bluuebunny/crossref_metadata_2025 huggingface dataset:
Melocoton: A Program Logic for Verified Interoperability Between OCaml and C
Authors: Guéneau Armaël , Hostert Johannes , Spies Simon , Sammler Michael , Birkedal Lars , Dreyer Derek
Published: October 2023

In recent years, there has been tremendous progress on developing program logics for verifying the correctness of programs in a rich and diverse array of languages. Thus far, however, such logics have assumed that programs are written entirely in a single programming language. In practice, this assumption rarely holds since programs are often composed of components written in different programming languages, which interact with one another via some kind of foreign function interface (FFI). In this paper, we take the first steps towards the goal of developing program logics for multi-language verification. Specifically, we present Melocoton, a multi-language program verification system for reasoning about OCaml, C, and their interactions through the OCaml FFI. Melocoton consists of the first formal semantics of (a large subset of) the OCaml FFI—previously only described in prose in the OCaml manual—as well as the first program logic to reason about the interactions of program components written in OCaml and C. Melocoton is fully mechanized in Coq on top of the Iris separation logic framework.
Simple Reference Immutability for System F
<:
Authors: Lee Edward , Lhoták Ondřej
Published: October 2023

Reference immutability is a type based technique for taming mutation that has long been studied in the
context of object-oriented languages, like Java. Recently, though, languages like Scala have blurred the lines
between functional programming languages and object oriented programming languages. We explore how
reference immutability interacts with features commonly found in these hybrid languages, in particular with
higher-order functions – polymorphism – and subtyping. We construct a calculus System F<:M which encodes
a reference immutability system as a simple extension of System F<: and prove that it satisfies the standard
soundness and immutability safety properties.
Inductive Program Synthesis Guided by Observational Program Similarity
Authors: Feser Jack , Dillig Işıl , Solar-Lezama Armando
Published: October 2023

We present a new general-purpose synthesis technique for generating programs from input-output examples. Our method, called metric program synthesis, relaxes the observational equivalence idea (used widely in bottom-up enumerative synthesis) into a weaker notion of observational similarity, with the goal of reducing the search space that the synthesizer needs to explore. Our method clusters programs into equivalence classes based on an expert-provided distance metric and constructs a version space that compactly represents “approximately correct” programs. Then, given a “close enough” program sampled from this version space, our approach uses a distance-guided repair algorithm to find a program that exactly matches the given input-output examples. We have implemented our proposed metric program synthesis technique in a tool called SyMetric and evaluate it in three different domains considered in prior work. Our evaluation shows that SyMetric outperforms other domain-agnostic synthesizers that use observational equivalence and that it achieves results competitive with domain-specific synthesizers that are either designed for or trained on those domains.
A Container-Usage-Pattern-Based Context Debloating Approach for Object-Sensitive Pointer Analysis
Authors: He Dongjie , Gui Yujiang , Li Wei , Tao Yonggang , Zou Changwei , Sui Yulei , Xue Jingling
Published: October 2023

In this paper, we introduce DebloaterX, a new approach for automatically identifying context-independent objects to debloat contexts in object-sensitive pointer analysis (
k
obj). Object sensitivity achieves high precision, but its context construction mechanism combines objects with their contexts indiscriminately. This leads to a combinatorial explosion of contexts in large programs, resulting in inefficiency. Previous research has proposed a context-debloating approach that inhibits a pre-selected set of context-independent objects from forming new contexts, improving the efficiency of
k
obj. However, this earlier context-debloating approach under-approximates the set of context-independent objects identified, limiting performance speedups.

We introduce a novel context-debloating pre-analysis approach that identifies objects as context-dependent only when they are potentially precision-critical to
k
obj based on three general container-usage patterns. Our research finds that objects containing no fields of ”abstract” (i.e., open) types can be analyzed context-insensitively with negligible precision loss in real-world applications. We provide clear rules and efficient algorithms to recognize these patterns, selecting more context-independent objects for better debloating. We have implemented DebloaterX in the Qilin framework and will release it as an open-source tool. Our experimental results on 12 standard Java benchmarks and real-world programs show that DebloaterX selects 92.4% of objects to be context-independent on average, enabling
k
obj to run significantly faster (an average of 19.3x when
k
= 2 and 150.2x when
k
= 3) and scale up to 8 more programs when
k
= 3, with only a negligible loss of precision (less than 0.2%). Compared to state-of-the-art alternative pre-analyses in accelerating
k
obj, DebloaterX outperforms Zipper significantly in both precision and efficiency and outperforms Conch (the earlier context-debloating approach) in efficiency substantially while achieving nearly the same precision.
Equality Saturation Theory Exploration à la Carte
Authors: Pal Anjali , Saiki Brett , Tjoa Ryan , Richey Cynthia , Zhu Amy , Flatt Oliver , Willsey Max , Tatlock Zachary , Nandi Chandrakana
Published: October 2023

Rewrite rules are critical in equality saturation, an increasingly popular technique
in optimizing compilers, synthesizers, and verifiers. Unfortunately,
developing high-quality rulesets is difficult and error-prone. Recent
work on automatically inferring rewrite rules does not scale to large
terms or grammars, and existing rule inference tools are monolithic and
opaque. Equality saturation users therefore struggle to guide inference and
incrementally construct rulesets. As a result, most users still
manually develop and maintain rulesets.

This paper proposes Enumo, a new domain-specific language for
programmable theory exploration. Enumo provides a small set of core
operators that enable users to strategically guide rule inference and
incrementally build rulesets. Short Enumo programs easily replicate
results from state-of-the-art tools, but Enumo programs can also scale
to infer deeper rules from larger grammars than prior approaches. Its
composable operators even facilitate developing new strategies for
ruleset inference. We introduce a new fast-forwarding strategy that does not require
evaluating terms in the target language, and can thus support domains
that were out of scope for prior work.

We evaluate Enumo and fast-forwarding across a variety of domains. Compared to
state-of-the-art techniques, enumo can synthesize better rulesets over a
diverse set of domains, in some cases matching the effects of
manually-developed rulesets in systems driven by equality saturation.
Structural Subtyping as Parametric Polymorphism
Authors: Tang Wenhao , Hillerström Daniel , McKinna James , Steuwer Michel , Dardha Ornela , Fu Rongxiao , Lindley Sam
Published: October 2023

Structural subtyping and parametric polymorphism provide similar flexibility and reusability to programmers. For example, both features enable the programmer to provide a wider record as an argument to a function that expects a narrower one. However, the means by which they do so differs substantially, and the precise details of the relationship between them exists, at best, as folklore in literature.

In this paper, we systematically study the relative expressive power of structural subtyping and parametric polymorphism. We focus our investigation on establishing the extent to which parametric polymorphism, in the form of row and presence polymorphism, can encode structural subtyping for variant and record types. We base our study on various Church-style λ-calculi extended with records and variants, different forms of structural subtyping, and row and presence polymorphism.

We characterise expressiveness by exhibiting compositional translations between calculi. For each translation we prove a type preservation and operational correspondence result. We also prove a number of non-existence results. By imposing restrictions on both source and target types, we reveal further subtleties in the expressiveness landscape, the restrictions enabling otherwise impossible translations to be defined. More specifically, we prove that full subtyping cannot be encoded via polymorphism, but we show that several restricted forms of subtyping can be encoded via particular forms of polymorphism.
Bring Your Own Data Structures to Datalog
Authors: Sahebolamri Arash , Barrett Langston , Moore Scott , Micinski Kristopher
Published: October 2023

The restricted logic programming language Datalog has become a popular implementation target for deductive-analytic workloads including social-media analytics and program analysis. Modern Datalog engines compile Datalog rules to joins over explicit representations of relations—often B-trees or hash maps. While these modern engines have enabled high scalability in many application domains, they have a crucial weakness: achieving the desired algorithmic complexity may be impossible due to representation-imposed overhead of the engine’s data structures. In this paper, we present the "Bring Your Own Data Structures" (Byods) approach, in the form of a DSL embedded in Rust. Using Byods, an engineer writes logical rules which are implicitly parametric on the concrete data structure representation; our implementation provides an interface to enable "bringing their own" data structures to represent relations, which harmoniously interact with code generated by our compiler (implemented as Rust procedural macros). We formalize the semantics of Byods as an extension of Datalog’s; our formalization captures the key properties demanded of data structures compatible with Byods, including properties required for incrementalized (semi-naïve) evaluation. We detail many applications of the Byods approach, implementing analyses requiring specialized data structures for transitive and equivalence relations to scale, including an optimized version of the Rust borrow checker Polonius; highly-parallel PageRank made possible by lattices; and a large-scale analysis of LLVM utilizing index-sharing to scale. Our results show that Byods offers both improved algorithmic scalability (reduced time and/or space complexity) and runtimes competitive with state-of-the-art parallelizing Datalog solvers.
Validating IoT Devices with Rate-Based Session Types
Authors: Iraci Grant , Chuang Cheng-En , Hu Raymond , Ziarek Lukasz
Published: October 2023

We develop a session types based framework for implementing and validating rate-based message passing systems in Internet of Things (IoT) domains. To model the indefinite repetition present in many embedded and IoT systems, we introduce a timed process calculus with a periodic recursion primitive. This allows us to model rate-based computations and communications inherent to these application domains. We introduce a definition of rate based session types in a binary session types setting and a new compatibility relationship, which we call rate compatibility. Programs which type check enjoy the standard session types guarantees as well as rate error freedom --- meaning processes which exchanges messages do so at the same rate. Rate compatibility is defined through a new notion of type expansion, a relation that allows communication between processes of differing periods by synthesizing and checking a common superperiod type. We prove type preservation and rate error freedom for our system, and show a decidable method for type checking based on computing superperiods for a collection of processes. We implement a prototype of our type system including rate compatibility via an embedding into the native type system of Rust. We apply this framework to a range of examples from our target domain such as Android software sensors, wearable devices, and sound processing.
Rapid: Region-Based Pointer Disambiguation
Authors: Chitre Khushboo , Kedia Piyus , Purandare Rahul
Published: October 2023

Interprocedural alias analyses often sacrifice precision for scalability. Thus, modern compilers such as GCC and LLVM implement more scalable but less precise intraprocedural alias analyses. This compromise makes the compilers miss out on potential optimization opportunities, affecting the performance of the application. Modern compilers implement loop-versioning with dynamic checks for pointer disambiguation to enable the missed optimizations. Polyhedral access range analysis and symbolic range analysis enable 𝑂 (1) range checks for non-overlapping of memory accesses inside loops. However, these approaches work only for the loops in which the loop bounds are loop invariants. To address this limitation, researchers proposed a technique that requires 𝑂 (𝑙𝑜𝑔 𝑛) memory accesses for pointer disambiguation. Others improved the performance of dynamic checks to single memory access by constraining the object size and alignment. However, the former approach incurs noticeable overhead due to its dynamic checks, whereas the latter has a noticeable allocator overhead. Thus, scalability remains a challenge.

In this work, we present a tool, Rapid, that further reduces the overheads of the allocator and dynamic checks proposed in the existing approaches. The key idea is to identify objects that need disambiguation checks using a profiler and allocate them in different regions, which are disjoint memory areas. The disambiguation checks simply compare the regions corresponding to the objects. The regions are aligned such that the top 32 bits in the addresses of any two objects allocated in different regions are always different. As a consequence, the dynamic checks do not require any memory access to ensure that the objects belong to different regions, making them efficient.

Rapid achieved a maximum performance benefit of around 52.94% for Polybench and 1.88% for CPU SPEC 2017 benchmarks. The maximum CPU overhead of our allocator is 0.57% with a geometric mean of -0.2% for CPU SPEC 2017 benchmarks. Due to the low overhead of the allocator and dynamic checks, Rapid could improve the performance of 12 out of 16 CPU SPEC 2017 benchmarks. In contrast, a state-of-the-art approach used in the comparison could improve only five CPU SPEC 2017 benchmarks.
P4R-Type: A Verified API for P4 Control Plane Programs
Authors: Larsen Jens Kanstrup , Guanciale Roberto , Haller Philipp , Scalas Alceste
Published: October 2023

Software-Defined Networking (SDN) significantly simplifies programming, reconfiguring, and optimizing network devices, such as switches and routers. The
de facto
standard for programming SDN devices is the P4 language. However, the flexibility and power of P4, and SDN more generally, gives rise to important risks. As a number of incidents at major cloud providers have shown, errors in SDN programs can compromise the availability of networks, leaving them in a non-functional state. The focus of this paper are errors in control-plane programs that interact with P4-enabled network devices via the standardized P4Runtime API. For clients of the P4Runtime API it is easy to make mistakes that may lead to catastrophic failures, despite the use of Google’s Protocol Buffers as an interface definition language.

This paper proposes P4R-Type, a novel verified P4Runtime API for Scala that performs static checks for P4 control plane operations, ruling out mismatches between P4 tables, allowed actions, and action parameters. As a formal foundation of P4R-Type, we present the
F
P4R
calculus and its typing system, which ensure that well-typed programs never get stuck by issuing invalid P4Runtime operations. We evaluate the safety and flexibility of P4R-Type with 3 case studies. To the best of our knowledge, this is the first work that formalises P4Runtime control plane applications, and a typing discipline ensuring the correctness of P4Runtime operations.
Machine Translation for Historical Research: A Case Study of Aramaic-Ancient Hebrew Translations
Authors: Liebeskind Chaya , Liebeskind Shmuel , Bouhnik Dan
Published: October 2023

In this article, by the ability to translate Aramaic to another spoken languages, we investigated machine translation in a cultural heritage domain for two primary purposes: evaluating the quality of ancient translations and preserving Aramaic (an endangered language). First, we detailed the construction of a publicly available Biblical parallel Aramaic-Hebrew corpus based on two ancient (early 2
nd
to late 4
th
century) Hebrew-Aramaic translations: Targum Onkelus and Targum Jonathan. Then using the statistical machine translation approach, which in our use case significantly outperforms neural machine translation, we validated the excepted high quality of the translations. The trained model failed to translate Aramaic texts of other dialects. However, when we trained the same statistical machine translation model on another Aramaic-Hebrew corpus of a different dialect (Zohar, 13
th
century), a very high translation score was achieved. We examined an additional important cultural heritage source of Aramaic texts, the Babylonian Talmud (early 3
rd
to late 5
th
century). Since we do not have a parallel Aramaic-Hebrew corpus of the Talmud, we used the model trained on the Bible corpus for translation. We performed an analysis of the results and suggest some potential promising future research.
The Tubulin Code, from Molecules to Health and Disease
Authors: McKenna Elizabeth D. , Sarbanes Stephanie L. , Cummings Steven W. , Roll-Mecak Antonina
Published: October 2023

Microtubules are essential dynamic polymers composed of α/β-tubulin heterodimers. They support intracellular trafficking, cell division, cellular motility, and other essential cellular processes. In many species, both α-tubulin and β-tubulin are encoded by multiple genes with distinct expression profiles and functionality. Microtubules are further diversified through abundant posttranslational modifications, which are added and removed by a suite of enzymes to form complex, stereotyped cellular arrays. The genetic and chemical diversity of tubulin constitute a tubulin code that regulates intrinsic microtubule properties and is read by cellular effectors, such as molecular motors and microtubule-associated proteins, to provide spatial and temporal specificity to microtubules in cells. In this review, we synthesize the rapidly expanding tubulin code literature and highlight limitations and opportunities for the field. As complex microtubule arrays underlie essential physiological processes, a better understanding of how cells employ the tubulin code has important implications for human disease ranging from cancer to neurological disorders.
Angular Dependence of Magnetization Behavior in Ni81Fe19 Nanowires by Micromagnetic Simulations
Authors: Sultan Musaab Salman
Published: October 2023

Nickel (Ni)-iron (Fe) alloy in the form of Ni81Fe19 (permalloy) is a widely used material in technological soft magnetic applications. Understanding the magnetization behavior in detail in such materials is substantial from both a scientific point of view and industrial demands. Therefore, the main purpose of the present article is to discuss the angular dependence of magnetization in Ni81Fe19 nanowires by micromagnetic simulation using the object-oriented micromagnetic framework (OOMMF) platform. These investigations have been implemented on different widths/thicknesses (T) up to 150 nm with an identical stretch of 1 µm. There was a reduction in the remanent magnetization by increasing the wire angle with respect to the magnetic field applied, which displayed excellent agreement with calculations performed theoretically. This was designated for the effect of shape anisotropy on behavior. The angular dependence of the switching behavior was analyzed and compared theoretically with the classical domain wall reversal models. The magnetic reversal for wires ≤30 nm was well defined by the uniform rotation of the Stoner–Wohlfarth model, whereas for nanostructures ≥50 nm was analyzed by the nonuniform rotation of the curling model. The critical thickness for the transition between these models was theoretically calculated and found to be around 30 ± 5 nm, which is in good agreement with the other findings presented in the literature using other materials of ferromagnetic wires. The micromagnetic spin structure was obtained instantaneously before and after switching events for relatively thick (150 nm) nanostructures at different angles, suggesting that the reversal is not as simple as predicted by the domain wall reversal of nonuniform rotation of the curling model.
Exploration of the Mechanism of Valsartan Treatment in Chronic Renal Failure: Network Pharmacology and Experimental Validation
Authors: Zhu Min , Wang Zhaoran , Zhu Ziming , Zhang Cuifeng , Wu Fanrong
Published: October 2023

Objective. To investigate the targets and mechanisms of valsartan in the treatment of chronic renal failure based on network pharmacology and animal experiment validation. Methods. The objectives of using valsartan were predicted with the PubChem and SwissTargetPrediction databases. Relevant targets of chronic renal failure have been searched in various disease databases, with the common purposes of drugs and diseases extracted. Network analysis was carried out with the STRING database to construct a protein-protein interaction (PPI) network, as Cytoscape 3.9.1 software was used to analyze network topology of the key targets and establish the “valsartan-core target gene” network. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed on core targets to explore their possible molecular mechanisms. The chronic renal failure mouse model was established by the plat method. Hematoxylin-eosin (H&E) and Masson staining observed morphological changes in renal problems of each group, as levels of serum Cre, BUN, T-SOD, and MDA in each group were detected by kit; real-time PCR was used to detect the relative expression of mRNA of TNF-αIL-1β, IL-6, and IL-10 in renal disease of mice in each group, with WB detect CALM, PKCα, and CaMKIV protein expression levels in renal disease from each group. Results. The network pharmacology approach identified 10 key targets for treatment of chronic renal failure with valsartan, including EGFR, PTGS2, PPARG, and ERBB2. KEGG enrichment analysis predicted that the drug exerted neuroactive ligand-receptor interaction, the calcium signaling pathway, the HIF-1 signaling pathway, the proteoglycans in cancer, PD-L1 expression, and the PD-1 checkpoint pathway in cancer. Results from animal experiments were compared to those of the model group, as renal function was significantly improved in the valsartan-dose group. The serum levels of Cre, BUN, and MDA and relative mRNA expression of TNF-α, IL-1β, and IL-6 decreased significantly, while serum T-SOD levels, relative mRNA expression of IL-10, and the protein expression level of CALM, PKCα, and CaMKIV increased significantly (

P

 < 0.05 and

P

 < 0.001). Conclusion. Valsartan yields certain renal protection, which may improve chronic renal failure in mice through the calcium signaling pathway.
Fractional Derivative Model for Analysis of HIV and Malaria Transmission Dynamics
Authors: Cheneke Kumama Regassa
Published: October 2023

In this study, a Caputo fractional derivative is employed to develop a model of malaria and HIV transmission dynamics with optimal control. Also, the model’s basic properties are shown, and the basic reproduction number is computed using the next-generation matrix method. Additionally, the order of fractional derivative analysis shows that the infected group decreases at the beginning for the higher-order of fractional derivative. Moreover, the early activation of memory effects through public health education reduces the impact of malaria and HIV infections on further progression and transmission. On the other hand, effective optimal controls reduce the occurrence and prevalence of HIV and malaria infections from the beginning to the end of the investigation. Finally, the numerical simulations are done for the justification of analytical solutions with numerical solutions of the model. Moreover, the MATLAB platform is incorporated for numerical simulation of the solutions.
Changes in Seed Quality during Seed Development and Maturation of Bambara Nut (Vigna subterranea (L.) Verdc.) Landraces
Authors: Oballim Gerard , Obura Morish , Opile Wilson Reuben , Ochuodho Julius Onyango
Published: October 2023

This study aimed at determining changes in the seed quality of bambara nut (BN) landraces during seed development and maturation so as to more precisely time seed harvest for better seed quality. Three bambara nut landraces, AbiBam001, LocalBam, and TVSU544, were sown in two field experimental sites in northern Uganda in October 2020 and 2021. Seeds were harvested at 83, 93, 103, 113, and 123 days after sowing (DAS) in the first experiment and at 123, 130, and 138 DAS in the second. Seeds were subjected to quality tests of seed dry weight, final germination percentage (FGP), germination velocity index (GVI), and seedling dry weight (SDW). All landraces showed significant differences

P
 
<
 
0.05

in seed weight and seedling dry weight at progressive developmental stages in the first experiment. All parameters showed no differences

P
 
>
 
0.05

in the second experiment except for the seed weight of AbiBam001 and the FGP of TVSU544. Both TVSU544 and LocalBam attained mass maturity (highest seed weight) at approximately 113 DAS, while AbiBam001 reached mass maturity at about 130 DAS. Seeds of the highest quality were obtained at 103 DAS for TVSU544 and at 113 DAS for both LocalBam and AbiBam001. For both AbiBam001 and TVSU544, the highest quality seeds occur before mass maturity, while for LocalBam, at about mass maturity. Seed harvest should be timed at 103−113, 113−123, and 120−130 DAS for TVSU544, LocalBam, and AbiBam001, respectively. The assessment of seed development before 83 DAS and maturation after 138 DAS in the main growing season will synchronize growing conditions with farmers’ practices and crucially provide a complete picture of the developmental patterns of the landraces.
Liquid Chromatography-Tandem Mass Spectrometry Detection of Human and Veterinary Drugs and Pesticides in Surface Water
Authors: Zhang Xiang-Pu , Zhang Shu , Xu Chun-Yan , Li Wei-Wei , Ling Hai-Bo , Luo Yang , Jian Kang , Li Tao , Yi Chuan
Published: October 2023

Antibiotics and pesticides are widespread in most rivers and lakes due to the overuse of antibiotics and pesticides, but there are few methods for simultaneous analysis of antibiotics and pesticides in aquatic environments. To address this knowledge gap, a concise and sensitive analytical method is proposed in which three classes of human and veterinary drugs (sulfonamides, macrolides, and hormones) and two classes of pesticides (organophosphorus and neonicotinoids) are simultaneously extracted and determined in surface water. The solid-phase extraction column with Cleanert PEP-2 was preconditioned sequentially with 6 mL of methanol, ultrapure water, and citric acid buffer (pH 3.0) each for simultaneous extraction and further purification. The forty-seven target analytes were analysed by LC-MS/MS in positive and negative ion modes. The LC separation was performed using a Sigma-Aldrich C18 column with 0.1% formic acid in water and acetonitrile as a gradient eluting mobile phase in positive ion mode. The internal standard method was used to overcome the inevitable matrix effects in LC-MS/MS analysis. The matrix effects of most target analytes were in the range of 27–151%. The recoveries of forty analytes in the three concentrations (10, 50, and 100 ng L−1) of surface water spiked samples ranged from 41 to 127%. The method quantitative limits of the analytes were in the range of 0.40–5.49 ng L−1. Application of the method to analyze samples in the eight runoff outlets of the Pearl River Delta showed that some antibiotics and pesticides were detected, and the concentration of parathion was as high as 154 ng L−1. A powerful tool for quickly and efficiently screening for contaminants in surface water has been presented.
Capnocytophaga canimorsus Infection in a 38-Year-Old Male after a Dog Bite
Authors: Ahsen Ahmad , Korsun Philip , Albahra Fadi , Nair Ranjit , Tariq Zain
Published: October 2023

Here, we present a unique case of a 38-year-old male with a history of alcohol use disorder and multiple sexual partners, who presented with fulminant sepsis with shock, multiorgan failure, and livedo racemosa after a dog bite the week prior. The patient was intubated on arrival and was started on vasopressors and antibiotics. Eventually, the patient’s clinical status improved, and he was transferred out of the intensive care unit. Blood cultures tested positive for oxidase-positive Gram-negative rods two days after collection, and species identification showed Capnocytophaga canimorsus.
FIGURE 5 from DNA2 Nuclease Inhibition Confers Synthetic Lethality in Cancers with Mutant p53 and Synergizes with PARP Inhibitors
Authors: Folly-Kossi Helena , Graves Joshua D. , Garan Lidija A. Wilhelms , Lin Fang-Tsyr , Lin Weei-Chin
Published: October 2023

d16 treatment inhibits ovarian cancer growth in vivo. A, NSG mice bearing MDAH-2774 xenografts were administered with d16 (30 mg/kg, twice/week) or vehicle (Veh) via intraperitoneal injection for 1 month. Data shown are the mean tumor volumes ± SD; n = 5 (Veh), or 7 (d16). *, P < 0.05 (two-tailed t test). B, Tumor weight. C, The mean mouse body weight ± SD. There was no statistical difference between these two groups. D, Representative images of H&E, Ki-67, and cleaved PARP1 staining of xenograft tumors. Scale bar, 100 µm. E, Quantification is shown in bar graphs. ***, P < 0.001, comparing Veh and d16 groups (two-tailed t test). F, Western blot analysis of the xenograft lysates showed the induction of γH2AX and PARP1 cleavage in many of the d16-treated xenografts compared with control. The bottom panels show the quantification of cleaved PARP1/full-length PARP1 and γH2AX/GAPDH from four Veh-treated and seven d16-treated xenografts. *, P < 0.05; **, P < 0.01 (two-tailed t test). G, CETSA was performed using the lysates of MDAH-2774 xenografts from mice treated with vehicle DMSO or d16. H, NSG mice bearing MDAH-2774 xenografts were administered with d16 (15 mg/kg, twice/week) or vehicle (Veh) via intraperitoneal injection for 3–4 weeks. Data shown are the mean tumor volume ± SD; n = 7 per group. **, P < 0.01 (two-tailed t test). I, The mean mouse body weight ± SD. There was no statistical difference between these two groups.
Data from DNA2 Nuclease Inhibition Confers Synthetic Lethality in Cancers with Mutant p53 and Synergizes with PARP Inhibitors
Authors: Folly-Kossi Helena , Graves Joshua D. , Garan Lidija A. Wilhelms , Lin Fang-Tsyr , Lin Weei-Chin
Published: October 2023

Abstract
The tumor suppressor p53 promotes tumor-suppressive activities including cell-cycle inhibition, apoptosis, senescence, autophagy, and DNA repair. However, somatic mutations in the TP53 gene are one of the most common alterations in human cancers. We previously showed that mutant p53 (mutp53) can bind TopBP1, an ATR activator, to attenuate its ATR-activating function. A partially defective ATR function caused by mutp53 makes cancer cells more vulnerable to inhibitors of other TopBP1-independent ATR activators, such as DNA2. DNA2 plays a role in homologous recombination (HR) repair by resecting DNA ends in double-strand breaks and preparing them for invasion of homologous duplex. Here we identify a new DNA2 inhibitor, namely d16, and show that d16 exhibits anticancer activities and overcomes chemotherapy resistance in mutp53-bearing cancers. Similar to DNA2 depletion, d16 treatment results in cell-cycle arrest mainly at S-phase. Moreover, reexpression of mutp53 in a p53-null cancer cell line makes cells more vulnerable to d16-mediated inhibition of ATR activity. As d16 also inhibits HR, a combination of d16 and PARP inhibitors displays synergistic induction of cell death. DNA2 is often overexpressed in cancer, particularly in cancer cells harboring mutp53. Overexpression of DNA2 is associated with poor outcome in ovarian cancer. Overall, our results provide a rationale to target DNA2 as a new synthetic lethality approach in mutp53-bearing cancers, and further extend the benefit of PARP inhibitors beyond BRCA-mutated cancers.
Significance:
This study identifies a new DNA2 inhibitor as a synthetic lethal targeted therapy for mutp53-harboring cancers, and provides a new therapeutic strategy by combining DNA2 inhibitors with PARP inhibitors for these cancers.
Inhaler Steroid Use Changes Oral and Airway Bacterial and Fungal Microbiome Profile in Asthma Patients
Authors: Oğuzülgen Kıvılcım , Öztürk Ayse Bilge , Bacceoğlu Ayşe , Aydın Ömür , Köycü Buhari Gözde , Damadoğlu Ebru , Öner Erkekol Ferda , Göksel Özlem , Karakaya Gül , Kalyoncu A. Fuat , Kalpaklıoğlu Füsun , Mungan Dilşad , Türktaş Haluk , Pur Özyiğit Leyla , Ergin Çağrı , Erdoğan Merve , Kalkancı Ayşe
Published: October 2023

Introduction: The full spectrum of bacterial and fungal species in adult asthma and the effect of inhaled corticosteroid use is not well described. The aim was to collect mouthwash and induced sputum samples from newly diagnosed asthma patients in the pretreatment period and in chronic asthma patients while undergoing regular maintenance inhaled corticosteroid therapy, in order to demonstrate the bacterial and fungal microbiome profile. Methods: The study included 28 asthmatic patients on inhaler steroid therapy, 25 steroid-naive asthmatics, and 24 healthy controls. Genomic DNA was isolated from induced sputum and mouthwash samples. Analyses were performed using bacterial primers selected from the 16S rRNA region for the bacterial genome and “panfungal” primers selected from the 5.8S rRNA region for the fungal genome. Results: Dominant genera in mouthwash samples of steroid-naive asthmatics were Neisseria, Haemophilus, and Rothia. The oral microbiota of asthmatic patients on inhaler steroid treatment included Neisseria, Rothia, and Veillonella species. Abundant genera in induced sputum samples of steroid-naive asthma patients were Actinomyces, Granulicatella, Fusobacterium, Peptostreptococcus, and Atopobium. Sputum microbiota of asthma patients taking inhaler steroids were dominated by Prevotella and Porphyromonas. Mucor plumbeus and Malassezia restricta species were abundant in the airways of steroid-naive asthma patients. Choanephora infundibulifera and Malassezia restricta became dominant in asthma patients taking inhaled steroids. Conclusion: The oral and airway microbiota consist of different bacterial and fungal communities in healthy and asthmatic patients. Inhaler steroid use may influence the composition of the oral and airway microbiota.
Adding SGLT2 Cotransporter Inhibitor to PPARγ Activator Does Not Provide an Additive Effect in the Management of Diabetes-Induced Vascular Dysfunction
Authors: Cinakova Aneta , Krenek Peter , Klimas Jan , Kralova Eva
Published: October 2023

Introduction: Endothelial dysfunction (ED) plays a key role in the pathogenesis of diabetic vascular complications. In monotherapy, dapagliflozin (Dapa) as well as pioglitazone (Pio) prevent the progression of target organ damage in both type 1 (T1DM) and type 2 diabetes. We investigated whether the simultaneous PPAR-γ activation and SGLT2 cotransporter inhibition significantly alleviate ED-related pathological processes and thus normalize vascular response in experimental T1DM. Methods: Experimental diabetes was induced by streptozotocin (STZ; 55 mg/kg, i.p.) in Wistar rats. Dapa (10 mg/kg), Pio (12 mg/kg), or their combination were administrated to the STZ rats orally. Six weeks after STZ administration, the aorta was excised for functional studies and real-time qPCR analysis. Results: In the aorta of diabetic rats, impaired endothelium-dependent and independent relaxation were accompanied by the imbalance between vasoactive factors (eNos, Et1) and overexpression of inflammation (Tnfα, Il1b, Il6, Icam, Vcam) and oxidative stress (Cybb) markers. Pio monotherapy normalized response to vasoactive substances and restored balance between Et1-eNos expression, while Dapa treatment was ineffective. Nevertheless, Dapa and Pio monotherapy significantly reverted inflammation and oxidative stress markers to normal values. The combination treatment exhibited an additive effect in modulating Il6 expression, reaching the effect of Pio monotherapy in other measured parameters. Conclusion: Particularly, Pio exerts a vasoprotective character when used in monotherapy. When combined with Dapa, it does not exhibit an expected additive effect within modulating vasoreactivity or oxidative stress, though having a significant influence on IL6 downregulation.
Acanthosis Nigricans in a Patient with Urothelial Carcinoma Treated with PD-L1 Inhibitor Avelumab, and Secondary Adrenal Insufficiency
Authors: Lai Fei Ya , Jordan Emmet
Published: October 2023

Acanthosis nigricans (AN) describes hyperkeratotic and hyperpigmented skin changes and its pathophysiology is linked to the activation of epidermal growth factor receptors. Current literature shows that AN is most commonly diagnosed at the time of the underlying pathology, which may occur under benign or malignant conditions. This case presentation demonstrates the occurrence of AN in a patient following the diagnosis of urothelial carcinoma and ongoing treatment with PD-L1 inhibitor immunotherapy. Subsequent investigations ruled out a secondary malignancy or disease progression; however, metabolic screening identified secondary glucocorticoid induced adrenal insufficiency. AN was persistent in this patient despite adequate treatment, which highlights its co-occurrence in both benign and paraneoplastic conditions.
Parental Experiences of Neonatal Care: A Nationwide Study on Determinants of Excellence
Authors: Linnér Agnes , Thernström Blomqvist Ylva , Jonsson Kristina , Lilliesköld Siri , Norman Mikael
Published: October 2023

Introduction: Infant- and family-centered developmental care can reduce adverse outcomes in both infants and parents. Parents’ experiences of the care and staff treatment remain to be evaluated. Methods: Parents of infants admitted to neonatal units in Sweden from July 2020 to May 2022 responded to a questionnaire with standardized questions about in-hospital care. Exposures were hospital, gestational age, length of hospital stay, unit level, and bed density. The proportions of parents rating aspects of neonatal care as excellent, defined as five on a Likert scale, and the determinants of excellence were described. The results were benchmarked with ratings in adult somatic care. Results: A total of 4,475/13,108 (34%) parents responded. The ratings of excellent care varied by question from 65% to 90%. The largest variation in excellence between neonatal units (range 43–80%) was found for “participation and involvement.” The proportion of excellence was significantly lower among parents of extremely preterm infants. Confidence in the staff was lower in parents of extremely preterm infants than in parents of term infants (56% vs. 83%). Longer hospital stays affected the experience of neonatal care adversely, whereas level of care and bed density were overall unrelated to the parental experience. Parents in neonatal care rated the care as excellent to a higher extent than patients cared for in adult medicine. Conclusion: A majority of parents rated neonatal care in Sweden as excellent. The less frequent ratings of excellence among parents of extremely preterm infants indicate that more could be done to optimize parental involvement and support.
Intravenous Immunoglobulin Therapy-Induced Erythema Multiforme in a Patient with Chronic Lymphocytic Leukemia
Authors: Konovalova Angelina , Gerula Natālja , Hartmane Ilona , Upeniece Ilze , Ščerbuks Mihails , Bernāte Kristīne , Reinberga Lelde , Mikažāns Ingmārs
Published: October 2023

This case report discusses immunoglobulin-induced erythema multiforme (EM), a rare and understudied condition that requires further investigation. The report presents the case of a 69-year-old woman with a history of chronic lymphocytic leukemia who developed an acute hypersensitivity reaction to intravenous gamma globulin medication. The patient received intravenous immunoglobulin (IVIG) to normalize and stabilize her immunoglobulin levels and reduce the risk of recurrent infections due to her immunodeficiency with predominantly antibody defects. However, after the second administration of the medication, the patient experienced an acute skin rash and was admitted to the hospital for treatment. The treatment plan included systemic desensitizing therapy, systemic antihistamine therapy, corticosteroid therapy, and local therapy. After a course of therapy, the patient’s skin condition improved, and her overall well-being improved. However, due to the acute hypersensitivity reaction, the IVIG therapy was discontinued. The multidisciplinary team of specialists concluded that the patient had developed EM. The discussion provides an overview of EM, including its causes, clinical presentation, diagnostic tools, and therapy principles. The discussion also describes the use of human IVIG preparations in treating various immunodeficient and inflammatory diseases, highlighting the importance of monitoring patients for adverse effects. The case of this patient underscores the potential risks associated with immunoglobulin therapy and emphasizes the need for healthcare providers to remain vigilant for adverse reactions. By promptly diagnosing and treating EM, healthcare providers can minimize its impact on patients’ overall well-being.
Atopy Does Not Influence the Clinical Outcome of Acute Urticaria: A Retrospective Study
Authors: Yang Xianjie , Liang Gaopeng , Wang Huan , Kong Minmin , Song Zhiqiang , Chen Qiquan
Published: October 2023

Background: Acute urticaria (AU) may be associated with atopy, but the relationship between atopic status and the clinical features of the disease has not been fully described. Objectives: The aim of the study was to determine the proportion of atopy in AU patients and to see whether atopy is related to the clinical characteristics of AU and whether it has an impact on the outcome of the disease. Materials and Method: A retrospective analysis of patients with AU was performed. Demographic data, clinical features, and laboratory results were compared and analyzed between the atopic and non-atopic AU (napAU). Results: In total, 139 participants were included. 54 (38.8%) patients were atopic AU (apAU) and 85 (61.2%) were napAU. Compared with napAU patients, apAU patients were more likely to have anaphylaxis, higher levels of C4, and lower levels of antistreptolysin. There were no significant differences between the two groups in terms of other clinical features, laboratory tests, the natural course of the disease, or disease outcomes. Conclusion: Atopy does exist in some patients with AU, and AU patients with an atopic background are at higher risk for anaphylaxis. Atopy does not influence the clinical outcome of AU and is not correlated with other clinical features and laboratory results of AU.
Localized Multifocal Retroperitoneal Ganglioneuroma with an Infiltrative Appearance on Imaging: A Case Report
Authors: Rich Joseph M. , Duddalwar Vinay A. , Aron Manju , Ter-Oganesyan Ramon , Hu Peter , Chopra Shefali , Cheng Phillip M.
Published: October 2023

Multifocal ganglioneuromas are characterized by the presence of multiple benign neuroepithelial tumor nodules and are less common than solitary tumors. A small percentage of ganglioneuromas present with a fatty appearance. Only a few cases of multifocal ganglioneuromas have been reported, due to both their rarity and minimal symptomatic presentation; therefore, generalizations about risk factors and predictive markers are very difficult. Here, we report a case of multifocal retroperitoneal ganglioneuroma with an infiltrative appearance on computed tomography (CT). The tumor demonstrated slow growth on multiple imaging studies and was associated with abdominal and flank pain. The aggressive appearance eventually led to surgical resection 18 months after the initial incidental finding on CT. Postsurgical analysis of the tumor on imaging was crucial in revealing its nodularity and infiltration, as well as for clarifying its retroperitoneal location inseparable from the adrenal gland. Histology demonstrated Schwann cells and ganglion cells without atypia or increased cellularity, and with no mitosis or necrosis seen. Our case highlights the consideration of ganglioneuroma with fatty infiltration in the differential diagnosis of a fatty tumor in the mediastinum or retroperitoneum. Additionally, our report differentiates multifocal ganglioneuroma with fatty infiltration from lipomatous ganglioneuroma on radiology and histopathology.
Association of ABCA13 Gene Variants with Autism Spectrum Disorder and Other Neuropsychiatric Disorders
Authors: Gerik-Celebi Hamide Betul , Unsel-Bolat Gul , Bolat Hilmi
Published: October 2023

Introduction: Autism spectrum disorder (ASD) is a neuropsychiatric disorder characterized by impaired social skills and limited or repetitive behaviors. In this study, we investigated the role of the ABCA13 gene in the etiopathogenesis of ASD. Methods: Single-nucleotide variants were evaluated in 79 ASD patients (59 males +20 females) with no established genetic etiology associated with ASD using whole-exome sequencing/clinical exome sequencing method. Family segregation analysis was performed using Sanger sequencing. We presented the clinical and genetic findings of these cases and their parents in detail. Results: We presented 10 different ABCA13 gene variants in cases with ASD and 10 parents carrying the same ABCA13 gene variant. There of these variants were likely pathogenic and seven variants were classified as variant of uncertain significance. Our cases had a comorbidity rate for attention deficit hyperactivity disorder (ADHD) as 70%. Various types of neuropsychiatric symptoms and diagnoses were detected including ADHD, anxiety disorder, intellectual disability, delay in speech, and febrile convulsion among the parents. Conclusion: To date, very few variants have been reported in the ABCA13 gene. Our findings enrich the role of ABCA13 gene may play a common role in the landscape of neuropsychiatric disorders.