Hard Cases Research Articles

Tailored nanodisc immobilization for one-step purification and reconstitution of cytochrome P450: A tool for membrane proteins' hard cases.

A novel nanodisc-based immobilization method was developed for high-efficient purification and reconstitution of cytochrome P450 in one step. Using membrane scaffold protein containing a histidine tag, charged-nanodiscs were prepared in the form of self-assembly of lipid-protein nanoparticles. Their properties including the particle diameter and its distribution and Zeta potential were controlled well by adjusting molar ratios of phospholipids to membrane scaffold protein. At an optimum lipid-to-membrane scaffold protein molar ratio of 60:1, uniformly regular-shaped and discoidal nanodiscs with an average particle diameter of 10nm and Zeta potential of -19mV were obtained. They can be well fractionated by size exclusion chromatography. Charged-nanodiscs were successfully immobilized onto Ni-chelating microspheres via histidine tags with a density of 6.6mg membrane scaffold protein/mL gel. After being packed in a column, chromatography studies demonstrated that this nanodisc-immobilized chromatographic medium had a specific binding to cytochrome P450 in rat liver microsome. Nanodiscs containing cytochrome P450 can be furthermore eluted from the column with a diameter of about 87.0nm and height of about 8.0nm, respectively. The purity of cytochrome P450 after purification increased 25 folds strikingly. This nanodisc-immobilized chromatography method is promising for the one-step purification and reconstitution of membrane protein.

The strength of weak bonds: Substituting bodily copresence in diplomatic social bonding

One of the central puzzles in the study of diplomacy is why some interactions between leaders result in positive social bonds, while others are mired in distrust and hostility. Recent research in the field of microsociology, the study of everyday interactions, most notably the pioneering research of American sociologist Randall Collins, suggests several critical ingredients for a successful interaction, including bodily copresence. In this article we interrogate this claim and provide theoretical reasons why textual communication may serve as a proxy for copresence in leader interactions. We demonstrate that while copresence, in the form of face-to-face interaction, is required for strong bond formation, mediated interaction in the form of letters can serve to create weak social bonds. The strength of weak bonds is in the reduction of distrust and the gradual development of trust that can be critical to the de-escalation of crises. Empirically, we explore our argument in two hard cases for social bond formation: the letters exchanged between Nikita Khrushchev and John F. Kennedy during the Cuban Missile Crisis and the interactions, both textual and face-to-face, between Mikhail Gorbachev and Ronald Reagan at the end of the Cold War. We conclude by pointing toward an interdisciplinary research agenda on the determinants of social bond formation in diplomacy.

Особенности первичной имплантации ИОЛ на фоне хронического увеита

Purpose. To determine possible postoperative complications and methods of their prevention in patients with history of chronic uveitis who underwent Phacoemulsification of cataract with primary IOL implantation. Material and methods. In this article we give clinical analysis of complications after phacoemulsification with primary IOL implantation in patients with history of chronic uveitis. 5 patients with this pathology were hospitalized during 2020. Results. In this work, we provide literature data on the topic of primary IOL implantation in such patients. Currently there is no united opinion on managing such patients. Nevertheless, many authors agree that by using acrylic lenses, prolonged pharmacotherapy, uveitis remission of more than 3 months primary IOL implantation can be safe, and we can get high visual acuity [14]. In hard cases, some authors used primary IOL implantation with primary posterior capsulorhexis, which helped them to lower rate of postoperative complications [2, 3, 11, 21, 24]. Nevertheless, there are cases where IOL cause untreatable uveitis and therefore the question of lens explanation arises [8]. Conclusion. When solving the question of primary IOL implantation during extracting cataract in patients with chronic uveitis for maximum safety we should consider the following: history of the patient's background disease and systemic treatment he is getting, frequency of former uveitic attacks, laboratory data at the time of operation. The patient needs preliminary sanitation of all possible sources of inflammation and infection, pharmacotherapeutical preparation (both topical and general). After operation patient is needed prolonged anti-inflammatory therapy (NAIDS and Corticosteroids) and dynamic observation despite calm eye condition. Key words: uveitis, cataract phacoemulsification, iol implantation.

Genetic parenthood and hard cases.

In a recent article Thomas Douglas and Katrien Devolder propose a theory of genetic parenthood according to which a human child can have only two genetic human parents. I argue this theory is arbitrarily narrow and fails to account for cases such as hybrids, cloning, chimerism, twinning, parthenogenesis, mitochondrial replacement techniques, and more. I propose an alternate theory of genetic parenthood, one that is prima facie consistent with our commonsense intuitions about genetic parenthood and relevant to a right to procreative autonomy.

Agency in compliance with institutions: The case of professional expert-organizations and politico-ethical agency

As contemporary organizational life is increasingly rule governed, organizational actors, most notably professionals, perform their work by complying with institutional rules, stemming from regulatory bodies external and internal to organizations. This begs a question of the role of agency in compliance with institutions that is largely ignored within organization theory. A weak form of agency in compliance is found in practice theory and practice-driven institutionalism, in terms of actors mindful enactments of institutions on the basis of mastering shared practices for applying institutional rules. These are characterized as first-order practices of compliance with institutions. Extending the Wittgensteinian-inspired philosophical foundation of practice theory, modes of compliance in so-called “hard cases,” where shared practices do not apply as a basis for agreement in following institutional rules, is conceptualized as second-order compliance practices, involving a strong mode of agency. In these cases, the aim is to reach agreement on how rules are to be applied beyond established first-order practices by engaging larger frameworks of shared forms of life and more open and explorative attitudes to move institutions forward for a common good. It is argued that second-order compliance can be understood as a politico-ethical mode of agency in the Kantian tradition, supplementing prevalent notions within organizational institutionalism of agency as primarily political.

Producing Genomic Sequences after Genome Scaffolding with Ambiguous Paths: Complexity, Approximation and Lower Bounds

Scaffolding is the final step in assembling Next Generation Sequencing data, in which pre-assembled contiguous regions (”contigs”) are oriented and ordered using information that links them (for example, mapping of paired-end reads). As the genome of some species is highly repetitive, we allow placing some contigs multiple times, thereby generalizing established computational models for this problem. We study the subsequent problems induced by the translation of solutions of the model back to actual sequences, proposing models and analyzing the complexity of the resulting computational problems. We find both polynomial-time and $$\mathcal {NP}$$ -hard special cases like planarity or bounded degree. Finally, we propose two polynomial-time approximation algorithms according to cut/weight score.

The Functions of Principle as the Basis of Court Decision in Hard Cases

The task of court is to produce just decisions. A court decision may be just if it coheres moral. Principle is praxis of moral. This article is to articulate that principle has significant meanings in court’s decisions. This is because principle is a moral standard that serves to be a reference for Court to settle hard cases equitably. In this writing, case approach is employed. In addition, it also uses comparative approach, in which court decisions of different countries are presented. The purpose of using comparative approach is to find similarities in referring to principle despite different jurisdictions and even different legal systems. From this study, it is found that principle may serve four functions to the court to reach equitable decisions. First, it may be a legal basis for the court to settle a case equitably in the absence of legal rule. In fact, not all human conducts are prescribed by law. It is frequently presumed that what is not prohibited is permitted to do. In this study, it is found that what is not forbidden is not necessarily permissible. The corner stone of determining whether or not it is permissible is principle. In this case, principle served to be legal basis directly applied by the court to avoid producing unjust judgment. Second, the principle has the derogatory function to supersede a statutory provision. In this case, applying such a provision may result in decision contrary to moral. This, certainly, contradicts the idea of the establishment of court of justice. It is justified, therefore, referring to the principle, the court supersedes such a statutory provision to bring about a just decision. Third, the principle serves to be a basis for the court to interpret obscure statutory provision governing the case. It is not unusual that statutory provision is obscure or ambiguous. Such a provision is hard to understand. Settling the case governed by such a provision appropriately, the court should interpret the provision sensibly.

An accelerated first-order method with complexity analysis for solving cubic regularization subproblems

We propose a first-order method to solve the cubic regularization subproblem (CRS) based on a novel reformulation. The reformulation is a constrained convex optimization problem whose feasible region admits an easily computable projection. Our reformulation requires computing the minimum eigenvalue of the Hessian. To avoid the expensive computation of the exact minimum eigenvalue, we develop a surrogate problem to the reformulation where the exact minimum eigenvalue is replaced with an approximate one. We then apply first-order methods such as the Nesterov’s accelerated projected gradient method (APG) and projected Barzilai-Borwein method to solve the surrogate problem. As our main theoretical contribution, we show that when an $$\epsilon$$ -approximate minimum eigenvalue is computed by the Lanczos method and the surrogate problem is approximately solved by APG, our approach returns an $$\epsilon$$ -approximate solution to CRS in $${\tilde{O}}(\epsilon ^{-1/2})$$ matrix-vector multiplications (where $${\tilde{O}}(\cdot )$$ hides the logarithmic factors). Numerical experiments show that our methods are comparable to and outperform the Krylov subspace method in the easy and hard cases, respectively. We further implement our methods as subproblem solvers of adaptive cubic regularization methods, and numerical results show that our algorithms are comparable to the state-of-the-art algorithms.

How Many Cases Are Easy?

Abstract Because judges are expected to decide cases through the impartial application of existing law, they are often reluctant to admit that they must make law in hard cases. Many judges claim that such hard cases are rare, constituting roughly 10 percent of cases. In stark contrast, economic models of the selection of disputes for litigation predict that easy cases will settle, so that only hard cases would remain in trial and appellate courts. Empirical indicators, such as dissent rates or voting differences between Democratic and Republican appointees, have yielded muddled conclusions about the proportion of easy and hard cases in appellate courts. In fact, none of these crude statistics relate directly to the proportion of easy cases. This article develops a new approach for empirically analyzing the proportion of easy cases. Although the easiness and hardness of cases are subjective, it is possible to estimate feasible combinations of the proportion of hard cases and clear errors. This approach relies only on the basic premise that reasonable judges should not disagree in easy cases. The article then illustrates this approach using two datasets of appeals. An analysis of asylum appeals in the 9th Circuit finds widespread disagreement, implying high proportions of hard cases, clear errors, or both. By contrast, voting data from labor and environmental cases in the D.C. Circuit is consistent with the claim that 90 percent of cases are easy and 1 percent of decisions are clear errors.

Profiling for the good: Patient profile tests and informed, autonomous decision making.

It is commonly held that, given multiple medically permissible ways of proceeding, each with a different impact on the patient's future, it is extremely important, and part of respecting patient autonomy, that patients not be under substantial pressure to defer to their physicians' presumed authority. Some, however, worry that the focus on patient autonomy can be detrimental and that, at least in cases where it is hard to grasp what it is really like to live with certain outcomes without any first-hand or second-hand experience, it is best if patient choice is firmly directed, or at least effectively nudged, by the recommendation of an experienced medical professional. The idea seems to be that, since physicians cannot get their patients to promptly assimilate a large amount of information and experience, physicians must, if they are to really help their patients make good decisions in hard cases, exert non-argumentative influence on them. But this neglects an interesting possibility, namely the possibility of influencing patients by providing them with evidence regarding what decisions have proved most satisfactory for patients with their profile. Approximations of patient profile tests are already employed in medical practice. But the potential of the profile-test approach in medical practice (and research) has been obscured by ongoing debate that neglects the significance of the approach with respect to the apparent dilemma faced by patients who need to make informed, autonomous decisions but cannot be expected to fully assimilate, in short order, the knowledge and experience of their physicians.

Visual Perception: How Better Imaging Can Make Things Worse

Summary Visual search is critical to daily life and to socially important tasks — from cancer screening to airport security. New research shows how a technological advancement can interact with the human visual system to improve search for one type of target while making matters worse for another. Part of the problem is that we are surprisingly bad at knowing where we have looked.

3D Object Detection Using Frustums and Attention Modules for Images and Point Clouds

Three-dimensional (3D) object detection is essential in autonomous driving. Three-dimensional (3D) Lidar sensor can capture three-dimensional objects, such as vehicles, cycles, pedestrians, and other objects on the road. Although Lidar can generate point clouds in 3D space, it still lacks the fine resolution of 2D information. Therefore, Lidar and camera fusion has gradually become a practical method for 3D object detection. Previous strategies focused on the extraction of voxel points and the fusion of feature maps. However, the biggest challenge is in extracting enough edge information to detect small objects. To solve this problem, we found that attention modules are beneficial in detecting small objects. In this work, we developed Frustum ConvNet and attention modules for the fusion of images from a camera and point clouds from a Lidar. Multilayer Perceptron (MLP) and tanh activation functions were used in the attention modules. Furthermore, the attention modules were designed on PointNet to perform multilayer edge detection for 3D object detection. Compared with a previous well-known method, Frustum ConvNet, our method achieved competitive results, with an improvement of 0.27%, 0.43%, and 0.36% in Average Precision (AP) for 3D object detection in easy, moderate, and hard cases, respectively, and an improvement of 0.21%, 0.27%, and 0.01% in AP for Bird’s Eye View (BEV) object detection in easy, moderate, and hard cases, respectively, on the KITTI detection benchmarks. Our method also obtained the best results in four cases in AP on the indoor SUN-RGBD dataset for 3D object detection.

Minimum Reload Cost Graph Factors

The concept of Reload cost in a graph refers to the cost that occurs while traversing a vertex via two of its incident edges. This cost is uniquely determined by the colors of the two edges. This concept has various applications in transportation networks, communication networks, and energy distribution networks. Various problems using this model are defined and studied in the literature. The problem of finding a spanning tree whose diameter with respect to the reload costs is smallest possible, the problems of finding a path, trail or walk with minimum total reload cost between two given vertices, problems about finding a proper edge coloring of a graph such that the total reload cost is minimized, the problem of finding a spanning tree such that the sum of the reload costs of all paths between all pairs of vertices is minimized, and the problem of finding a set of cycles of minimum reload cost, that cover all the vertices of a graph, are examples of such problems. In this work we focus on the last problem. Noting that a cycle cover of a graph is a 2-factor of it, we generalize the problem to the problem of finding an r-factor of minimum reload cost of an edge colored graph. We prove several NP-hardness results for special cases of the problem. Namely, bounded degree graphs, planar graphs, bounded total cost, and bounded number of distinct costs. For the special case of r = 2, our results imply an improved NP-hardness result. On the positive side, we present a polynomial-time solvable special case which provides a tight boundary between the polynomial and hard cases in terms of r and the maximum degree of the graph. We then investigate the parameterized complexity of the problem, prove W[1]-hardness results and present an FPT-algorithm.

Transnational Intellectual Property Governance on the Internet

This article documents and classifies instances of transnational intellectual property (IP) enforcement and licensing on the Internet with a particular focus on the territorial reach of the respective regimes. Regarding IP enforcement, I show that the bulk of transnational or even global measures is adopted in the context of “voluntary” self-regulation by various intermediaries, namely domain name registrars, access and host providers, search engines, and advertising and payment services. Global IP licensing is, in contrast, less prevalent than one might expect. It is practically limited to freely accessible Open Content, whereas markets for fee-based services remain territorially fragmented. Overall, three layers of IP governance on the Internet can be distinguished. Based on global licenses, Open Content is freely accessible everywhere. Plain IP infringements are equally combatted on a worldwide scale. Territorial fragmentation persists, instead, in the market segment of fee-based services and in hard cases of conflicts of IP laws/rights. All three universal norms (global accessibility, global illegality, global fragmentation) are supported by a quite solid, “rough” global consensus.

Solving equation systems in ω-categorical algebras

We study the computational complexity of deciding whether a given set of term equalities and inequalities has a solution in an [Formula: see text]-categorical algebra [Formula: see text]. There are [Formula: see text]-categorical groups where this problem is undecidable. We show that if [Formula: see text] is an [Formula: see text]-categorical semilattice or an abelian group, then the problem is in P or NP-hard. The hard cases are precisely those where [Formula: see text] has a uniformly continuous minor-preserving map to the clone of projections on a two-element set. The results provide information about algebras [Formula: see text] such that [Formula: see text] does not satisfy this condition, and they are of independent interest in universal algebra. In our proofs we rely on the Barto–Pinsker theorem about the existence of pseudo-Siggers polymorphisms. To the best of our knowledge, this is the first time that the pseudo-Siggers identity has been used to prove a complexity dichotomy.

Soft law, legal ethics and the corporate lawyer: confronting human rights and sustainability norms

We are all familiar with the old adage that hard cases make for bad law. This symposium riffs off that idea to inquire whether soft law can make for (great) ethical lawyering? To interrogate this q...

Voting on Abortion Again and Again and Again: Campaign Efforts and Effects

Voting on Abortion Again and Again and Again:Campaign Efforts and Effects Theresa Reidy (bio) On 25 May 2018 the Eighth Amendment of Bunreacht na hÉireann, the Irish Constitution, was repealed in a referendum vote, and abortion provision in Ireland was significantly liberalized as a result. Repeal had been expected. The Yes side led opinion polls during the campaign, and polls over many years indicated that attitudes to abortion had been transformed from the conservative views that dominated in the 1980s. But the size of the Yes victory and the large turnout among voters were a surprise to many. Abortion policy has assailed Irish politics for nearly four decades, and the 2018 referendum was the sixth time a question had been put to the people on aspects of abortion policy since the first referendum in 1983. By 2018 the central issues had been extensively debated over a long period, but with notable evidence of a change in tone and complexity. Early debates leading to the 1983 vote were marked by absolutist arguments and traditional belief systems on the part of the dominant anti-abortion side, and the first referendum campaign has been singled out for its "rancor and divisiveness."1 However, by the time of the fifth abortion referendum in 2002, Fiachra Kennedy could characterize the debate as comprised of a "series of moral conundrums."2 A succession of "hard cases," legal judgments, and sustained campaigns inside and outside of parliament led the [End Page 21] government to move toward a sixth referendum, and the first with a liberalizing intent. But a cautious route was taken to the sixth referendum. The government first convened a national Citizens' Assembly (a deliberative forum) to review the issue, an Oireachtas committee considered the recommendations of the Citizens' Assembly, and then a decision was taken to proceed to a further referendum vote. This article seeks to unpack the impact of the long (thirty-five-year), intermediate (two years of Citizens' Assembly and parliamentary deliberation), and the short (four-week) campaigns on voting at the referendum. The analysis will focus on three interconnected aspects of campaigns which draw from the work of Pippa Norris.3 She argues that campaigns generally have three objectives: priming, persuasion, and mobilization. Priming is agenda-setting; it refers to the efforts by campaign participants to communicate key messages to voters and to shape the terrain on which the debate will take place. Essentially, priming seeks to set the parameters for the debate, delineating what the issue is about, its most important questions, and the ideas and evidence that are most relevant. Persuasion refers to the art of influencing voters and convincing them of the merits of the arguments being put forward. Campaigners need voters to make up their mind on a question, i.e., to decide. Campaigns are always focused on undecided voters and seek to sway these to their side of the issue with selected evidence, arguments, and personal stories. Opinion reversal (changing the opinion of a voter) is a more challenging task than opinion formation.4 And finally, mobilization refers to turnout—"getting out the vote." Winning the argument is only useful if voters go to the polls and express their preferences. Campaigners will often provide assistance to voters with registering to vote, accessing polling-day information, and, especially in later stages of a campaign, promoting participation. The 2018 referendum vote is interesting because like all other referendums it had an immediate campaign period, but crucially, [End Page 22] abortion politics also featured frequently on the political agenda over the preceding thirty-five years. Therefore, the decision also had an unusually prolonged debate period. With this context in mind, this article addresses three questions: First, what factors were to the fore for voters in decision-making at the referendum (priming)? Second, when did voters arrive at their final decision on the abortion question (persuasion)? And third, what effect did the active campaign have on turnout (mobilization)? After providing an outline of the explanations of opinion formation, analysis of opinion change at referendums, and a short overview of campaign features, the article deploys its core analysis in sections three and four. In these discussions the priming...

Artificial Nutrition and Hydration and Care at the End of Life

New Natural Law Theory and the Catholic medico-moral tradition often lead to similar conclusions in hard cases regarding end-of-life care. Considering the provision of artificial nutrition and hydration to patients suffering from post-coma unresponsive wakefulness, however, brings to light subtle ways in which NNL differs from the centuries-old natural law tradition. In this essay, I formalize the methodology embedded within the casuistry of the medico-moral tradition and show how it differs from NNL with respect to the role played by double-effect reasoning and the perspective for analyzing cases regarding care for those who cannot speak for themselves. Importantly, the ordinary/extraordinary means distinction has never historically been understood as an application of double effect and logically cannot be so understood. Given the outsized role that double effect plays in NNL, the theory leads to conclusions that deviate from the Catholic medico-moral tradition and creates additional burdens and duties for the sick.

Health Crises and the Limited Role of Contract Law

The COVID-19 pandemic of 2020-21 has focused our attention on contract law’s response when unanticipated circumstances make performance impractical or frustrated or performance would cause harm to the public. The pandemic has disrupted contracts between landlord and tenant, employer and employee, universities and students, to name a few, but has contract law provided a clear path to determine who must bear the risk of loss of such events? The purpose of this essay is to suggest that current contract law’s many and varied, sometimes even contradictory, rules and principles relevant to shaping a response to a health crisis can offer only limited guidance to courts and lawyers in the challenging cases. Further, contract law’s uncertainty in these cases reinforces the more general perspective that judicial decisions in contract cases (and more generally) often depend, not on doctrine, but on a pragmatic analyses of the facts, policies and equities. Although this taste of realism is not a revelation, in fact, there may be no better example of the limits of contract law, as administered by courts, than its response to contract disputes during a public health crisis.Part I of this essay inventories the plethora of contract law issues raised when a health crisis makes performance problematic and when no federal or state regulation is in place to resolve the dispute. Part II assesses what such circumstances reveal about the nature of contract law: First, contract law’s set of responses reinforce legal theorists who have long argued that, at least in hard cases, contract law is subjective and uncertain. Second, contract law’s main contribution in such cases is to identify the questions that should be asked and to provide a roadmap to follow. Part III, the Conclusion, offers a word about post-pandemic contract law.

Sędzia w poszukiwaniu absurdów prawnych

In some cases judges have to deal with legal absurdities, which have an adverse impact on the legal system and on the situation of parties to legal transactions. There are judges who fail to notice legal absurdities or just wave them aside, for instance, driven by a formalistic creed of application of law, but there are also judges who know how to discover and skillfully remove them. The aim of this paper is an attempt to establish what set of circumstances (factors) may influence judges’ ability to discover legal absurdities in the cases they decide. An analysis of selected judgements leads to several important conclusions concerning the issue of judges discovering legal absurdities. (1) Judges use different methods to track down legal absurdities, although some similarities between them are noticeable; (2) The search for legal absurdities is done in the context of a judge’s discretionary power. (3) Judges discover legal absurdities in both in easy and hard cases. (4) In order to track down a legal absurdity it may be necessary to assess not only the legal text, but also an act of application of law. (5) Judges consider all facts of a given case, including its unique circumstances, to discover a legal absurdity. (6) Tracking down legal absurdities is strictly and directly connected with knowledge of different kinds of legal absurdities.