bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploiting the Sparseness of Control-Flow and Call Graphs for Efficient and On-Demand Algebraic Program Analysis
Authors: Conrado Giovanna Kobus , Goharshady Amir Kafshdar , Kochekov Kerim , Tsai Yun Chen , Zaher Ahmed Khaled
Published: October 2023

Algebraic Program Analysis (APA) is a ubiquitous framework that has been employed as a unifying model for various problems in data-flow analysis, termination analysis, invariant generation, predicate abstraction and a wide variety of other standard static analysis tasks. APA models program summaries as elements of a regular algebra . Suppose that a summary inAis assigned to every transition of the program and that we aim to compute the effect of running the program starting at linesand ending at linet. APA first computes a regular expression capturing all program paths of interest. In case of intraprocedural analysis, models all paths fromstot, whereas in the interprocedural case it models all interprocedurally-valid paths, i.e. ‍paths that go back to the right caller function when a callee returns. This regular expression is then interpreted over the algebra to obtain the desired result. Suppose the program hasnlines of code and each evaluation of an operation in the regular algebra takesO(k) time. It is well-known that a single APA query, or a set of queries with the same starting points, can be answered inO(n· α(n) ·k), where α is the inverse Ackermann function. In this work, we consider an on-demand setting for APA: the program is given in the input and can be preprocessed. The analysis has to then answer a large number of on-line queries, each providing a pair (s,t) of program lines which are the start and end point of the query, respectively. The goal is to avoid the significant cost of running a fresh APA instance for each query. Our main contribution is a series of algorithms that, after a lightweight preprocessing ofO(n· lgn·k), answer each query inO(k) time. In other words, our preprocessing has almost the same asymptotic complexity as a single APA query, except for a sub-logarithmic factor, and then every future query is answered instantly, i.e. ‍by a constant number of operations in the algebra. We achieve this remarkable speedup by relying on certain structural sparsity properties of control-flow and call graphs (CFGs and CGs). Specifically, we exploit the fact that control-flow graphs of real-world programs have a tree-like structure and bounded treewidth and nesting depth and that their call graphs have small treedepth in comparison to the size of the program. Finally, we provide experimental results demonstrating the effectiveness and efficiency of our approach and showing that it beats the runtime of classical APA by several orders of magnitude.
A Deductive Verification Infrastructure for Probabilistic Programs
Authors: Schröer Philipp , Batz Kevin , Kaminski Benjamin Lucien , Katoen Joost-Pieter , Matheja Christoph
Published: October 2023

This paper presents a quantitative program verification infrastructure for discrete
probabilistic programs.
Our infrastructure can be viewed as the probabilistic analogue of Boogie:
its central components are an intermediate verification language (IVL) together with a real-valued logic.
Our IVL provides a programming-language-style for expressing verification
conditions whose validity implies the correctness of a program under investigation.
As our
focus is on verifying quantitative properties such as bounds on
expected outcomes, expected run-times, or termination
probabilities, off-the-shelf IVLs based on Boolean first-order logic do not
suffice.
Instead, a paradigm shift from the standard Boolean to a real-valued domain is required.

Our IVL features quantitative generalizations of standard
verification constructs such as assume- and assert-statements. Verification conditions are generated by a
weakest-precondition-style semantics, based on our real-valued logic.
We show that
our verification infrastructure supports natural encodings of numerous verification
techniques from the literature. With our SMT-based implementation, we automatically verify a variety of benchmarks. To the best of our knowledge, this establishes the first deductive verification
infrastructure for expectation-based reasoning about probabilistic programs.
Greedy Implicit Bounded Quantification
Authors: Cui Chen , Jiang Shengyi , Oliveira Bruno C. d. S.
Published: October 2023

Mainstream object-oriented programming languages such as Java, Scala, C#, or TypeScript have polymorphic type systems with subtyping and bounded quantification. Bounded quantification, despite being a pervasive and widely used feature, has attracted little research work on type-inference algorithms to support it. A notable exception is local type inference, which is the basis of most current implementations of type inference for mainstream languages. However, support for bounded quantification in local type inference has important restrictions, and its non-algorithmic specification is complex.

In this paper, we present a variant of kernel
F
≤
, which is the canonical calculus with bounded quantification, with implicit polymorphism. Our variant, called
F
≤

b

, comes with a declarative and an algorithmic formulation of the type system. The declarative type system is based on previous work on bidirectional typing for predicative higher-rank polymorphism and a greedy approach to implicit instantiation. This allows for a clear declarative specification where programs require few type annotations and enables implicit polymorphism where applications omit type parameters. Just as local type inference, explicit type applications are also available in
F
≤

b

if desired. This is useful to deal with impredicative instantiations, which would not be allowed otherwise in
F
≤

b

. Due to the support for impredicative instantiations, we can obtain a completeness result with respect to kernel
F
≤
, showing that all the well-typed kernel
F
≤
programs can type-check in
F
≤

b

. The corresponding algorithmic version of the type system is shown to be sound, complete, and decidable. All the results have been mechanically formalized in the Abella theorem prover.
Type-Safe Dynamic Placement with First-Class Placed Values
Authors: Zakhour George , Weisenburger Pascal , Salvaneschi Guido
Published: October 2023

Several distributed programming language solutions have been proposed to reason about the placement of data, computations, and peers interaction. Such solutions include, among the others, multitier programming, choreographic programming and various approaches based on behavioral types. These methods statically ensure safety properties thanks to a complete knowledge about placement of data and computation at compile time. In distributed systems, however, dynamic placement of computation and data is crucial to enable performance optimizations, e.g., driven by data locality or in presence of a number of other constraints such as security and compliance regarding data storage location. Unfortunately, in existing programming languages, dynamic placement conflicts with static reasoning about distributed programs: the flexibility required by dynamic placement hinders statically tracking the location of data and computation.

In this paper we present Dyno, a programming language that enables static reasoning about dynamic placement. Dyno features a type system where values are explicitly placed, but in contrast to existing approaches, placed values are also first class, ensuring that they can be passed around and referred to from other locations. Building on top of this mechanism, we provide a novel interpretation of dynamic placement as unions of placement types. We formalize type soundness, placement correctness (as part of type soundness) and architecture conformance. In case studies and benchmarks, our evaluation shows that Dyno enables static reasoning about programs even in presence of dynamic placement, ensuring type safety and placement correctness of programs at negligible performance cost. We reimplement an Android app with ∼ 7 K LOC in Dyno, find a bug in the existing implementation, and show that the app's approach is representative of a common way to implement dynamic placement found in over 100 apps in a large open-source app store.
Formal Verification of Quantum Programs: Theory, Tools, and Challenges
Authors: Lewis Marco , Soudjani Sadegh , Zuliani Paolo
Published: October 2023

Over the past 27 years, quantum computing has seen a huge rise in interest from both academia and industry. At the current rate, quantum computers are growing in size rapidly backed up by the increase of research in the field. Significant efforts are being made to improve the reliability of quantum hardware and to develop suitable software to program quantum computers.

In contrast, the verification of quantum programs has received relatively less attention. Verifying programs is especially important in the quantum setting due to how difficult it is to program complex algorithms correctly on resource-constrained and error-prone quantum hardware. Research into creating verification frameworks for quantum programs has seen recent development, with a variety of tools implemented using a collection of theoretical ideas.

This survey aims to be a short introduction into the area of formal verification of quantum programs, bringing together theory and tools developed to date. Further, this survey examines some of the challenges that the field may face in the future, namely the development of complex quantum algorithms.
A Spatially-Aware Data-Driven Approach to Automatically Geocoding Non-Gazetteer Place Names
Authors: Sharma Praval , Samal Ashok , Soh Leen-Kiat , Joshi Deepti
Published: October 2023

Human and natural processes such as navigation and natural calamities are intrinsically linked to the geographic space and described using place names. Extraction and subsequent geocoding of place names from text are critical for understanding the onset, progression, and end of these processes. Geocoding place names extracted from text requires using an external knowledge base such as a gazetteer. However, a standard gazetteer is typically incomplete. Additionally, widely used place name geocoding—also known as toponym resolution—approaches generally focus on geocoding ambiguous but known gazetteer place names. Hence, there is a need for an approach to automatically geocode
non
-gazetteer place names. In this research, we demonstrate that patterns in place names are not spatially random. Places are often named based on people, geography, and history of the area and thus exhibit a degree of similarity. Similarly, places that co-occur in text are likely to be spatially proximate as they provide geographic reference to common events. We propose a novel data-driven spatially-aware algorithm,
Bhugol
, that leverages the spatial patterns and the spatial context of place names to automatically geocode the non-gazetteer place names. The efficacy of Bhugol is demonstrated using two diverse geographic areas – USA and India. The results show that Bhugol outperforms well-known state-of-the-art geocoders.
Explorations and Exploitation for Parity-based RAIDs with Ultra-fast SSDs
Authors: Wang Shucheng , Cao Qiang , Jiang Hong , Lu Ziyi , Yao Jie , Chen Yuxing , Pan Anqun
Published: October 2023

Following a conventional design principle that pays more fast-CPU-cycles for fewer slow-I/Os, popular software storage architecture Linux Multiple-Disk (MD) for parity-based RAID (e.g., RAID5 and RAID6) assigns one or more centralized worker threads to efficiently process all user requests based on multi-stage asynchronous control and global data structures, successfully exploiting characteristics of slow devices, e.g., Hard Disk Drives (HDDs). However, we observe that, with high-performance NVMe-based Solid State Drives (SSDs), even the recently added multi-worker processing mode in MD achieves only limited performance gain because of the severe lock contentions under intensive write workloads.

In this paper, we propose a novel stripe-threaded RAID architecture, StRAID, assigning a dedicated worker thread for each stripe-write (one-for-one model) to sufficiently exploit high parallelism inherent among RAID stripes, multi-core processors, and SSDs. For the notoriously performance-punishing partial-stripe writes that induce extra read and write I/Os, StRAID presents a two-stage stripe write mechanism and a two-dimensional multi-log SSD buffer. All writes first are opportunistically batched in memory, and then are written into the primary RAID for aggregated full-stripe writes or conditionally redirected to the buffer for partial-stripe writes. These buffered data are strategically reclaimed to the primary RAID. We evaluate a StRAID prototype with a variety of benchmarks and real-world traces. StRAID is demonstrated to outperform MD by up to 5.8 times in write throughput.
Automated Test Suite Generation for Software Product Lines Based on Quality-Diversity Optimization
Authors: Xiang Yi , Huang Han , Li Sizhe , Li Miqing , Luo Chuan , Yang Xiaowei
Published: October 2023

A Software Product Line (SPL) is a set of software products that are built from a variability model. Real-world SPLs typically involve a vast number of valid products, making it impossible to individually test each of them. This arises the need for automated test suite generation, which was previously modeled as either a single-objective or a multi-objective optimization problem considering only objective functions. This article provides a completely different mathematical model by exploiting the benefits of Quality-Diversity (QD) optimization that is composed of not only an objective function (e.g.,
t
-wise coverage or test suite diversity) but also a user-defined behavior space (e.g., the space with test suite size as its dimension). We argue that the new model is more suitable and generic than the two alternatives because it provides at a time a large set of diverse (measured in the behavior space) and high-performing solutions that can ease the decision-making process. We apply MAP-Elites, one of the most popular QD algorithms, to solve the model. The results of the evaluation, on both realistic and artificial SPLs, are promising, with MAP-Elites significantly and substantially outperforming both single- and multi-objective approaches, and also several state-of-the-art SPL testing tools. In summary, this article provides a new and promising perspective on the test suite generation for SPLs.
CLFuzz: Vulnerability Detection of Cryptographic Algorithm Implementation via Semantic-aware Fuzzing
Authors: Zhou Yuanhang , Ma Fuchen , Chen Yuanliang , Ren Meng , Jiang Yu
Published: October 2023

Cryptography is a core component of many security applications, and flaws hidden in its implementation will affect the functional integrity or, more severely, pose threats to data security. Hence, guaranteeing the correctness of the implementation is important. However, the semantic characteristics (e.g., diverse input data and complex functional transformation) challenge those traditional program validation techniques (e.g., static analysis and dynamic fuzzing). In this article, we propose CLFuzz, a semantic-aware fuzzer for the vulnerability detection of cryptographic algorithm implementation. CLFuzz first extracts the semantic information of targeted algorithms including their cryptographic-specific constraints and function signatures. Based on them, CLFuzz generates high-quality input data adaptively to trigger error-prone situations efficiently. Furthermore, CLFuzz applies innovative logical cross-check that strengthens the logical bug detection ability. We evaluate CLFuzz on the widely used implementations of 54 cryptographic algorithms. It outperforms state-of-the-art cryptographic fuzzing tools. For example, compared with Cryptofuzz, it achieves a coverage speedup of 3.4× and increases the final coverage by 14.4%. Furthermore, CLFuzz has detected 12 previously unknown implementation bugs in 8 cryptographic algorithms (e.g., CMAC in OpenSSL and Message Digest in SymCrypt), most of which are security-critical and have been successfully collected in the national vulnerability database (7 in NVD/CNVD) and is awarded by the Microsoft bounty program (2 for $1,000).
Quantifying Aging-Induced Irreversible Volume Change of Porous Electrodes
Authors: Garrick Taylor R. , Miao Yong , Macciomei Eric , Fernandez Miguel , Weidner John W.
Published: October 2023

Automotive manufacturers are working to improve cell and pack design by increasing their performance, durability, and range. One of the critical factors to consider as the industry moves towards materials with higher energy density is the ability to consider the irreversible volume change characteristic of the accelerated SEI layer growth tied to the large volume change and particle cracking typically associated with active material strain. As the time from initial design to manufacture of electric vehicle is decreased in order to rapidly respond to consumer demands and widespread adoption of electric vehicles, the ability to link aging and volume change to end of life vehicle requirements using virtual tools is critical. In this study, apply a mechano-electrochemical model to determine the irreversible volume change at the electrode and cell level, allowing for virtual design iterations to predict the volume change at battery cell aged states.
Effect of heat stress on heat shock protein expression and hypertrophy-related signaling in the skeletal muscle of trained individuals
Authors: Fennel Zachary J. , Ducharme Jeremy B. , Berkemeier Quint N. , Specht Jonathan W. , McKenna Zachary J. , Simpson Shandy E. , Nava Roberto C. , Escobar Kurt A. , Hafen Paul S. , Deyhle Michael R. , Amorim Fabiano T. , Mermier Christine M.
Published: October 2023

We show that acute resistance exercise followed by whole body heat stress increases the expression of HSPA and increases activation of the Akt-mTOR cascade in a physically active and resistance-trained population.
An oral glucose tolerance test does not affect cerebral blood flow: role of NOS
Authors: Carter Katrina J. , Ward Aaron T. , Al-Subu Awni , Wilson Allen D. , Zevin Erika L. , Serlin Ronald C. , Eldridge Marlowe , Wieben Oliver , Schrage William G.
Published: October 2023

Animal data indicate that insulin triggers a robust nitric oxide synthase (NOS)-mediated dilation in cerebral arteries similar to the peripheral tissue vasodilation observed in healthy adults. Insulin’s role in regulating cerebral blood flow (CBF) in humans remains unclear but may be important for understanding the links between insulin resistance, diminished CBF, and poor brain health outcomes. We tested the hypothesis that an oral glucose challenge (oral glucose tolerance test, OGTT), which increases systemic insulin and glucose, would acutely increase CBF in healthy adults due to NOS-mediated vasodilation, and that changes in CBF would be greater in anterior regions where NOS expression or activity may be greater. In a randomized, single-blind approach, 18 young healthy adults (24 ± 5 yr) underwent magnetic resonance imaging (MRI) with a placebo before and after an OGTT (75 g glucose), and 11 of these adults also completed an NG-monomethyl-l-arginine (l-NMMA) visit. Four-dimensional (4-D) flow MRI quantified macrovascular CBF and arterial spin labeling (ASL) quantified microvascular perfusion. Subjects completed baseline imaging with a placebo (or l-NMMA), then consumed an OGTT followed by MRI scans and blood sampling every 10–15 min for 90 min. Contrary to our hypothesis, total CBF ( P = 0.17) and global perfusion ( P > 0.05) did not change at any time point up to 60 min after the OGTT, and no regional changes were detected. l-NMMA did not mediate any effect of OGTT on CBF. These data suggest that insulin-glucose challenge does not acutely alter CBF in healthy adults.
Deciphering the Molecular Mechanism of Escin against Neuropathic Pain: A Network Pharmacology Study
Authors: Li Xi , Wu Yating , Wang Haoyan , Li Zaiqi , Ding Xian , Dou Chongyang , Hu Lin , Du Guizhi , Wei Guihua
Published: October 2023

Background. Escin is the main active component in Aesculus hippocastanum. It has been demonstrated that escin has anti‐inflammatory properties. This study combined the methods of network pharmacology, molecular docking, and molecular dynamics to explore the molecular mechanism of escin against neuropathic pain (NP). Methods. The Swiss Target Prediction and the Pharm Mapper database were employed for predicting the targets of escin. Also, the candidate targets of NP were gathered via the databases including Therapeutic Targets, DisGeNet, GeneCards, DrugBank, and OMIM. Subsequently, the network of protein‐protein interaction was screened for the key targets by the software Cytoscape 3.8.0. Then, the intersection of these targets was analysed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment. Additionally, we further investigated the ligand‐target interactions by molecular docking and molecular dynamics simulations. Results. In total, 94 escin targets were predicted by network pharmacology. Among them, SRC, MMP9, PTGS2, and MAPK1 were the core candidate targets. Subsequently, the analysis of GO and KEGG enrichment revealed that escin affected NP by regulating protein kinase C, MAP kinase, TRP channels, the T‐cell receptors signaling pathway, and the TNF signaling pathway. The results of molecular docking and molecular dynamics simulation confirmed that escin not only had a strong binding activity with the four core target proteins but also stably combined in 50 ns. Conclusions. Our study revealed that escin acts on the core targets SRC, MMP9, PTGS2, MAPK1, and associated enrichment pathways to alleviate neuronal inflammation and regulate the immune response, thus exerting anti‐NP efficacy. This study provided innovative ideas and methods for the promising treatment of escin in relieving NP.
Spectral Efficiency Analysis for Uplink Multicell Massive MIMO Cellular Communication System under Fading Channels
Authors: Abebaw Yibeltal , Shakya Rajeev K. , Gelmecha Demissie Jobir , Ware Eshetu Tessema
Published: October 2023

In multicell massive MIMO system, the maximum limit on area throughput can be achieved by improving spectral efficiency and cell density, as well as bandwidth. In order to evaluate the area throughput for such scenarios, the spectral efficiency (SE) that utilizes the linear zero forcing uplink combining scheme, can be modeled under the Rician fading channel and the BS in case of up-links, is responsible to estimate the channel. Different from existing work, the proposed model incorporates various estimators such as minimum mean square error (MMSE), element-wise minimum mean square error estimators under Rician fading. The multicell scenarios with uplink (UL) massive MIMO has been analyzed using the proposed model under different cases such as pilot reuse factor, coherence block length, different number of antennas, and different estimators. The simulation results and analysis are presented based on these parameters. It is found that the average summation of SE per cell can be improved by optimizing MMSE channel estimation using ZF UL combiner, installing multiple BS antennas, serving multiple number of UEs per cell, and using efficient pilot reuse factor. The MMSE and ZF uplink combining are found to be more suitable in improving SE as compared to MMSE-MR. For example, the uplink SE of MMSE channel estimator for pilot reuse factors, 1, 3, and 4, is calculated as 22.5 bit/s/Hz/cell, 22.3 bit/s/Hz/cell, and 21 bit/s/Hz/cell, respectively. The uplink SE for EW-MMSE channel estimator with pilot reuse factors, 1, 3, and 4, is calculated as 22.5 bit/s/Hz/cell, 22 bit/s/Hz/cell, and 22 bit/s/Hz/cell, respectively. For the uplink SE of LS channel estimators, it can be 17.9 bit/s/Hz/cell, 20.2 bit/s/Hz/cell, and 20 bit/s/Hz/cell with pilot reuse factors as f = 1, 3, and 4, respectively. So, for f = 3, the maximum calculated uplink SE for MMSE, EW-MMSE, and LS is 17.6 bit/s/Hz/cell, 17.8 bit/s/Hz/cell, and 13 bit/s/Hz/cell, respectively. It can be concluded that the improved performance is obtained by reducing the pilot contamination at a pilot reuse factor f = 3 with different values of SNR, coherence block length, number of UEs, and number of BS antennas. There is also trade-off between the pilot contamination mitigation and the larger SE. However, there is not much effect on coherence block as when it increases, then the SE increases as well.
A Multistation 3D Point Cloud Automated Global Registration and Accurate Positioning Method for Railway Tunnels
Authors: Wang Jijun , Wei Xiao , Wang Weidong , Wang Jin , Peng Jun , Wang Sicheng , Zaheer Qasim , You Jia , Xiong Jianping , Qiu Shi
Published: October 2023

Terrestrial laser scanning (TLS) technology has the advantages of wide range, high efficiency, and low cost in spatial information collection, so it is widely used in infrastructure monitoring and measurement. During TLS application, the registration and positioning of the point cloud have a direct impact on the quality of the data and the validity of the results. The linear distribution of the tunnel structure and the lack of significant features present challenges in the registration and positioning of 3D point clouds in railway tunnels. The commonly used registration methods are difficult to achieve high registration accuracy and are prone to propagation errors, which reduce the accuracy and effectiveness of results. To achieve accurate registration and positioning of multistation clouds in railway tunnels, we propose a coordinate-based global registration method. To determine the coordinates of scan points in the reference coordinate system and the direction of the reference coordinate system, a few fixed control points are used during the data collection stage. Consequently, each station cloud can be precisely positioned and automatically registered in the reference coordinate system without accumulating or propagating errors. In addition, the coordinate-based registration method eliminates the introduction of errors due to artificial target setting and feature point extraction, as well as the problem of accurately positioning the entire point cloud in the reference coordinate system, thereby enhancing the accuracy, efficiency, and automation levels of cloud registration. The experiment demonstrates that the coordinate-based global registration method is robust and applicable in complex scenes, and it is suitable for the accurate positioning and registration of multistation clouds in linear and curved railway tunnels. The coordinate-based registration method reduces the amount of error in the global registration link by 65% when compared to the point-based registration method, and the point cloud accuracy has reached fine registration, ensuring that fine-grained inverse modeling of the tunnel structure can be performed.
Lung Cancer Classification in Histopathology Images Using Multiresolution Efficient Nets
Authors: Anjum Sunila , Ahmed Imran , Asif Muhammad , Aljuaid Hanan , Alturise Fahad , Ghadi Yazeed Yasin , Elhabob Rashad
Published: October 2023

Histopathological images are very effective for investigating the status of various biological structures and diagnosing diseases like cancer. In addition, digital histopathology increases diagnosis precision and provides better image quality and more detail for the pathologist with multiple viewing options and team annotations. As a result of the benefits above, faster treatment is available, increasing therapy success rates and patient recovery and survival chances. However, the present manual examination of these images is tedious and time‐consuming for pathologists. Therefore, reliable automated techniques are needed to effectively classify normal and malignant cancer images. This paper applied a deep learning approach, namely, EfficientNet and its variants from B0 to B7. We used different image resolutions for each model, from 224 × 224 pixels to 600 × 600 pixels. We also applied transfer learning and parameter tuning techniques to improve the results and overcome the overfitting problem. We collected the dataset from the Lung and Colon Cancer Histopathological Image LC25000 image dataset. The dataset acquisition consists of 25,000 histopathology images of five classes (lung adenocarcinoma, lung squamous cell carcinoma, benign lung tissue, colon adenocarcinoma, and colon benign tissue). Then, we performed preprocessing on the dataset to remove the noisy images and bring them into a standard format. The model’s performance was evaluated in terms of classification accuracy and loss. We have achieved good accuracy results for all variants; however, the results of EfficientNetB2 stand excellent, with an accuracy of 97% for 260 × 260 pixels resolution images.
Evaluation of Efficacy and Safety of Topical Nanoliposomal Amphotericin B 0.4% Gel as a Potential Treatment for Onychomycosis: An Interventional Pilot Clinical Study
Authors: Firooz Alireza , Zamani Shayan , Ghadrei Aliasghar , Ayatollahi Azin , Tamimi Pegah , Khamesipour Ali , Jafari Mahmoodreza , Fattahi Mahsa
Published: October 2023

Onychomycosis is a frequent fungal nail disease that is hard to treat and, in most cases, needs long‐term therapy with oral agents. Traditionally, oral agents are favored over topical agents, but it should not be overlooked that they come with broad adverse effects and concomitant drug interactions, which can be unsuitable for many individuals. Therefore, alternative approaches need to be addressed by the medical team for numerous cases. On the other hand, local administration of antimicrobials can come as advantageous because of having a more selective site of activity, avoiding off‐target systemic adverse effects, and rapid administration at the site of infection. In this study, we are evaluating a new topical delivery method of amphotericin B. To investigate the efficacy and safety of topical nanoliposomal amphotericin B 0.4% as a possible therapeutic option, this pilot, single‐group, before‐after clinical study was conducted on 15 onychomycosis patients. The evaluation was processed during 36 weeks of follow‐up and on three endpoints of week 12, week 24, and week 36, for both clinical and mycological responses. Three patients were excluded; of the remaining 12, 50% showed a complete cure, 16.66% had an effective clinical response, 16.66% had a partial clinical response, and 16.66% showed no response at week 12. Mycological cure was calculated as 50% at week 12. At week 24, our measurements were calculated as 91.66% for complete cure, 8.33% for no response, and 91.66% for mycological cure. One patient reported nail plate detachment at week 2 but continued the topical application; follow‐up between weeks 2 and 24 showed a complete cure and regrowth of healthy nails. No other adverse effects were detected. Overall, our study suggests that topical nanoliposomal amphotericin B 0.4% is an effective treatment, which is accessible, affordable, and user‐friendly, has minimum adverse effects, and could be regarded as an alternative treatment for those ineligible for systemic therapy. This trial is registered with IRCT20150101020514N18.
Incident Cardiovascular Disease Risk among Older Asian, Native Hawaiian and Pacific Islander Breast Cancer Survivors
Authors: Hashibe Mia , Wei Mei , Lee Catherine J. , Tao Randa , Koric Alzina , Wang Jing , Daud Anees , Tay Djin , Shen Jincheng , Lee Yuan-chin A. , Chang Chun-Pin E.
Published: October 2023

Background:

Cardiotoxicity among breast cancer survivors is associated with chemotherapy and radiation therapy. The risk of cardiovascular disease (CVD) among Asian, Native Hawaiian and Pacific Islander (ANHPI) breast cancer survivors in the United States is unknown.

Methods:

We used the SEER-Medicare linked database to estimate the risk of CVD among older breast cancer survivors. International Classification of Disease diagnosis codes were used to identify incident CVD outcomes. Cox proportional hazards models were used to estimate HRs and 95% confidence intervals (CI) comparing ANHPI with Non-Hispanic White (NHW) patients with breast cancer for CVD, and among ANHPI race and ethnicity groups.

Results:

A total of 7,122 ANHPI breast cancer survivors and 21,365 NHW breast cancer survivors were identified. The risks of incident heart failure and ischemic heart disease were lower among ANHPI compared with NHW breast cancer survivors (HRheart failure, 0.72; 95% CI, 0.61–0.84; HRheart disease, 0.74; 95% CI, 0.63–0.88). Compared with Japanese patients with breast cancer, Filipino, Asian Indian and Pakistani, and Native Hawaiian breast cancer survivors had higher risks of heart failure. ischemic heart disease and death. Among ANHPI breast cancer survivors, risk factors for heart failure included older age, higher comorbidity score, distant cancer stage and chemotherapy.

Conclusions:

Our results support heterogeneity in CVD outcomes among breast cancer survivors among ANHPI race and ethnicity groups. Further research is needed to elucidate the disparities experienced among ANHPI breast cancer survivors.

Impact:

Filipino, Asian Indian and Pakistani, and Native Hawaiian patients with breast cancer had higher risks of heart failure, ischemic heart disease and death among ANHPI patients with breast cancer.
Landscape of Clinical Resistance Mechanisms to FGFR Inhibitors in FGFR2-Altered Cholangiocarcinoma
Authors: Wu Qibiao , Ellis Haley , Siravegna Giulia , Michel Alexa G. , Norden Bryanna L. , Fece de la Cruz Ferran , Balasooriya Eranga Roshan , Zhen Yuanli , Silveira Vanessa S. , Che Jianwe , Corcoran Ryan B. , Bardeesy Nabeel
Published: October 2023

Purpose:

FGFR inhibitors are effective in FGFR2-altered cholangiocarcinoma, leading to approval of reversible FGFR inhibitors, pemigatinib and infigratinib, and an irreversible inhibitor, futibatinib. However, acquired resistance develops, limiting clinical benefit. Some mechanisms of resistance have been reported, including secondary FGFR2 kinase domain mutations. Here, we sought to establish the landscape of acquired resistance to FGFR inhibition and to validate findings in model systems.

Experimental Design:

We examined the spectrum of acquired resistance mechanisms detected in circulating tumor DNA or tumor tissue upon disease progression following FGFR inhibitor therapy in 82 FGFR2-altered cholangiocarcinoma patients from 12 published reports. Functional studies of candidate resistance alterations were performed.

Results:

Overall, 49 of 82 patients (60%) had one or more detectable secondary FGFR2 kinase domain mutations upon acquired resistance. N550 molecular brake and V565 gatekeeper mutations were most common, representing 63% and 47% of all FGFR2 kinase domain mutations, respectively. Functional studies showed different inhibitors displayed unique activity profiles against FGFR2 mutations. Interestingly, disruption of the cysteine residue covalently bound by futibatinib (FGFR2 C492) was rare, observed in 1 of 42 patients treated with this drug. FGFR2 C492 mutations were insensitive to inhibition by futibatinib but showed reduced signaling activity, potentially explaining their low frequency.

Conclusions:

These data support secondary FGFR2 kinase domain mutations as the primary mode of acquired resistance to FGFR inhibitors, most commonly N550 and V565 mutations. Thus, development of combination strategies and next-generation FGFR inhibitors targeting the full spectrum of FGFR2 resistance mutations will be critical.
FIGURE 8 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

Combination of d16 and talazoparib treatment inhibits ovarian cancer growth in vivo. MDAH-2774 cells were subcutaneously implanted into the right flank of NSG mice. Xenografts were randomized into four groups: control (Veh), d16 (20 mg/kg, i.p., twice/week), talazoparib (Tala; 0.5 mg/kg, i.p., once daily, 5 days per week), or combination of d16 and talazoparib (n = 3 in Veh group, n = 4 in the other groups) for 5 weeks. A, Final tumor volume. B, Final tumor weight. C, Mouse body weight. D, Representative IHC images of Ki67 and cleaved PARP1 of xenograft tumor tissues. Quantification is shown in bar graphs. Scale bar, 100 µm. Results are presented as mean ± SD. *, P < 0.05; **, P < 0.01 (two-tailed t test).
FIGURE 6 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

DNA2 inhibitor d16 decreases HR repair. A, Quantification of HR activity in HEK293T cells using the TLR assay after treatment with d16 (20 µmol/L). **, P < 0.01 (two-tailed t test). A representative set of flow profiles are shown in Supplementary Fig. S6. B, MDAH-2774 cells were treated with d16, RU or both for 8 hours. After fixation and permeabilization, immunostaining was performed with an anti-RAD51 rabbit antibody, followed by Texas Red X-conjugated anti-rabbit secondary antibody. Nuclei were stained with Hoechst 33258. Pictures shown are representative images at 100X magnification. C, Quantification of RAD51 foci-positive cells. ***, P < 0.001 (two-tailed t test). D, Immunoblotting shows the expression of DNA2, Rad51, γH2AX, or β-actin in the whole-cell lysates. The Ub-γH2AX signals were quantified using NIH ImageJ software.
FIGURE 1 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

DNA2 is upregulated in many types of cancer, which is at least in part mediated by mutant p53. A, Expression of DNA2 is significantly elevated in 14 cancers from TCGA database compared with normal tissues. Tumor samples are denoted with bolded lines. Significance is calculated by Mann–Whitney U test. AC, adenocarcinoma; SC, squamous cell carcinoma; CC, clear cell; CS, carcinosarcoma; EC, endometrial carcinoma. B, Expression of DNA2 in breast invasive carcinoma, lung squamous carcinoma, uterine corpus endometrial carcinoma, and ovarian serous carcinoma from TCGA dataset based on TP53 mutation status. The data from other types of cancer are shown in Supplementary Fig. S1. WT: wild type. C, Depletion of mutp53 decreased DNA2 mRNA expression in MDA-MB-231 and MDA-MB-468 cells. Gene expression data were extracted from GSE26262 (32) and GSE31812 (33), in which gene expression was performed using Affymetrix microarray and normalized using the Robust Multichip Average (RMA) algorithm (34). In MDA-MB-468 cells, the short hairpin RNA (shRNA) against mutp53 was induced by doxycycline (Dox). D, DNA2 mRNA and protein expression in p53-null H1299 cells transfected with either an empty vector, WT p53, or indicated mutp53 (V143A, R175H, R248W, R249S, and R273H). Forty-eight hours after transfection, DNA2 mRNA was measured by qRT-PCR and normalized by GAPDH. *, P < 0.05; **, P < 0.01; and ***, P < 0.001 indicating statistically significant difference (two-tailed t test). Right: p53 and DNA2 immunoblots. The relative intensities of DNA2 protein were quantified by NIH ImageJ software, and normalized by loading control GAPDH. E, Depletion of mutant p53 decreases DNA2 protein levels. MDA-MB-468, MDAH-2774 or BT549 cells stably expressing either a scrambled shRNA or a mutp53 shRNA were harvested and the total cell lysates were subjected to immunoblotting using antibodies specific to DNA2, p53 or GAPDH. The relative intensities of DNA2 were quantified by NIH ImageJ software, and normalized by loading control GAPDH. The right panel shows the fold difference of DNA2 protein in MDA-MB-468 (n = 3 biological replicates), MDAH-2774 (n = 4 biological replicates), or BT549 (n = 2 biological replicates) stably expressing a scrambled shRNA versus a mutp53 shRNA. F, Box plots of DNA2 mRNA expression in chemotherapy responder or nonresponder patients (defined by relapse-free survival at 6 months) of serous ovarian cancer. Data were analyzed from TCGA dataset using ROC plotter platform. Left: all chemotherapy; middle: platin; right: taxane.
Mood Impairment in Patients with Olfactory Loss Predicts a More Pronounced Recovery of Olfactory Function
Authors: Sabiniewicz Agnieszka , Hummel Thomas
Published: October 2023

Background: Here, we refer to our publication “Symptoms of depression change with olfactory function” [Sci Rep. 2022 Apr 5;12(1):5656]. Objectives: Depression decreases with olfactory improvement, but the question remains open of whether patients who indicate more suffering regarding mood impairment exhibit a different pattern of recovery from olfactory loss compared to those who suffer less. Method: In the course of an additional investigation of our previously published dataset, we established groups of participants (N = 171) with low (≤8 points on a depression [ADSL] scale; 47%; n = 45) and high (≥14 points on ADSL scale; 53%; n = 53) mood impairment. Results: We found that the group that reported more sufferance on a depression [ADSL] scale improved more in change of olfactory function, and, more importantly, odor discrimination change over a period of an average of 11 months. Conclusion: Patients, who suffered more, as indicated by higher scores on ADSL scale, may have been more willing to commit to the study protocol, and thus their improvement was more notable.
A Novel Partial Deletion of the TBL1XR1 Gene Detected Using SNP Array in a Patient with Motor Delay, Growth Failure, and Klinefelter Syndrome
Authors: García-Payá Elena , Sirera Sirera Paula , Huertas-García Isabel , Hernández Romero Sofía Daniela , Olivas García Julia
Published: October 2023

Introduction: Co-existence pathogenic copy number variation with aneuploidy is a rare phenomenon. Whole TBL1XR1 gene deletions are described and associated with autosomal dominant intellectual development disorder-41 (#616944). However, the phenotypical expression of the TBL1XR1 partial deletion is poorly described. Case Presentation: We describe the case of a male, aged 18 months, who presented delayed motor development, gait disturbance, mild generalized hypotonia, minor dysmorphic features, and growth failure, in addition to Klinefelter syndrome (KS). The single nucleotide polymorphism array revealed the de novo pathogenic interstitial deletion of chromosome 3q26.32 of 202 kb size that encompassed the first two exons of one relevant coding gene: TBL1XR1 (*608,628). Conclusion: We report a male without clinical signs of KS and overlapped phenotypical features with another TBL1XR1-related disease: Pierpont syndrome (#602342). This patient extends the phenotypic spectrum of TBL1XR1 gene pathogenic variants.
AN ECONOMETRIC ANALYSIS ON THE DETERMINANTS OF ENERGY CONSUMPTION IN TURKEY
Authors: DEMİRTAŞ Işıl , BAŞ Burak
Published: October 2023

Turkey has experienced rapid population growth, rapid urbanization and industrialization in recent years. Therefore, Turkey's demand for energy has been increasing over the years. Also the main issue is Turkey's foreign dependency on energy resources. Researching the determinants of energy consumption is important in terms of developing policies for more efficient use of energy. For this reason, the determinants of energy consumption in Turkey were analyzed using the ARDL Boundary Test and the Toda-Yamamoto causality test, based on data from 1980-2020. While fossil fuel energy consumption as the dependent variable in the model, GDP, export rate and the ratio of fixed capital investments to GDP are independent variables. As a result of the analysis, it was determined that there is a longrun relationship between the variables. An increase in economic growth by 1 percent, increases energy consumption by 0.34%. An increase in exports by 1 percent increases energy consumption by 0.57% in the long run while an increase in fixed capital investments by 1 percent, increases energy consumption by 0.15%. As a result of the causality analysis, it was concluded that there is one-way causality from GDP growth to energy consumption. It has been determined that there is a one-way causality running from fixed capital investments and exports to energy consumption.
Diversified ESG Evaluation by Rating Agencies and Net Carbon Tax to Regain Optimal Portfolio Allocation
Authors: Yoshino Naoyuki , Yuyama Tomonori , Taghizadeh-Hesary Farhad
Published: October 2023

Environmental, Society, and Governance (ESG) investments have become increasingly popular in recent years, and, at the same time, many rating agencies provide ESG scores for each company. This means that the ESG investment model may have moved from the traditional two-factor model of risk-return to a three-factor model adding an ESG component to it. This paper highlights the potential for distortion of asset allocation through the shift from traditional risk-return considerations to ESG score considerations. This is equally true for green bonds, resulting in the potential for asset allocation to be distorted by green bond criteria. Furthermore, we show that imposing a net carbon tax on greenhouse gas (GHG) emissions is a measure to correct this distortion in asset allocation and make asset allocation more risk-return based, in addressing global environmental issues.
Adaptive Filter Model of Cerebellum for Biological Muscle Control With Spike Train Inputs
Authors: Wilson Emma
Published: October 2023

Prior applications of the cerebellar adaptive filter model have included a range of tasks within simulated and robotic systems. However, this has been limited to systems driven by continuous signals. Here, the adaptive filter model of the cerebellum is applied to the control of a system driven by spiking inputs by considering the problem of controlling muscle force. The performance of the standard adaptive filter algorithm is compared with the algorithm with a modified learning rule that minimizes inputs and a simple proportional-integral-derivative (PID) controller. Control performance is evaluated in terms of the number of spikes, the accuracy of spike input locations, and the accuracy of muscle force output. Results show that the cerebellar adaptive filter model can be applied without change to the control of systems driven by spiking inputs. The cerebellar algorithm results in good agreement between input spikes and force outputs and significantly improves on a PID controller. Input minimization can be used to reduce the number of spike inputs, but at the expense of a decrease in accuracy of spike input location and force output. This work extends the applications of the cerebellar algorithm and demonstrates the potential of the adaptive filter model to be used to improve functional electrical stimulation muscle control.