Achilles Heel Research Articles

Deterioration mechanism of vanadium dioxide smart coatings during natural aging: Uncovering the role of water

Vanadium dioxide (VO2) has already been widely concerned as a thermochromic smart window material. However, the Achilles heel of VO2 is susceptible to degradation by water and oxygen in the air, which has limited its commercialization. Until now, it has remained unclear what effect water has on the deterioration of VO2, hindering the solution to this dilemma. In this work, the degradation mechanism of VO2 during natural aging was proposed based on density functional theory (DFT) calculation and experimental analysis, and the role of water in the degradation process was discussed in detail. The results showed that water affects the deterioration reaction by influencing the adsorption behavior of oxygen on the VO2 surface, destroying the dense structure, and participating in the reaction in the form of combined water. This work fills the degradation mechanism gap of VO2, helps to design high-performance structures of VO2-based smart coatings, and provides theoretical guidance to solve the problem of VO2 weatherability.

Modeling of toughening effect in rigid particulate-filled polymer composites by artificial intelligence: a review

Low fracture toughness is the Achilles heel of many polymers for practical application, particularly for long-term and special applications such as medical implants and critical part design. The toughening of polymers is a complicated process, and the toughening mechanisms in many composite systems have not yet been fully understood. Machine learning (ML) has emerged as a promising tool for modeling various complex systems in the field of materials science. In this respect, ML appears to be an effective, affordable, and accurate technique in the modeling of the toughening process. This review article provides an overview of the recent ML-based approach for analyzing toughening effects in rigid particulate-filled polymer composites. The results summarized here would contribute to further possibilities for researchers to explore emerging trends for designing toughing and high-performance polymers.

Efficacy of shockwave C2 coronary intravascular lithotripsy for management of severely calcified left anterior descending stenosis

Severely calcified coronary lesions remain a formidable hurdle for percutaneous coronary intervention as it averts the stent delivery and complete stent apposition. To overcome this Achilles heel of an interventional cardiology, a current US FDA approved method named shockwave intravascular lithotripsy (S-IVL; Shockwave Medical, Inc) is used for its treatment. Herein, we report a case of a 53-year-old dyslipidemic male with severely calcified left anterior descending artery (LAD) lesion that was successfully treated with S-IVL and drug-eluting stent implantation. At first, the patient was presented with complaints of chest pain and breathlessness. His coronary angiogram revealed heavily calcified stenosis in diffuse mid LAD—completely totally occluded mid-diagonal (D) 1 that was checked through retrograde filling via collateral and calcified stenosis in ostial D2, mild stenosis in ostial left circumflex and mild stenosis at distal before crux 50% stenosis in dominant right coronary artery. Following this, it was decided to proceed with primary percutaneous coronary intervention with S-IVL to LAD. After successful delivery of S-IVL to LAD, a Tetriflex sirolimus eluting stent (Sahajanand Medical Technologies Ltd., Surat, India) was successfully implanted at LAD. Finally, the patient’s condition was stabilized and discharged after two days of index procedure.

Thin‐film nanocomposite forward osmosis membrane with polydopamine @UiO‐66‐NH2‐modified polypropylene support and its antifouling property

AbstractPolypropylene (PP) porous flat membrane is ultrathin and has high porosity, which is suitable for the support of forward osmosis (FO) membrane. However, its high hydrophobicity is its Achilles heel. In this study, dopamine and UiO‐66‐NH2 were co‐deposited onto the surface of PP support, and then interfacial polymerization was performed to fabricate a thin‐film nanocomposite (TFN) FO membrane. The reaction‐generated polydopamine improved the hydrophilicity of PP membrane, and at the same time enhanced the adhering of UiO‐66‐NH2 to the support. The experimental results indicated that the UiO‐66‐NH2 nanoparticles were anchored evenly on the surface of the support, which improved the water flux of FO membrane from 11.1 LMH (TFC, TFN‐0 without UiO‐66‐NH2) to 20.7 LMH (TFN‐0.1, with 0.1 wt% UiO‐66‐NH2) using 1 mol/L NaCl as the draw solution in FO mode. Compared with TFC membrane, TFN‐0.1 membrane also exhibited relative lower specific salt flux (~0.252) and structural parameter (~379 μm). When separating sodium alginate foulant, the normalized water flux recovery ratio of TFN‐0.1 was remained 0.89, and most of the fouling was reversible, as for TFC membrane the data decreased to 0.76 after 2 cycles of operation. These results suggested that UiO‐66‐NH2 modified FO membrane exhibited good permeation and antifouling property.

Democratic Backsliding and the Unravelling of the EU Legal Order

Democratic Backsliding and the Unravelling of the EU Legal Order Ronan McCrea (bio) The political world of the EU has often been accused of being a Potemkin village. It had a flag, a parliament and elections, but behind this façade the voters were not really engaged.1 This has fueled a tendency to easily perceive existential crises for the Union. With no real European demos, EU political institutions were seen as hollow and commentators found it easy to predict that they would be swept away when faced with a serious political problem. However, the Union’s legal situation was the opposite. Here a fairly modest institutional impression, namely a single international court sitting in Luxembourg, belied a deeply integrated, almost federal, legal order in which national courts across the Union applied EU law and rulings of the Court of Justice day in day out in the cases that came before them. Academics studying European integration noted the particular prominence of the role of law in the building of the EU, going so far as to describe the process as one of ‘integration through law’ in a seminal study from the late 1980s.2 And they had a point. Enforcement is usually the Achilles heel of international law. Often only states can make complaints of breaches of international obligations and adjudication of such complaints takes place in front of international tribunals whose rulings are difficult to enforce. But EU law was different. The European Court ruled in the 1960s that EU law could be invoked by individuals in front of their national courts and that national judges had a duty to give effect to EU in their rulings (this is known as ‘direct effect’) and to set aside any national law that clashed with EU law (this is known as primacy).3 National judges, for a number of reasons, went along with this and thereby transformed the nature of the European integration project.4 The acceptance of primacy and direct effect had a huge impact on the importance of EU law. Rather than being, as much international law is, a difficult to enforce declaration on paper, EU law was fully binding. This meant that the Union did not need to rely on the Commission to sue states [End Page 168] to hold them to their EU law obligations, it had hundreds of millions of citizens who could potentially enforce EU law against their governments. What is more, if a government defies a ruling of an international court it can be politically embarrassing, but defying the ruling of a national judge would cause a constitutional crisis. With national judges upholding EU law, governments found it very difficult not to comply with European obligations. If the EU legislation was only been a non-binding recommendation rather than binding law, the Union would be a much less powerful political actor. Because its law was really law, member states and the wider world had to pay much more attention to the Union’s decisions. Therefore, the legal integration provided by the caselaw of the Court of Justice gave, from the 1970s onwards, the Union strength and relevance which the degree of political integration did not then justify and which provided an important impetus to the political integration which followed in the 1990s and 2000s. However, I will suggest that we may be witnessing the reversal of the previous situation where legal integration was the Union’s strength and political integration its weakness. Recently the Union’s political integration seems to have shown resilience and momentum while the legal integration, traditionally its strength, is eroding. Political resilience Underestimating the resilience of the European integration project has been a fairly consistent theme of the past decade and a half, particularly amongst anglosphere writers. This is not just a matter of Brexiteer wishful thinking. Leftwing writers such as Paul Krugman in the US were convinced that the Eurozone crisis would bring down the single currency5 while the migration crisis of 2015, Brexit a year later and then the initially limited and ineffective EU response early in the COVID crisis all brought forth statements that the Union was in a crisis it might not survive.6 In...

Modeling the B-cell receptor signaling on single cell level reveals a stable network circuit topology between nonmalignant B cells and chronic lymphocytic leukemia cells and between untreated cells and cells treated with kinase inhibitors.

B-cell receptor (BCR) signaling is central for the pathomechanism of chronic lymphocytic leukemia (CLL), and inhibitors of BCR signaling have substantially improved treatment options. To model malignant and nonmalignant BCR signaling, we quantified five components of BCR signaling (ZAP70/SYK, BTK, PLCγ2, AKT, ERK1/2) in single cells from primary human leukemic cells and from nonmalignant tissue. We measured signaling activity in a time-resolved manner after stimulation with BCR crosslinking by anti-IgM and/or anti-CD19 and with or without inhibition of phosphatases with H2 O2 . The phosphorylation of BCR signaling components was increased in malignant cells compared to nonmalignant cells and in IGHV unmutated CLL cells compared to IGHV mutated CLL cells. Intriguingly, inhibition of phosphatases with H2 O2 led to higher phosphorylation levels of BCR components in CLL cells with mutated IGHV compared to unmutated IGHV. We modeled the connectivity of the cascade components by correlating signal intensities across single cells. The network topology remained stable between malignant and nonmalignant cells. To additionally test for the impact of therapeutic compounds on the network topology, we challenged the BCR signaling cascade with inhibitors for BTK (ibrutinib), PI3K (idelalisib), LYN (dasatinib) and SYK (entospletinib). Idelalisib treatment resulted in similar effects in malignant and nonmalignant cells, whereas ibrutinib was mostly active on CLL cells. Idelalisib and ibrutinib had complementary effects on the BCR signaling cascade whose activity was further reduced upon dasatinib and entospletinib treatment. The characterization of the molecular circuitry of leukemic BCR signaling will allow a more refined targeting of this Achilles heel.

The catalytic mechanism of the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2)

Methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) is a new drug target that is expressed in cancer cells but not in normal adult cells, which provides an Achilles heel to selectively kill cancer cells. Despite the availability of crystal structures of MTHFD2 in the inhibitor- and cofactor-bound forms, key information is missing due to technical limitations, including (a) the location of absolutely required Mg2+ ion, and (b) the substrate-bound form of MTHFD2. Using computational modeling and simulations, we propose that two magnesium ions are present at the active site whereby (i) Arg233, Asp225, and two water molecules coordinate , while together with Arg233 stabilize the inorganic phosphate (Pi); (ii) Asp168 and three water molecules coordinate , and further stabilizes Pi by forming a hydrogen bond with two oxygens of Pi; (iii) Arg201 directly coordinates the Pi; and (iv) through three water-mediated interactions, Asp168 contributes to the positioning and stabilization of , and Pi. Our computational study at the empirical valence bond level allowed us also to elucidate the detailed reaction mechanisms. We found that the dehydrogenase activity features a proton-coupled electron transfer with charge redistribution connected to the reorganization of the surrounding water molecules which further facilitates the subsequent cyclohydrolase activity. The cyclohydrolase activity then drives the hydration of the imidazoline ring and the ring opening in a concerted way. Furthermore, we have uncovered that two key residues, Ser197/Arg233, are important factors in determining the cofactor (NADP+/NAD+) preference of the dehydrogenase activity. Our work sheds new light on the structural and kinetic framework of MTHFD2, which will be helpful to design small molecule inhibitors that can be used for cancer treatment.

PVP-Modified Multifunctional Bi2WO6 Nanosheets for Enhanced CT Imaging and Cancer Radiotherapy.

Malignant tumors are one of the main causes of human death. The clinical treatment of malignant tumors is usually surgery, chemotherapy, radiotherapy, and so forth. Radiotherapy, as a traditional and effective treatment method for cancer, is widely used in clinical practice, but the radiation resistance of tumor cells and the toxic side effects to normal cells are still the Achilles heel of radiotherapy. Multifunctional inorganic high-atom nanomaterials are expected to enhance the effect of tumor radiotherapy. Tungsten and bismuth, which contain elements with high atomic coefficients, have strong X-ray energy attenuation capability. We synthesized Bi2WO6 nanosheets (NSs) using a hydrothermal synthesis method and modified polyvinylpyrrolidone (PVP) on their surface to make them more stable. PVP–Bi2WO6 NSs have a variety of effects after absorbing X-rays (such as the photoelectric effect and Compton effect) and release a variety of particles such as photoelectrons, Compton electrons, auger electrons, and so forth, which can react with organic molecules or water in cells, generate a large number of free radicals, and promote cell apoptosis, thereby improving the effect of radiotherapy. We show through γ-H2AX and DCFH-DA probe analysis experiments that PVP–Bi2WO6 NSs can effectively increase cell DNA damage and reactive oxygen species formation under X-ray irradiation. Clone formation analysis showed that PVP–Bi2WO6 NSs can effectively suppress cell colony formation under X-ray irradiation. These versatile functions endow PVP–Bi2WO6 NSs with enhanced radiotherapy efficacy in animal models. In addition, PVP–Bi2WO6 NSs can also be used as contrast agents for X-ray computed tomography (CT) imaging with obvious effects. Therefore, PVP–Bi2WO6 NSs can be used as CT imaging contrast agents and tumor radiotherapy sensitizers and have potential medical applications.

Editor's Introduction

Editor's Introduction

Which is the Achilles heel of gastrointestinal stromal tumour and how to use it for the future?—a review of novel therapeutic paradigms

Which is the Achilles heel of gastrointestinal stromal tumour and how to use it for the future?—a review of novel therapeutic paradigms

Rhomboid pseudoproteases: An Achilles heel's for BCL-2/IP3R-dependent resistance to ER stress-induced cell death

Anti-apoptotic BCL-2 targets and inhibits IP3 receptors (IP3Rs), thereby preventing apoptosis by limiting ER-mitochondrial Ca2+ flux. Recently, Dulloo et al. (2022), Nat. Comm. 13:1257[6] revealed a novel role for rhomboid pseudoproteases in ER stress-induced apoptosis by stripping BCL-2 from IP3Rs, thereby enabling pro-apoptotic Ca2+ signaling.

Preparing for the Next Blockade: Non-ferrous Metals and the Strategic Economic Policy of the Third Reich

Abstract This article refutes a fundamental assumption behind the Western powers’ ‘long-war strategy’ in 1939, and casts doubt on the conventional wisdom regarding the alleged unpreparedness of Nazi Germany for a longer war. It does so by re-examining Germany’s war-preparedness through the lens of those raw materials that were of vital importance for the production of all armaments: non-ferrous metals. Contemporaries believed that these metals were the Achilles heel of the Nazi war economy because Germany had to cover its consumption predominantly with imports from overseas, which meant that it was extremely vulnerable to a sea blockade. But this article challenges these assumptions and shows that the Nazi war-planners were prepared for a longer war because of the lessons learned from the Great War, which they had carefully and covertly studied. The statistics compiled in this article demonstrate that it was the preparations based on these lessons rather than contingencies and non-predictable events, such as the access to occupied Europe due to unexpected victories, that were primarily responsible for the fact that Germany did not run out of metals during the Second World War. Germany lost the war not because of a lack of economic preparation, at least not in the field of metals, but because of the strategic decision to start a war which was bound to draw in an ever more superior coalition of enemies the longer it lasted.

Dual-Targeted Therapy Circumvents Non-Genetic Drug Resistance to Targeted Therapy.

The introduction of various targeted agents into the armamentarium of cancer treatment has revolutionized the standard care of patients with cancer. However, like conventional chemotherapy, drug resistance, either preexisting (primary or intrinsic resistance) or developed following treatment (secondary or acquired resistance), remains the Achilles heel of all targeted agents with no exception, via either genetic or non-genetic mechanisms. In the latter, emerging evidence supports the notion that intracellular signaling pathways for tumor cell survival act as a mutually interdependent network via extensive cross-talks and feedback loops. Thus, dysregulations of multiple signaling pathways usually join forces to drive oncogenesis, tumor progression, invasion, metastasis, and drug resistance, thereby providing a basis for so-called “bypass” mechanisms underlying non-genetic resistance in response to targeted agents. In this context, simultaneous interruption of two or more related targets or pathways (an approach called dual-targeted therapy, DTT), via either linear or parallel inhibition, is required to deal with such a form of drug resistance to targeted agents that specifically inhibit a single oncoprotein or oncogenic pathway. Together, while most types of tumor cells are often addicted to two or more targets or pathways or can switch their dependency between them, DTT targeting either intrinsically activated or drug-induced compensatory targets/pathways would efficiently overcome drug resistance caused by non-genetic events, with a great opportunity that those resistant cells might be particularly more vulnerable. In this review article, we discuss, with our experience, diverse mechanisms for non-genetic resistance to targeted agents and the rationales to circumvent them in the treatment of cancer, emphasizing hematologic malignancies.

Discovery of AZD4625, a Covalent Allosteric Inhibitor of the Mutant GTPase KRASG12C.

KRAS is an archetypal high-value intractable oncology drug target. The glycine to cysteine mutation at codon 12 represents an Achilles heel that has now rendered this important GTPase druggable. Herein, we report our structure-based drug design approach that led to the identification of 21, AZD4625, a clinical development candidate for the treatment of KRASG12C positive tumors. Highlights include a quinazoline tethering strategy to lock out a bio-relevant binding conformation and an optimization strategy focused on the reduction of extrahepatic clearance mechanisms seen in preclinical species. Crystallographic analysis was also key in helping to rationalize unusual structure-activity relationship in terms of ring size and enantio-preference. AZD4625 is a highly potent and selective inhibitor of KRASG12C with an anticipated low clearance and high oral bioavailability profile in humans.

Explaining SyntheticA PrioriKnowledge: The Achilles Heel of Transcendental Idealism?

AbstractThis article considers an apparent Achilles heel for Kant’s transcendental idealism, concerning his account of how synthetica prioriknowledge is possible. The problem is that while Kant’s distinctive attempt to explain synthetica prioriknowledge lies at the heart of his transcendental idealism, this explanation appears to face a dilemma: either the explanation generates a problematic regress, or the explanation it offers gives us no reason to favour transcendental idealism over transcendental realism. In the article, I consider G. E. Moore’s version of the problem, which I argue has not yet received an adequate response. Instead, I offer a way out of this dilemma by focusing on the normativity rather than the metaphysics of the mind.

Bridging Disciplines: Applications of Forensic Science and Industrial Hemp.

Forensic laboratories are required to have analytical tools to confidently differentiate illegal substances such as marijuana from legal products (i.e., industrial hemp). The Achilles heel of industrial hemp is its association with marijuana. Industrial hemp from the Cannabis sativa L. plant is reported to be one of the strongest natural multipurpose fibers on earth. The Cannabis plant is a vigorous annual crop broadly separated into two classes: industrial hemp and marijuana. Up until the eighteenth century, hemp was one of the major fibers in the United States. The decline of its cultivation and applications is largely due to burgeoning manufacture of synthetic fibers. Traditional composite materials such as concrete, fiberglass insulation, and lumber are environmentally unfavorable. Industrial hemp exhibits environmental sustainability, low maintenance, and high local and national economic impacts. The 2018 Farm Bill made way for the legalization of hemp by categorizing it as an ordinary agricultural commodity. Unlike marijuana, hemp contains less than 0.3% of the cannabinoid, Δ9-tetrahydrocannabinol, the psychoactive compound which gives users psychotropic effects and confers illegality in some locations. On the other hand, industrial hemp contains cannabidiol found in the resinous flower of Cannabis and is purported to have multiple advantageous uses. There is a paucity of investigations of the identity, microbial diversity, and biochemical characterizations of industrial hemp. This review provides background on important topics regarding hemp and the quantification of total tetrahydrocannabinol in hemp products. It will also serve as an overview of emergent microbiological studies regarding hemp inflorescences. Further, we examine challenges in using forensic analytical methodologies tasked to distinguish legal fiber-type material from illegal drug-types.

Rupture Post-Endovascular Aneurysm Repair: Are We Missing the Signs?

The rate of re-intervention and rupture post-endovascular aneurysm repair (EVAR) has always been its Achilles heel, with post-EVAR surveillance an essential component to enable timely re-intervention and reduce this rupture risk. Andersson et al.1 present a 10 year study across five Swedish hospitals. They retrospectively analysed all post-EVAR ruptures to determine whether precursors of rupture would have been detected using a structured computed tomography (CT) analysis.

Revisiting the Extinction of the RNA World

The ribozyme world is thought to have evolved the burdensome complexity of peptide and protein synthesis because the 20 amino acid side chains are catalytically superior. Instead, I propose that the Achilles heel of the RNA world that led to the extinction of riboorganisms was RNA’s polyanionic charges that could not be covalently neutralized stably by phosphotriester formation. These charges prevented development of hydrophobic cores essential for integration into membranes and many enzymatic reactions. In contrast, the phosphotriester modification of DNA is stable. So, the fact that the charge was never removed in DNA evolution gives further credence to proteins coming before DNA.

Successful Cold Atmospheric Plasma Therapy of Driveline Infections in Patients with Left Ventricular Assist Devices

<h3>Purpose</h3> Driveline infections are still the Achilles heel of continuous flow left ventricular assist devices (cfLVAD) for morbidity and mortality in cfLVAD patients. Over the last years, cold atmospheric plasma (CAP) has been safely and effectively used to treat wound infections in different clinical indications. Thus, in this study we evaluated CAP therapy of superficial driveline infections (SDI). <h3>Methods</h3> 24 patients (20male, 4 female), who received a cfLVAD between 2012 and 2018, developed a SDI. In total 30 CAP plasma jet treatments were applied, 16 patients were treated in hospital, 8 patients in the ambulance and 6 patients were treated in both. All wounds were treated with CAP starting from the day of diagnosis of SDI. <h3>Results</h3> The average number of CAP applications per case was 9.06 times (1-101), median duration of hospital stay due to SDI was 41.35 days (5-254). 21 patients were additional treated with antibiotics (70%). In 9 patients (30%) an ascending driveline infection (ADI) occurred, which required surgical revision. The 3 month event free survival was 21 patients (70 %). There were no adverse side effects of CAP therapy observed and there were no abnormalities of cfLVAD during CAP treatment. <h3>Conclusion</h3> We demonstrate that CAP therapy could be effectively and safely applied in cfLVAD patients with SDI. Using CAP 70% of our cases with SDI were prevented from ADI. Future studies have to show if ambulant CAP therapy of superficial cfLVAD wound infections has the potential to prevent progression of infection or to avoid SDI infection at all.

Association of Outflow Cannula Angulation with Adverse Neurological Events in Patients with CF-LVAD

<h3>Purpose</h3> Adverse neurological outcomes are the Achilles heel of the current day LVAD technology and are associated with worse survival. Our previous data suggests that outflow cannula (OFC) angles measured using cardiac CT may correlate with stroke in continuous-flow HeartMate II patients. Therefore, the aim of our study was to assess the relationship of inflow cannula (IFC) and outflow cannula (OFC) position with neurological outcomes centrifugal flow pumps (HM3 and HVAD). <h3>Methods</h3> 108 patients underwent LVAD implantation between 2015 and 2019 at our institution. Of these, 68 patients underwent cardiac CT, and 6 were excluded due to poor image quality. Of these patients, a total of 32 neurological events (NE) occurred in 20 patients. These cases were compared to patients with CT data who did not have NEs. 2D angle measurements were performed on positions of OFC relative to the ascending aorta and IFC relative to the mitral valve. Further we used a novel point-based 3D measurement system to determine the angles in an x-y-z plane. Baseline demographic data and outcome data were collected for all patients. Optimal cut-point of the OFC angle was determined using ROC curve analysis. <h3>Results</h3> Of the 62 patients recruited for this study, 65% had HM3 and 35% had HVAD. The median OFC angle on 2D in patients with NE was 59.8 degrees relative to the aorta, compared with a median angle of 51.7 degrees in patients without NE (p=0.02). Similarly on 3D angle measurements, a median OFC angle of 86.7 degree was observed in patients with NE, compared to a median angle of 77.4 degrees in patients without NE (p=0.01). IFC angle was not associated with an increased risk of NE. The ROC curve analysis showed optimal OFC angle was < 53 degrees in 2D measurements, with sensitivity of 79% and specificity of 61% at predicting NEs. In 3D measurements the optimal OFC angle was less than < 83 degrees with a sensitivity of 79% and a specificity of 61% at predicting NEs. <h3>Conclusion</h3> Optimal angulation of the outflow cannula in LVAD patients can lead to decreased risk for HRAE. Using cardiac CT chest imaging for 2D and 3D measurements, an optimal outflow cannula angulation of < 53 degrees and < 83 degrees, respectively, should be preferred to minimize the risk for HRAE in patients with centrifugal flow LVAD support.