-printable polymer filaments for 3D dual-pattern encryption. This article outlines a universal principle for developing MOF-based room-temperature multi-light-emitting materials and a strategy for multidimensional information encryption with enhanced capacity and security.
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Thermococcus onnurineus NA1, a hyperthermophilic carboxydotrophic archaeon, produces H2 through CO oxidation catalyzed by proteins encoded in a carbon monoxide dehydrogenase (CODH) gene cluster. TON_1525 with a DNA-binding helix-turn-helix (HTH) motif is a putative repressor regulating the transcriptional expression of the codh gene cluster. The T55I mutation in TON_1525 led to enhanced H2 production accompanied by the increased expression of genes in the codh cluster. Here, TON_1525 was demonstrated to be a dimer. Monomeric TON_1525 adopts a novel 'eighth note' symbol-like fold (referred to as 'eighth note' fold regulator, EnfR), and the dimerization mode of EnfR is unique in that it has no resemblance to structures in the Protein Data Bank. According to footprinting and gel shift assays, dimeric EnfR binds to a 36-bp pseudo-palindromic inverted repeat in the promoter region of the codh gene cluster, which is supported by an in silico EnfR/DNA complex model and mutational studies revealing the implication of N-terminal loops as well as HTH motifs in DNA recognition. The DNA-binding affinity of the T55I mutant was lowered by â¼15-fold, for which the conformational change of N-terminal loops is responsible. In addition, transcriptome analysis suggested that EnfR could regulate diverse metabolic processes besides H2 production.
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Research on autonomous driving technology is actively underway to solve the facing problems in the agricultural field. Combine harvesters used in East Asian countries, including Korea, are tracked-type vehicles. The steering control system of the tracked vehicle has different characteristics from the wheeled vehicle used in the agricultural tractor. In this paper, a dual GPS antenna-based autonomous driving system and path tracking algorithm were developed for a robot combine harvester. An α-turn-type work path generation algorithm and a path tracking algorithm were developed. The developed system and algorithm were verified through experiments using actual combine harvesters. The experiment consisted of an experiment with harvesting work and an experiment without harvesting work. In the experiment without harvesting work, an error of 0.052 m occurred during working driving and 0.207 m during turning driving. In the experiment where the harvesting work was carried out, an error of 0.038 m occurred during work driving and 0.195 m during turning driving. As a result of comparing the non-work area and driving time to the results of manual driving, the self-driving experiment with harvesting work showed an efficiency of 76.7%.
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BACKGROUND: The effect of hypercarbia on lung oxygenation during thoracic surgery remains unclear. OBJECTIVE: To investigate the effect of hypercarbia on lung oxygenation during one-lung ventilation in patients undergoing thoracic surgery and evaluate the incidence of postoperative pulmonary complications. DESIGN: Prospective randomised controlled trial. SETTING: A tertiary university hospital in the Republic of Korea from November 2019 to December 2020. PATIENTS: Two hundred and ninety-seven patients with American Society of Anaesthesiologists physical status II to III, scheduled to undergo elective lung resection surgery. INTERVENTION: Patients were randomly assigned to Group 40, 50, or 60. An autoflow ventilation mode with a lung protective ventilation strategy was applied to all patients. Respiratory rate was adjusted to maintain a partial pressure of arterial carbon dioxide of 40â±â5âmmHg in Group 40, 50â±â5âmmHg in Group 50 and 60â±â5âmmHg in Group 60 during one-lung ventilation and at the end of surgery. MAIN OUTCOME MEASURES: The primary outcome was the arterial oxygen partial pressure/fractional inspired oxygen ratio after 60âmin of one-lung ventilation. RESULTS: Data from 262 patients were analysed. The partial pressure/fractional inspired oxygen ratio was significantly higher in Group 50 and Group 60 than in Group 40 (269.4 vs. 262.9 vs. 214.4; P â<â0.001) but was not significantly different between Group 50 and Group 60. The incidence of postoperative pulmonary complications was comparable among the three groups. CONCLUSION: Permissive hypercarbia improved lung oxygenation during one-lung ventilation without increasing the risk of postoperative pulmonary complications or the length of hospital stay. TRIAL REGISTRATION: NCT04175379.
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Ventilação Monopulmonar , Cirurgia Torácica , Humanos , Ventilação Monopulmonar/efeitos adversos , Estudos Prospectivos , Pulmão/cirurgia , Respiração Artificial/efeitos adversos , Hipercapnia , Oxigênio , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Volume de Ventilação PulmonarRESUMO
Neuromorphic computing (NC) architecture inspired by biological nervous systems has been actively studied to overcome the limitations of conventional von Neumann architectures. In this work, we propose a reconfigurable NC block using a flash-type synapse array, emerging positive feedback (PF) neuron devices, and CMOS peripheral circuits, and integrate them on the same substrate to experimentally demonstrate the operations of the proposed NC block. Conductance modulation in the flash memory enables the NC block to be easily calibrated for output signals. In addition, the proposed NC block uses a reduced number of devices for analog-to-digital conversions due to the super-steep switching characteristics of the PF neuron device, substantially reducing the area overhead of NC block. Our NC block shows high energy efficiency (37.9 TOPS/W) with high accuracy for CIFAR-10 image classification (91.80%), outperforming prior works. This work shows the high engineering potential of integrating synapses and neurons in terms of system efficiency and high performance.
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Redes Neurais de Computação , Sinapses , Sinapses/fisiologia , Neurônios/fisiologiaRESUMO
The occurrence of superconductivity in proximity to various strongly correlated phases of matter has drawn extensive focus on their normal state properties, to develop an understanding of the state from which superconductivity emerges1-4. The recent finding of superconductivity in layered nickelates raises similar interests5-8. However, transport measurements of doped infinite-layer nickelate thin films have been hampered by materials limitations of these metastable compounds: in particular, a high density of extended defects9-11. Here, by moving to a substrate (LaAlO3)0.3(Sr2TaAlO6)0.7 that better stabilizes the growth and reduction conditions, we can synthesize the doping series of Nd1-xSrxNiO2 essentially free from extended defects. In their absence, the normal state resistivity shows a low-temperature upturn in the underdoped regime, linear behaviour near optimal doping and quadratic temperature dependence for overdoping. This is phenomenologically similar to the copper oxides2,12 despite key distinctions-namely, the absence of an insulating parent compound5,6,9,10, multiband electronic structure13,14 and a Mott-Hubbard orbital alignment rather than the charge-transfer insulator of the copper oxides15,16. We further observe an enhancement of superconductivity, both in terms of transition temperature and range of doping. These results indicate a convergence in the electronic properties of both superconducting families as the scale of disorder in the nickelates is reduced.
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BACKGROUND: Exercise capacity is known to be an independent predictor of cardiovascular events and mortality. However, most previous studies were based on Western populations. Further study is warranted for Asian patients according to ethnic or national standards. We aimed to compare prognostic values of Korean and Western nomograms for exercise capacity in Korean patients with cardiovascular disease (CVD). METHODS: In this retrospective cohort study, we enrolled 1,178 patients (62 ± 11 years; 78% male) between June 2015 and May 2020, who were referred for cardiopulmonary exercise testing in our cardiac rehabilitation program. The median follow-up period was 1.6 years. Exercise capacity was measured in metabolic equivalents by direct gas exchange method during the treadmill test. The nomogram for exercise capacity from healthy Korean individuals and a previous landmark Western study was used to determine the percentage of predicted exercise capacity. The primary endpoint was the composite of major adverse cardiovascular events (MACE; all-cause death, myocardial infarction, repeat revascularization, stroke and hospitalization for heart failure). RESULTS: A multivariate analysis showed that the risk of primary endpoint was more than double (hazard ratio [HR], 2.20; 95% confidence interval [CI], 1.10-4.40) in the patients with lower exercise capacity (< 85% of predicted) by Korean nomogram. The lower exercise capacity was one of the strong independent predictors along with left ventricular ejection fraction, age, and level of hemoglobin. However, the lower exercise capacity by Western nomogram could not predict the primary endpoint (HR, 1.33; 95% CI, 0.85-2.10). CONCLUSION: Korean patients with CVD with lower exercise capacity have higher risk of MACE. Considering inter-ethnic differences in cardiorespiratory fitness, the Korean nomogram provides more suitable reference values than the Western nomogram to determine lower exercise capacity and predict cardiovascular events in Korean patients with CVD.
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Doenças Cardiovasculares , Humanos , Masculino , Feminino , Tolerância ao Exercício , Estudos Retrospectivos , Volume Sistólico , Função Ventricular Esquerda , República da CoreiaRESUMO
The search for superconductivity in infinite-layer nickelates was motivated by analogy to the cuprates, and this perspective has framed much of the initial consideration of this material. However, a growing number of studies have highlighted the involvement of rare-earth orbitals; in that context, the consequences of varying the rare-earth element in the superconducting nickelates have been much debated. Here, we show notable differences in the magnitude and anisotropy of the superconducting upper critical field across the La-, Pr-, and Nd-nickelates. These distinctions originate from the 4f electron characteristics of the rare-earth ions in the lattice: They are absent for La3+, nonmagnetic for the Pr3+ singlet ground state, and magnetic for the Nd3+ Kramer's doublet. The unique polar and azimuthal angle-dependent magnetoresistance found in the Nd-nickelates can be understood to arise from the magnetic contribution of the Nd3+ 4f moments. Such robust and tunable superconductivity suggests potential in future high-field applications.
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This study demonstrates transparent and flexible capacitive pressure sensors using a high-k ionic gel composed of an insulating polymer (poly(vinylidene fluoride-co-trifluoroethylene-co-chlorofluoroethylene), P(VDF-TrFE-CFE)) blended with an ionic liquid (IL; 1-ethyl-3-methylimidazolium bis(trifluoromethylsulfonyl) amide, [EMI][TFSA]). The thermal melt recrystallization of the P(VDF-TrFE-CFE):[EMI][TFSA] blend films develops the characteristic topological semicrystalline surface of the films, making them highly sensitive to pressure. Using optically transparent and mechanically flexible graphene electrodes, a novel pressure sensor is realized with the topological ionic gel. The sensor exhibits a sufficiently large air dielectric gap between graphene and the topological ionic gel, resulting in a large variation in capacitance before and after the application of various pressures owing to the pressure-sensitive reduction of the air gap. The developed graphene pressure sensor exhibits a high sensitivity of 10.14 kPa-1 at 20 kPa, rapid response times of <30 ms, and durable device operation with 4000 repeated ON/OFF cycles. Furthermore, broad-range detections from lightweight objects to human motion are successfully achieved, demonstrating that the developed pressure sensor with a self-assembled crystalline topology is potentially suitable for a variety of cost-effective wearable applications.
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Nickel-based superconductors provide a long-awaited experimental platform to explore possible cuprate-like superconductivity. Despite similar crystal structure and d electron filling, however, superconductivity in nickelates has thus far only been stabilized in thin-film geometry, raising questions about the polar interface between substrate and thin film. Here we conduct a detailed experimental and theoretical study of the prototypical interface between Nd1-xSrxNiO2 and SrTiO3. Atomic-resolution electron energy loss spectroscopy in the scanning transmission electron microscope reveals the formation of a single intermediate Nd(Ti,Ni)O3 layer. Density functional theory calculations with a Hubbard U term show how the observed structure alleviates the polar discontinuity. We explore the effects of oxygen occupancy, hole doping and cation structure to disentangle the contributions of each for reducing interface charge density. Resolving the non-trivial interface structure will be instructive for future synthesis of nickelate films on other substrates and in vertical heterostructures.
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The Jahn-Teller effect, in which electronic configurations with energetically degenerate orbitals induce lattice distortions to lift this degeneracy, has a key role in many symmetry-lowering crystal deformations1. Lattices of Jahn-Teller ions can induce a cooperative distortion, as exemplified by LaMnO3 (refs. 2,3). Although many examples occur in octahedrally4 or tetrahedrally5 coordinated transition metal oxides due to their high orbital degeneracy, this effect has yet to be manifested for square-planar anion coordination, as found in infinite-layer copper6,7, nickel8,9, iron10,11 and manganese oxides12. Here we synthesize single-crystal CaCoO2 thin films by topotactic reduction of the brownmillerite CaCoO2.5 phase. We observe a markedly distorted infinite-layer structure, with ångström-scale displacements of the cations from their high-symmetry positions. This can be understood to originate from the Jahn-Teller degeneracy of the dxz and dyz orbitals in the d7 electronic configuration along with substantial ligand-transition metal mixing. A complex pattern of distortions arises in a [Formula: see text] tetragonal supercell, reflecting the competition between an ordered Jahn-Teller effect on the CoO2 sublattice and the geometric frustration of the associated displacements of the Ca sublattice, which are strongly coupled in the absence of apical oxygen. As a result of this competition, the CaCoO2 structure forms an extended two-in-two-out type of Co distortion following 'ice rules'13.