Restricted Variants Research Articles

Gene-echocardiography: refining genotype-phenotype correlations in cardiomyopathy patients with restrictive phenotype

Abstract Background The restrictive phenotype, the least frequent and genetically complex form of cardiomyopathy, is the focus of this investigation. The aim is to clarify the association between restrictive phenotype and genetic variants in cardiomyopathy patient. Methods We utilized whole-exome sequencing in a cohort of 568 cardiomyopathy patients and performed echocardiographic evaluations to identify restrictive phenotypes. Comprehensive analysis of cardiac characteristics and functionality was also undertaken. Results Among the cohort, 33 patients exhibited a restrictive phenotype. These patients were distributed as follows: 7 within the restrictive cardiomyopathy group (RCM), 20 in the hypertrophic cardiomyopathy group (HRCM), and 6 in the dilated cardiomyopathy group (HDRCM). A notable prevalence of gene mutations, mainly in the MYBPC3 gene, was found in these individuals. We observed that mutation carriers, characterized by smaller aortic sinus dimension, demonstrated an association with the mutation and diminished myocardial work. Furthermore, MYBPC3 mutation carriers showed a thicker ventricular wall and a higher predisposition for septal hypertrophy. Both HRCM and HDRCM groups displayed consistent hypertrophic manifestations, with the latter demonstrating a higher frequency of interventricular septal hypertrophy. The 5-year survival rate was calculated at 54.5%, with gene mutations not significantly affecting longevity. Conclusion Genetic factors profoundly influence the restrictive phenotype of cardiomyopathy. There is a strong link between restrictive phenotype and genetic variants in cardiomyopathy, providing a foundation for more accurate genetic testing and personalized management of patients. The emerging "gene-echocardiography" concept may refine the accuracy and productivity of genetic counseling and testing in cardiomyopathy.

Popularity on the roommate diversity problem

A recently introduced restricted variant of the multidimensional stable roommates problem is the roommate diversity problem: each agent belongs to one of two types (e.g., red and blue), and the agents' preferences over the rooms solely depend on the fraction of agents of their own type among their roommates. We study this variant with the notion of popularity.We show that in the roommate diversity problem with the room size fixed to 2, the problem becomes tractable. Particularly, a popular partitioning of agents is guaranteed to exist and can be computed in polynomial time. Additionally, a mixed popular partitioning of agents is always guaranteed to exist in any roommate diversity game. By contrast, when there are no restrictions on the room size of a roommate diversity game, a popular partitioning may fail to exist and the problem becomes intractable.

Diverse Pairs of Matchings

AbstractWe initiate the study of the Diverse Pair of (Maximum/ Perfect) Matchings problems which given a graph G and an integer k, ask whether G has two (maximum/perfect) matchings whose symmetric difference is at least k. Diverse Pair of Matchings (asking for two not necessarily maximum or perfect matchings) is $$\textsf{NP}$$ NP -complete on general graphs if k is part of the input, and we consider two restricted variants. First, we show that on bipartite graphs, the problem is polynomial-time solvable, and second we show that Diverse Pair of Maximum Matchings is $$\textsf{FPT}$$ FPT parameterized by k. We round off the work by showing that Diverse Pair of Matchings has a kernel on $${\mathcal {O}}(k^2)$$ O ( k 2 ) vertices.

Cooperative security against interdependent risks

Firms in interorganizational networks are exposed to interdependent risks that are transferable across partner firms, such as contamination in food supply chains or data breaches in technology networks. They can be decomposed into intrinsic risks a firm faces from its own operations and extrinsic risks transferred from its partners. Firms have access to two security strategies: either they can independently eliminate both intrinsic and extrinsic risks by securing their links with partners or, alternatively, firms can cooperate with partners to eliminate sources of intrinsic risk in the network. We develop a graph‐theoretic model of interdependent security and demonstrate that the network‐optimal security strategy can be computed in polynomial time. Then, we use cooperative game‐theoretic tools to examine, under different informational assumptions, whether firms can sustain the network‐optimal security strategy via suitable cost‐sharing mechanisms. We design a novel cost‐sharing mechanism: a restricted variant of the well‐known Shapley value, the agreeable allocation, that is easy to compute, bilaterally implementable, ensures stability, and is fair. However, the agreeable allocation need not always exist. Interestingly, we find that in networks with homogeneous cost parameters, the presence of locally dense clusters of connected firms precludes the existence of the agreeable allocation, while the absence of sufficiently dense clusters (formally, k‐cores) guarantees its existence. Finally, using the SDC Platinum database, we consider all interfirm alliances formed in the food manufacturing sector from 2006 to 2020. Then, with simulated cost parameters, we examine the practical feasibility of identifying bilaterally implementable security cost‐sharing arrangements in these alliances.

Voice Markers in Septuagint Greek in the Light of Hebrew Interference: A Corpus‐Based Study on the Aorist System of the Book of Genesis*

AbstractIn this paper, we examine the behaviour of so‐called passive and middle aorist forms in the Greek reflected in the Genesis of the Septuagint. The Septuagint, and Biblical Greek more generally, displays a considerable aberration with respect to other varieties of Ancient Greek regarding the relative frequency of passive vis‐à‐vis middle aorist forms. Here, we explore this feature of Septuagint Greek in some detail, showing that there is a more or less consistent, binary system at this stage, where the passive aorist is the preferred expression of monoargumental detransitive clauses, while the middle primarily appears in biargumental detransitive clauses. A comparison with the original text in Biblical Hebrew suggests that its binyanim system, with systematic distinction between transitive and detransitivising stems, may have played a key role in accelerating this process, which was already present in earlier stages of Greek. This process resulted in a general ousting of the aorist middle, which essentially became a lexically restricted variant of the active voice.

Immuno-inflammatory markers of syntropic cardiovascular diseases

Objective: To study the immuno-inflammatory markers of coronary heart disease, arterial hypertension and their combined course. The research work included 116 patients with cardiovascular disease of middle and old age. The average age of patients is 62.4±1.27. All patients were examined at the Bukhara branch of the Republican scientific and practical Center for emergency medical care. During the analysis, it was found that the level of systolic arterial blood pressure directly depends on the concentration of fibrinogen – r = 0.30 and oppositely depends on the concentration of procalcitonin (PCT) – r = -0.3 and IL-6 – r = -0.26. At the same time, a noticeable positive association of heart rate with creatinine in the blood – r = 0.35 was also revealed. The established connections show the contribution of inflammation syndrome (immune) in the progression of hypertension, or rather, indicators of the progression of hypertension in coronary heart disease are creatinine, fibrinogen, PCT and IL-6. Due to the high and noticeable correlation with the studied immuno-biochemical parameters of blood and functional parameters of the heart, IL-6 is a more informative indicator of the progression of coronary heart disease with the risk of complications and multiple organ failure. Thus, the established connections in our studies allow us to include the conclusion that, along with the above, risk factors for the development of rupture and/ or aneurysm of the aorta in CHD are an increase in the blood level of complement C3, IL-17 and PCT. Consequently, with an increase in the level of VEGF in the blood in CHD AS, the risk of an increase in the thickness of the LV in the diastole increases, and an increase in IL-6, IL-17A and urea in the blood shows a decrease in the thickness of the LV in the diastole, which makes it possible to differentiate the restrictive variant from the hypertrophic form in atypical angina. Due to the high and noticeable correlation with the studied immuno-biochemical parameters of blood and functional parameters of the heart, IL-6 is a more informative indicator of the progression of coronary artery disease with the risk of complications and multiple organ failure.

The 2CNF Boolean formula satisfiability problem and the linear space hypothesis

We aim at investigating the solvability/insolvability of nondeterministic logarithmic-space (NL) decision, search, and optimization problems parameterized by natural size parameters using simultaneously polynomial time and sub-linear space. We are particularly focused on 2SAT3—a restricted variant of the 2CNF Boolean (propositional) formula satisfiability problem in which each variable of a given 2CNF formula appears at most 3 times in the form of literals—parameterized by the total number mvbl(ϕ) of variables of each given Boolean formula ϕ. We propose a new, practical working hypothesis, called the linear space hypothesis (LSH), which asserts that (2SAT3,mvbl) cannot be solved in polynomial time using only “sub-linear” space (i.e., mvbl(x)εpolylog(|x|) space for a constant ε∈[0,1)) on all instances x. Immediate consequences of LSH include L≠NL, LOGDCFL≠LOGCFL, and SC≠NSC. For our investigation, we fully utilize a key notion of “short reductions”, under which the class PsubLIN of all parameterized polynomial-time sub-linear-space solvable problems is indeed closed.

Understanding the effects of higher-order assembly on the structure of the sulfite reductase.

The redox state of sulfur determines its bioavailbility and its reduction to sulfide is required for assimilation of sulfur into amino acids and cofactors.The NADPH-dependent assimilatory sulfite reductase (SiR) is a metabolic enzyme that performs the six-electron reduction of sulfite to sulfide. Escherichia coli SiR is composed of eight flavoprotein (SiRFP, ⍺) and four hemoprotein (SiRHP, β) subunits that associate in α8:β4 holoenzyme. This dodecameric assembly is unique because SiRs from other sulfur reducing organisms are dimers of reductase and oxidase subunits. Both SiR subunits are modular. SiRFP is a fusion between flavodoxin domain and a ferredoxin-NADP+ reductase domain that assembles through its 52 N-terminal amino acids into an octamer. SiRHP is a monomeric metalloenzyme that houses the active site. Despite almost 30 years of effort across many laboratories, structures of SiR complexes have remained recalcitrant to X-ray crystallography and cryo-EM because of its structural heterogeneity aising from intrinsically disordered regions throughout the complex, including the flexible linker joining SiRFP's flavin binding domain. Thus we do not know how the domains assemble, which leaves a gap in understanding about how these domains coordinate to perform electron transfer. Here, we use neutron contrast variation (NCV) and small angle neutron scattering (SANS) to observe the relative subunit positioning within the SiR complex. To better understand the electron transfer mechanism, we have generated conformationally restricted variant of SiRFP that either locks its flavin binding domains in an open conformation by shortening the linker between domains, or in closed conformation by engineering disulfide bonds. SANS and NCV study reveal SiR's asymmetric complex, and the resulting maps supports a redundant, cis/trans mechanism of electron transfer between the reductase subunits as well as between the tightly or transiently bound reductase and oxidase domains.

Syndromes of gas exchange disorders in patients with pulmonary tuberculosis

Introduction. Measurement of diffusion in the lung is important in the diagnosis and management of most pulmonary diseases. The analysis of diffusion lung capac-ity (DLCO) in combination with body plethysmography is useful for the interpretation of the causes of pulmo-nary gas exchange disorders. The aim: to determine the leading syndromes of pulmonary gas exchange disorders in patients with pulmonary tuberculosis (PT). Materials and methods. 608 patients (244/364 M/W) with veri-fied PT with smoking history of less than 10 pack/years were examined. Spirometry, body plethysmography, and DLCO were performed by the single-breath breath-hold-ing method. Results. DLCO decrease was detected in the majority of patients with PT (76%): in 94% of patients with massive fibrous-cavernous PT, 79.4% with disseminated PT and more than 60% of patients with infiltrative foci, local cavities, tuberculomas. In patients without ventilation dis-orders (58.4%), DLCO decrease was caused by damage to the alveolar capillary membrane, less often by air trapping (35.1%), other cases were rare. In the obstructive variant, mixed disorders of gas exchange (38.2%) and air trapping (34.1%) were most typical. In the restrictive variant, gas exchange surface reduction (62.5%) and mixed disorders (30%) prevailed. In mixed ventilation disorders, the mixed pulmonary gas exchange disorders were most often de-tected (63.8%) and the gas exchange surface reduction was quite common (36.2%) also. Conclusion. Alveolar cap-illary membrane damage (35.1%) and air trapping (28.1%) were most common in patients with PT. The mixed variant and gas exchange surface reduction were detected less frequently (24.7 and 12.1%, respectively), but these syn-dromes led to the most significant DLCO decrease.

The Problem of Discovery in Version Control Systems

Version Control Systems, used by developers to keep track of the evolution of their code, model repositories as Merkle graphs of revisions. In order to synchronize efficiently between different instances of a repository, they need to determine the common knowledge that they share. This process is called discovery.In this paper, we provide theoretical definitions for the problem of discovery, establish some universal upper and lower bounds on the amount of data that needs to be exchanged, as well as NP-hardness for a restricted variant (with only 2 round-trips). We also present and analyze some algorithms that are used in extant VCSs, such as Mercurial and Git, and propose an algorithm based on chain-decomposition.

Spatial prepositions for original (and richer) meanings: the case of Spanish

Spatio-temporal prepositions like hasta ‘until’ find crucially distinct uses across Spanish varieties. In many cases, uses disallowed in more restrictive variants alternate nontrivially with canonical P distribution, raising pressing questions on spatiotemporal prepositions, lexicalized denotational properties, and their potential exploitation in complex semantic representations. In Central American varieties in particular, Ps like hasta ‘up to’ show puzzling behavior in two instances: (i) with spatial situation verbs and copulas, in nondynamic, nondurative predications locating an object relative to a perspectival landmark; (ii) with punctual verbs, situating the V-described happening relative to a distal (temporal) vantage point. Both cases are unexpected for general crosslanguage principles touching on aspectual requirements imposed by projective or directional Ps and the specific nature of the verbs combined. Here, we draw on a general crosslanguage condition for otherwise unpredicted uses of directional spatial Ps building on perspectival location and extend the analysis to accommodate progressive uses in the locative/temporal domain accordingly. We follow the premise that directional/projective prepositions express directions on an interval, and that such directions can be defined either by inherent ground properties or by the relative position of an observer. In noncanonical uses, we contend, the object is situated relative to a landmark serving as origo of the relevant conceptual space. Polar coordinates in the analysis guarantee proper inclusion of all points in the perspectival path, accommodating negation effects accordingly.

Complexity Limitations on One-turn Quantum Refereed Games

This paper studies complexity theoretic aspects of quantum refereed games, which are abstract games between two competing players that send quantum states to a referee, who performs an efficiently implementable joint measurement on the two states to determine which of the player wins. The complexity class QRG(1) contains those decision problems for which one of the players can always win with high probability on yes-instances and the other player can always win with high probability on no-instances, regardless of the opposing player’s strategy. This class trivially contains QMA ∪co-QMA and is known to be contained in PSPACE. We prove stronger containments on two restricted variants of this class. Specifically, if one of the players is limited to sending a classical (probabilistic) state rather than a quantum state, the resulting complexity class CQRG(1) is contained in ∃⋅PP (the nondeterministic polynomial-time operator applied to PP); while if both players send quantum states but the referee is forced to measure one of the states first, and incorporates the classical outcome of this measurement into a measurement of the second state, the resulting class MQRG(1) is contained in P ⋅PP (the unbounded-error probabilistic polynomial-time operator applied to PP).

Group Activity Selection with Few Agent Types

In this paper we establish the complexity map for the Group Activity Selection Problem (GASP), along with two of its prominent variants called sGASP and gGASP, focusing on the case when the number of types of agents is the parameter. In all these problems, one is given a set of agents (each with their own preferences) and a set of activities, and the aim is to assign agents to activities in a way which satisfies certain global as well as preference-based conditions. Our positive results, consisting of one fixed-parameter algorithm and one XP algorithm, rely on a combination of novel Subset Sum machinery (which may be of general interest) and identifying certain compression steps that allow us to focus on solutions with a simpler, well-defined structure (in particular, they are “acyclic”). These algorithms are complemented by matching lower bounds, which among others close a gap to a recently obtained tractability result of Gupta et al. (in: Algorithmic game theory—10th international symposium, SAGT 2017, vol 10504 of lecture notes in computer science, Springer, 2017). In this direction, the techniques used to establish W[1]-hardness of sGASP are of particular interest: as an intermediate step, we use Sidon sequences to show the W[1]-hardness of a highly restricted variant of multi-dimensional Subset Sum, which may find applications in other settings as well.

Clinical and Genetic Analysis of Multiple Osteochondromas in A Cohort of Argentine Patients.

Multiple Osteochondromatosis (MO, MIM 133700 & 133701), an autosomal dominant O-glycosylation disorder (EXT1/EXT2-CDG), can be associated with a reduction in skeletal growth, bony deformity, restricted joint motion, shortened stature and pathogenic variants in two tumor suppressor genes, EXT1 and EXT2. In this work, we report a cross-sectional study including 35 index patients and 20 affected family members. Clinical phenotyping of all 55 affected cases was obtained, but genetic studies were performed only in 35 indexes. Of these, a total of 40% (n = 14) had a family history of MO. Clinical severity scores were class I in 34% (n:18), class II in 24.5% (n:13) and class III in 41.5% (n:22). Pathogenic variants were identified in 83% (29/35) probands. We detected 18 (62%) in EXT1 and 11 (38%) in EXT2. Patients with EXT1 variants showed a height z-score of 1.03 SD lower than those with EXT2 variants and greater clinical severity (II-III vs. I). Interestingly, three patients showed intellectual impairment, two patients showed a dual diagnosis, one Turner Syndrome and one hypochondroplasia. This study improves knowledge of MO, reporting new pathogenic variants and forwarding the worldwide collaboration necessary to promote the inclusion of patients into future biologically based therapeutics.

Towards Automated Discovery of God-Like Folk Algorithms for Rubik’s Cube

We present a multi-objective meta-search procedure that constructs candidate algorithms for state-space search puzzles like Rubik's cube. The candidate algorithms take the form of macro databases, i.e., rule tables that specify sequences of actions to perform in different states. Rules are repeatedly applied until the puzzle is solved. The objectives favor candidates that are god-like (solving the puzzle in fewer steps) and folk-like (having fewer rules in the macro database). We build each candidate with a non-deterministic rule table construction, and then optimize over the non-deterministic choice points to find candidates near the Pareto-optimal trades-offs between godliness and folksiness. We prove that the rule table construction is correct: it always terminates and solves every state at termination. This is verified empirically on the full 2x2x2 "pocket" cube, where correct (but unoptimized) constructions take under one hour and the total number of rules is less than 10% the number of possible states. We also empirically assess the multi-objective optimization on restricted variants of the cube with up to 29K possible states, showing relative improvements in the objectives between 14-20%. Avenues for scaling up the method in future work are discussed.

Discourse functions of lexical bundles in Indonesian EFL learners’ argumentative essays: A corpus study

Lexical bundles are functional units that are essential to building texts. However, lexical bundles vary due to some aspects, e.g., nativity, professionalism, text genre, etc. This study explored functional categories of lexical bundles in EFL written production, i.e., argumentative essays, focusing on 3-, 4-, and 5-word sequences employed by English major students in Indonesia. The data were taken from a learner corpus comprising 169 argumentative essays with 87.939 tokens. The lexical bundles were identified by using computerized and manual procedures. The identified bundles were then classified into functional categories and subcategories by Hyland. The results show that all functional categories were identified in the learner corpus proving the importance of those functions in students’ essays. Regarding the distribution, research-oriented bundles are the most frequent bundles in the corpus, while text-oriented bundles are the least frequent. Although all functional categories were found, the structuring signals (a subcategory of text-oriented bundles) were absent in the corpus. Moreover, this study found the gap between tokens and types of each bundle function, indicating the restricted variants of bundles used by the learners. Considering the low frequency of text-oriented bundles, the absence of structuring bundles, and restricted bundles, thus the exposure of more lexical bundles serving multiple functions in writing materials is necessary, especially bundles used for organizing and structuring texts.

Solving the Target-Value Search Problem

This paper addresses the Target-Value Search (TVS) problem, which is the problem of finding a path between two nodes in a graph whose cost is as close as possible to a given target value, T. This problem has been previously addressed: first, for directed acyclic graphs; second, for general graphs under the assumption that nodes can be revisited given that the same edge can not be traversed twice. In this work we focus on a more restrictive variant of the same problem where nodes can not be revisited. We prove that this variant is NP-complete and discuss novel theoretical properties and provide empirical results to solve this problem optimally.

Fixed-parameter tractability for the Tree Assembly problem

Calculating the “distance” between two given objects with respect to a designated “editing” operation is a hot research area in bioinformatics, where the “distance” is always defined as the minimum number of the “editing” operations required to transform one object into the other one. One of the famous problems in the area is the Minimum Common String Partition problem, which is the simplified variant of the Minimum Tree Cut/Paste Distance problem. Within the paper, we consider another simplified variant of the Minimum Tree Cut/Paste Distance problem, named Tree Assembly problem, of which the edge-deletion operations are specified. More specifically, the Tree Assembly problem aims to transform a given forest into a given tree by edge-addition operations only. In our investigations, we present a fixed-parameter algorithm with runtime 2O(klog⁡k)nO(1) for the Tree Assembly problem, where k is the number of trees in the given forest, and n is the number of nodes in the given tree and forest. Additionally, we give a polynomial time algorithm for a restricted variant of the problem.

New and improved algorithms for unordered tree inclusion

The tree inclusion problem is, given two node-labeled trees P and T (the “pattern tree” and the “target tree”), to locate every minimal subtree in T (if any) that can be obtained by applying a sequence of node insertion operations to P. Although the ordered tree inclusion problem is solvable in polynomial time, the unordered tree inclusion problem is NP-hard. The currently fastest algorithm for the latter is a classic algorithm by Kilpeläinen and Mannila from 1995 that runs in O(d22dmn) time, where m and n are the sizes of the pattern and target trees, respectively, and d is the degree of the pattern tree. Here, we develop a new algorithm that runs in O(d2dmn2) time, improving the exponential factor from 22d to 2d by considering a particular type of ancestor-descendant relationships that is suitable for dynamic programming. We also study restricted variants of the unordered tree inclusion problem.

New results on multi-level aggregation

In the Multi-Level Aggregation Problem (MLAP ), requests for service arrive at the nodes of an edge-weighted rooted tree T. Each service is represented by a subtree X of T that contains its root. This subtree X serves all requests that are pending in the nodes of X, and the cost of this service is equal to the total weight of X. Each request also incurs a waiting cost between its arrival and service time. The objective is to minimize the total waiting cost of all requests plus the total cost of all service subtrees.The currently best online algorithms for the MLAP achieve competitive ratios polynomial in the tree depth, while the best lower bound is only 3.618. In this paper, we report some progress towards closing this gap, by improving this lower bound and providing several tight bounds for restricted variants of MLAP: (1) We first study a Single-Phase variant of MLAP where all requests are released at the beginning and expire at some unknown time θ, for which we provide an online algorithm with optimal competitive ratio of 4. (2) We prove a lower bound of 4 on the competitive ratio for MLAP, even when the tree is a path. We complement this with a matching upper bound for the deadline variant of MLAP on paths.Additionally, we provide two results for the offline case: (3) We prove that the Single-Phase variant can be solved optimally in polynomial time, and (4) we give a simple 2-approximation algorithm for offline MLAP with deadlines.