bluuebunny/crossref_metadata_2025 huggingface dataset:
State Reconciliation Defects in Infrastructure as Code
Authors: Hassan Md Mahadi , Salvador John , Santu Shubhra Kanti Karmaker , Rahman Akond
Published: July 2024

In infrastructure as code (IaC), state reconciliation is the process of querying and comparing the infrastructure state prior to changing the infrastructure. As state reconciliation is pivotal to manage IaC-based computing infrastructure at scale, defects related to state reconciliation can create large-scale consequences. A categorization of state reconciliation defects, i.e., defects related to state reconciliation, can aid in understanding the nature of state reconciliation defects. We conduct an empirical study with 5,110 state reconciliation defects where we apply qualitative analysis to categorize state reconciliation defects. From the identified defect categories, we derive heuristics to design prompts for a large language model (LLM), which in turn are used for validation of state reconciliation.

From our empirical study, we identify 8 categories of state reconciliation defects, amongst which 3 have not been reported for previously-studied software systems. The most frequently occurring defect category is inventory, i.e., the category of defects that occur when managing infrastructure inventory. Using an LLM with heuristics-based paragraph style prompts, we identify 9 previously unknown state reconciliation defects of which 7 have been accepted as valid defects, and 4 have already been fixed. Based on our findings, we conclude the paper by providing a set of recommendations for researchers and practitioners.
Can Large Language Models Transform Natural Language Intent into Formal Method Postconditions?
Authors: Endres Madeline , Fakhoury Sarah , Chakraborty Saikat , Lahiri Shuvendu K.
Published: July 2024

Informal natural language that describes code functionality, such as code comments or function documentation, may contain substantial information about a program’s intent. However, there is typically no guarantee that a program’s implementation and natural language documentation are aligned. In the case of a conflict, leveraging information in code-adjacent natural language has the potential to enhance fault localization, debugging, and code trustworthiness. In practice, however, this information is often underutilized due to the inherent ambiguity of natural language, which makes natural language intent challenging to check programmatically. The “emergent abilities” of Large Language Models (LLMs) have the potential to facilitate the translation of natural language intent to programmatically checkable assertions. However, it is unclear if LLMs can correctly translate informal natural language specifications into formal specifications that match programmer intent. Additionally, it is unclear if such translation could be useful in practice. In this paper, we describe nl2postcondition, the problem of leveraging LLMs for transforming informal natural language to formal method postconditions, expressed as program assertions. We introduce and validate metrics to measure and compare different nl2postcondition approaches, using the correctness and discriminative power of generated postconditions. We then use qualitative and quantitative methods to assess the quality of nl2postcondition postconditions, finding that they are generally correct and able to discriminate incorrect code. Finally, we find that via LLMs has the potential to be helpful in practice; generated postconditions were able to catch 64 real-world historical bugs from Defects4J.
A Transferability Study of Interpolation-Based Hardware Model Checking for Software Verification
Authors: Beyer Dirk , Chien Po-Chun , Jankola Marek , Lee Nian-Ze
Published: July 2024

Assuring the correctness of computing systems is fundamental to our society and economy,

and
formal verification
is a class of techniques approaching this issue with mathematical rigor.

Researchers have invented numerous algorithms to automatically prove

whether a computational model, e.g., a software program or a hardware digital circuit,

satisfies its specification.

In the past two decades,
Craig interpolation
has been widely used in both hardware and software verification.

Despite the similarities in the theoretical foundation between hardware and software verification,

previous works usually evaluate interpolation-based algorithms

on only one type of verification tasks (e.g., either circuits or programs),

so the conclusions of these studies do not necessarily transfer to different types of verification tasks.

To investigate the transferability of research conclusions from hardware to software,

we adopt two performant approaches of interpolation-based hardware model checking,

(1)
Interpolation-Sequence-Based Model Checking
(Vizel and Grumberg, 2009) and

(2)
Intertwined Forward-Backward Reachability Analysis Using Interpolants
(Vizel, Grumberg, and Shoham, 2013),

for software verification.

We implement the algorithms proposed by the two publications in the software verifier CPAchecker

because it has a software-verification adoption

of the first interpolation-based algorithm for hardware model checking from 2003,

which the two publications use as a comparison baseline.

To assess whether the claims in the two publications transfer to software verification,

we conduct an extensive experiment on the largest publicly available suite

of safety-verification tasks for the programming language C.

Our experimental results show that

the important characteristics of the two approaches for hardware model checking

are transferable to software verification,

and that the cross-disciplinary algorithm adoption is beneficial,

as the approaches adopted from hardware model checking were able to tackle tasks unsolvable by existing methods.

This work consolidates the knowledge in hardware and software verification and

provides open-source implementations to improve the understanding of the compared interpolation-based algorithms.
Glitch Tokens in Large Language Models: Categorization Taxonomy and Effective Detection
Authors: Li Yuxi , Liu Yi , Deng Gelei , Zhang Ying , Song Wenjia , Shi Ling , Wang Kailong , Li Yuekang , Liu Yang , Wang Haoyu
Published: July 2024

With the expanding application of Large Language Models (LLMs) in various domains, it becomes imperative to comprehensively investigate their unforeseen behaviors and consequent outcomes. In this study, we introduce and systematically explore the phenomenon of “glitch tokens”, which are anomalous tokens produced by established tokenizers and could potentially compromise the models’ quality of response. Specifically, we experiment on seven top popular LLMs utilizing three distinct tokenizers and involving a totally of 182,517 tokens. We present categorizations of the identified glitch tokens and symptoms exhibited by LLMs when interacting with glitch tokens. Based on our observation that glitch tokens tend to cluster in the embedding space, we propose GlitchHunter, a novel iterative clustering-based technique, for efficient glitch token detection. The evaluation shows that our approach notably outperforms three baseline methods on eight open-source LLMs. To the best of our knowledge, we present the first comprehensive study on glitch tokens. Our new detection further provides valuable insights into mitigating tokenization-related errors in LLMs.
Analyzing Quantum Programs with LintQ: A Static Analysis Framework for Qiskit
Authors: Paltenghi Matteo , Pradel Michael
Published: July 2024

As quantum computing is rising in popularity, the amount of quantum programs and the number of developers writing them are increasing rapidly. Unfortunately, writing correct quantum programs is challenging due to various subtle rules developers need to be aware of. Empirical studies show that 40–82% of all bugs in quantum software are specific to the quantum domain. Yet, existing static bug detection frameworks are mostly unaware of quantum-specific concepts, such as circuits, gates, and qubits, and hence miss many bugs. This paper presents LintQ, a comprehensive static analysis framework for detecting bugs in quantum programs. Our approach is enabled by a set of abstractions designed to reason about common concepts in quantum computing without referring to the details of the underlying quantum computing platform. Built on top of these abstractions, LintQ offers an extensible set of ten analyses that detect likely bugs, such as operating on corrupted quantum states, redundant measurements, and incorrect compositions of sub-circuits. We apply the approach to a newly collected dataset of 7,568 real-world Qiskit-based quantum programs, showing that LintQ effectively identifies various programming problems, with a precision of 91.0% in its default configuration with the six best performing analyses. Comparing to a general-purpose linter and two existing quantum-aware techniques shows that almost all problems (92.1%) found by LintQ during our evaluation are missed by prior work. LintQ hence takes an important step toward reliable software in the growing field of quantum computing.
Revealing Software Development Work Patterns with PR-Issue Graph Topologies
Authors: de Souza Cleidson R. B. , Ma Emilie , Wong Jesse , Yoon Dongwook , Beschastnikh Ivan
Published: July 2024

How software developers work and collaborate, and how we can best support them is an important topic for software engineering research. One issue for developers is a limited understanding of work that has been done and is ongoing. Modern systems allow developers to create Issues and pull requests (PRs) to track and structure work. However, developers lack a coherent view that brings together related Issues and PRs.

In this paper, we first report on a study of work practices of developers through Issues, PRs, and the links that connect them. Specifically, we mine graphs where the Issues and PRs are nodes, and references (links) between them are the edges. This graph-based approach provides a window into a set of collaborative software engineering practices that have not been previously described. Based on a qualitative analysis of 56 GitHub projects, we report on eight types of work practices alongside their respective PR/Issue topologies.

Next, inspired by our findings, we developed a tool called WorkflowsExplorer to help developers visualize and study workflow types in their own projects. We evaluated WorkflowsExplorer with 6 developers and report on findings from our interviews.

Overall, our work illustrates the value of embracing a topology-focused perspective to investigate collaborative work practices in software development.
DAInfer: Inferring API Aliasing Specifications from Library Documentation via Neurosymbolic Optimization
Authors: Wang Chengpeng , Zhang Jipeng , Wu Rongxin , Zhang Charles
Published: July 2024

Modern software systems heavily rely on various libraries, necessitating understanding API semantics in static analysis. However, summarizing API semantics remains challenging due to complex implementations or the unavailability of library code. This paper presents DAInfer, a novel approach for inferring API aliasing specifications from library documentation. Specifically, we employ Natural Language Processing (NLP) models to interpret informal semantic information provided by the documentation, which enables us to reduce the specification inference to an optimization problem. Furthermore, we propose a new technique called neurosymbolic optimization to efficiently solve the optimization problem, yielding the desired API aliasing specifications. We have implemented DAInfer as a tool and evaluated it upon Java classes from several popular libraries. The results indicate that DAInfer infers the API aliasing specifications with a precision of 79.78% and a recall of 82.29%, averagely consuming 5.35 seconds per class. These obtained aliasing specifications further facilitate alias analysis, revealing 80.05% more alias facts for API return values in 15 Java projects. Additionally, the tool supports taint analysis, identifying 85 more taint flows in 23 Android apps. These results demonstrate the practical value of DAInfer in library-aware static analysis.
MTAS: A Reference-Free Approach for Evaluating Abstractive Summarization Systems
Authors: Zhu Xiaoyan , Jiang Mingyue , Zhang Xiao-Yi , Nie Liming , Ding Zuohua
Published: July 2024

Abstractive summarization (AS) systems, which aim to generate a text for summarizing crucial information of the original document, have been widely adopted in recent years. Unfortunately, factually unreliable summaries may still occur, leading to unexpected misunderstanding and distortion of information. This calls for methods that can properly evaluate the quality of AS systems. Yet, the existing reference-based evaluation approach for AS relies on reference summaries as well as automatic evaluation metrics (e.g., ROUGE). Therefore, the reference-based evaluation approach is highly restricted by the availability and quality of reference summaries as well as the capability of existing automatic evaluation metrics. In this study, we propose MTAS, a novel metamorphic testing based approach for evaluating AS in a reference-free way. Our two major contributions are (i) five metamorphic relations towards AS, which involve semantic-preserving and focus-preserving transformations at the document level, and (ii) a summary consistency evaluation metric SCY, which measures the alignment between a pair of summaries by incorporating both the semantic and factual consistency. Our experimental results show that the proposed metric SCY has a significantly higher correlation with human judgment as compared to a set of existing metrics. It is also demonstrated that MTAS can break the dependence on reference summaries, and it successfully reports a large number of summary inconsistencies, revealing various summarization issues on state-of-the-art AS systems.
CrossCert: A Cross-Checking Detection Approach to Patch Robustness Certification for Deep Learning Models
Authors: Zhou Qilin , Wei Zhengyuan , Wang Haipeng , Jiang Bo , Chan Wing-Kwong
Published: July 2024

Patch robustness certification is an emerging kind of defense technique against adversarial patch attacks with provable guarantees. There are two research lines: certified recovery and certified detection. They aim to correctly label malicious samples with provable guarantees and issue warnings for malicious samples predicted to non-benign labels with provable guarantees, respectively. However, existing certified detection defenders suffer from protecting labels subject to manipulation, and existing certified recovery defenders cannot systematically warn samples about their labels. A certified defense that simultaneously offers robust labels and systematic warning protection against patch attacks is desirable. This paper proposes a novel certified defense technique called CrossCert. CrossCert formulates a novel approach by cross-checking two certified recovery defenders to provide unwavering certification and detection certification. Unwavering certification ensures that a certified sample, when subjected to a patched perturbation, will always be returned with a benign label without triggering any warnings with a provable guarantee. To our knowledge, CrossCert is the first certified detection technique to offer this guarantee. Our experiments show that, with a slightly lower performance than ViP and comparable performance with PatchCensor in terms of detection certification, CrossCert certifies a significant proportion of samples with the guarantee of unwavering certification.
A Survey on Convolutional Neural Networks and Their Performance Limitations in Image Recognition Tasks
Authors: Rangel Gabriela , Cuevas-Tello Juan C. , Nunez-Varela Jose , Puente Cesar , Silva-Trujillo Alejandra G.
Published: July 2024

Convolutional neural networks (CNNs) have shown outstanding image classification performance, having been successfully applied in several real‐world applications. However, there are performance limitations encountered in CNNs and few works have pointed out these limitations across the literature. Therefore, this survey aims to provide a comprehensive explanation of both the importance and performance limitations of CNNs on image classification tasks. In this paper, we start with a brief CNN background and follow the main CNN architectures along with their contributions and benchmark datasets. We propose a classification of the CNNs performance limitations, which are grouped into four categories: labeled datasets, translation invariance, adversarial attacks, and spatial relationship. In addition, we describe some approaches that are currently being developed to overcome these performance limitations. Finally, we introduce specific ongoing research to address these performance limitations through capsule networks (CapsNets) and CNNs combined with CapsNets.
Factors Associated with Multiple Sexual Partnerships among Young Women in Southern African Countries: A Pooled Multilevel Analysis
Authors: Mbele Stephina Kgomotso
Published: July 2024

Background. Multiple sexual partnerships are one of the sexual behaviors that predispose young women to different negative outcomes, including sexually transmitted infections (STIs). This study aimed to examine the factors associated with multiple sexual partnerships among young women in selected Southern African countries. Materials and Methods. This study used cross‐sectional secondary data from the Demographic and Health Surveys of six countries in southern Africa (Lesotho, Namibia, Malawi, South Africa, Zambia, and Zimbabwe). The data were collected using probability sampling (with a stratified two‐stage cluster design) and structured questionnaires. This study used a weighted sample of 29,348 young women aged 15–24 years. The study included univariate, bivariate, and multilevel logistic regression (MLR) analysis. Moreover, a two‐level model was used to measure the relationship between the selected explanatory factors and multiple sexual partnerships. Results. The overall prevalence of multiple sexual partnerships was 2.2% for the selected countries, and it differed by country. The factors associated with multiple sexual partnerships were age, marital status, educational level, employment status, having an STI, non‐condom use, age at first sex, sex of the household head, and type of residence. The findings showed some variation in multiple sexual partnerships across communities. The findings from the MLR revealed that multiple sexual partnerships were high among women who were never married, no longer married, women with lower levels of education, and women who were employed. Moreover, higher odds of multiple sexual partnerships were found among women who had an STI, women from rich households, and women residing in Lesotho and South Africa. Conclusion. The study revealed that young women’s multiple sexual partnerships in Southern Africa are influenced by various sociodemographic factors. The study’s findings suggest a need for educational programs that focus on sexual health and economic empowerment, especially among unmarried and less educated women, thus reducing the associated risks and enhancing wellbeing.
Analysis of Enterprise Financial Risk Early Warning Model Based on the Evidence Theory and Whitening Weight Function
Authors: Zhang Tianjiao , Chen Qiangxing , Zhu Xiaolong
Published: July 2024

Enterprise financial risk refers to the uncertainty of financial status caused by various internal and external factors during investment, financing, operations, and other activities, which may result in losses for the enterprise. Agricultural group enterprises engage in diversified businesses and have a large number of transactions. Characteristics such as natural disasters, financing difficulties, and strong seasonality of income and expenditure make agricultural enterprises face greater financial risks. Based on the perspective of evidence fusion, this paper takes the JS Agricultural Reclamation Group as the research object, puts forward a financial risk early warning model based on evidence theory, and innovatively puts forward the basic probability assignment of evidence obtained by whitening weight function, and uses evidence theory to fuse uncertain risk information. This paper makes an empirical study of 420 subsidiaries of the group and selects 10 subsidiaries as case study objects. The results show that the model proposed in this study can improve the prediction accuracy of the group’s intelligent financial decision system and the existing literature and reduce the subjective factors and information loss in the risk assessment process. In addition, this study provides the probability interval of early warning results, which can expose small probability risks and provide a more reliable basis for regulators, enterprise managers, and investors to make efficient and correct decisions.
Prevalence of Human Intestinal Parasitic Infections and Associated Risk Factors among School Children in Hakim District, Harari Regional State, Eastern Ethiopia
Authors: Mekonnen Eshetu , Sadik Nuredin
Published: July 2024

Background. The goal of this study was to determine the prevalence of intestinal parasitic infections and associated risk factors in the Hakim district of Harari Regional state, Eastern Ethiopia. This region is known for its high incidence of intestinal parasitic infections among socioeconomically disadvantaged communities in the tropics and subtropics. Materials and Methods. A cross‐sectional study was carried out in a school setting from September 2021 to May 2022. The study involved 333 participants, including 158 males and 175 females, who were selected using a stratified systematic random sampling method. The stool samples were analyzed using both direct wet mount and formal ether concentration techniques, which were examined microscopically. A structured questionnaire was used to gather information on potential risk factors, and the data were analyzed using SPSS version 20. The P‐value < 0.05 was considered statistically significant. Results. Out of 333 students screened, 96 (28.8%) tested positive for one or more intestinal parasites. The highest infection rate was recorded for G. lamblia at 28 (8.8%), followed by E. histolytica at 27 (8.1%). The overall prevalence of parasitic infections was 55 (16.5%). The lowest helminth infection rates were found for A. lumbricoides at 13 (3.9%), hookworm at 11 (3.3%), and T. trichiura at 10 (3%). The most significant risk factors associated with a high risk of Intestinal Parasitic Infections (IPIs) were sex, family size, latrine availability, defecation habit, frequency of hand washing, regular latrine cleaning habit, water source, and knowledge (P  < 0.05). However, there was no correlation between IPI prevalence and age, latrine type, or hand washing facility. Conclusion. Based on the research, it was found that IPIs are commonly seen among elementary school children in the Hakim district. To address this issue, it is recommended that the study area implement intensive healthcare interventions, trainings, and mass treatments for the treatment of IPIs.
Supplementary Figure S5 from BRD9 Degradation Disrupts Ribosome Biogenesis in Multiple Myeloma
Authors: Kurata Keiji , Samur Mehmet K. , Liow Priscilla , Wen Kenneth , Yamamoto Leona , Liu Jiye , Morelli Eugenio , Gulla Annamaria , Tai Yu-Tzu , Qi Jun , Hideshima Teru , Anderson Kenneth C.
Published: July 2024

BRD9 co-localized with BRD4 and MYC in ribosome biogenesis gene transcription start sites (TSS).
Supplementary Figure S4 from BRD9 Degradation Disrupts Ribosome Biogenesis in Multiple Myeloma
Authors: Kurata Keiji , Samur Mehmet K. , Liow Priscilla , Wen Kenneth , Yamamoto Leona , Liu Jiye , Morelli Eugenio , Gulla Annamaria , Tai Yu-Tzu , Qi Jun , Hideshima Teru , Anderson Kenneth C.
Published: July 2024

BRD9 occupies promoter regions of target gene.
Supplementary Data S1 from BRD9 Degradation Disrupts Ribosome Biogenesis in Multiple Myeloma
Authors: Kurata Keiji , Samur Mehmet K. , Liow Priscilla , Wen Kenneth , Yamamoto Leona , Liu Jiye , Morelli Eugenio , Gulla Annamaria , Tai Yu-Tzu , Qi Jun , Hideshima Teru , Anderson Kenneth C.
Published: July 2024

Correlations of dBRD9-A susceptibility
Supplementary Figure S4 from Race-Related Differences in Sipuleucel-T Response among Men with Metastatic Castrate–Resistant Prostate Cancer
Authors: Heath Elisabeth I. , Thakur Archana , Chen Wei , Hwang Clara , Paller Channing J. , Cackowski Frank C. , Boerner Julie L. , Heilbrun Lance , Smith Melanie P. , Schalk Dana L. , Schienschang Amy , Whitaker Sarah A. , Polend Amanda , Smith Daryn , Vaishampayan Ulka N. , Dickow Brenda , Lum Lawrence G.
Published: July 2024

Overall survival post-sipuleucel-T by race.
p53R172H and p53R245W Hotspot Mutations Drive Distinct Transcriptomes in Mouse Mammary Tumors Through a Convergent Transcriptional Mediator
Authors: McDaniel Joy M. , Morrissey Rhiannon L. , Dibra Denada , Patel Lalit R. , Xiong Shunbin , Zhang Yun , Chau Gilda P. , Su Xiaoping , Qi Yuan , El-Naggar Adel K. , Lozano Guillermina
Published: July 2024

Aggressive breast cancers harbor TP53 missense mutations. Tumor cells with TP53 missense mutations exhibit enhanced growth and survival through transcriptional rewiring. To delineate how TP53 mutations in breast cancer contribute to tumorigenesis and progression in vivo, we created a somatic mouse model driven by mammary epithelial cell-specific expression of Trp53 mutations. Mice developed primary mammary tumors reflecting the human molecular subtypes of luminal A, luminal B, HER2-enriched, and triple-negative breast cancer with metastases. Transcriptomic analyses comparing MaPR172H/− or MaPR245W/− mammary tumors to MaP−/− tumors revealed (1) differences in cancer-associated pathways activated in both p53 mutants and (2) Nr5a2 as a novel transcriptional mediator of distinct pathways in p53 mutants. Meta-analyses of human breast tumors corroborated these results. In vitro assays demonstrate mutant p53 upregulates specific target genes that are enriched for Nr5a2 response elements in their promoters. Co-immunoprecipitation studies revealed p53R172H and p53R245W interact with Nr5a2. These findings implicate NR5A2 as a novel mediator of mutant p53 transcriptional activity in breast cancer.

Significance:

Our findings implicate NR5A2 as a novel mediator of mutant p53 transcriptional activity in breast cancer. NR5A2 may be an important therapeutic target in hard-to-treat breast cancers such as endocrine-resistant tumors and metastatic triple-negative breast cancers harboring TP53 missense mutations.
Basic Calculus
Authors: CATOLOS ELVIRA C , DEJARLO JENISUS O
Published: July 2024

"This worktext on Basic Calculus is designed particularly for senior high school students under the K – 12 Basic Education Curriculum. The contents are parallel to the learning competency as indicated in the curriculum guide for Basic Calculus. It also aims to prepare them for higher education which is one of the thrusts of the K – 12 Basic Education Curriculum. In every chapter , there is the introduction of mathematical concepts and followed by several illustrative examples. This provides the students better understanding and appreciation of the lessons. Sufficient exercises for home studies are provided in each chapter to further strengthen and test the students’ understanding of the topics. Hence, students are given the opportunity to assess their understanding of the concepts."
The OHStat Guidelines for Reporting Observational Studies and Clinical Trials in Oral Health Research: Manuscript Checklist
Authors: Best A.M. , Lang T.A. , Greenberg B.L. , Gunsolley J.C. , Ioannidou E. ,   Task Force on Design and Analysis in Oral Health Research
Published: July 2024

Adequate and transparent reporting is necessary for critically appraising published research. Yet, ample evidence suggests that the design, conduct, analysis, interpretation, and reporting of oral health research could be greatly improved. Accordingly, the Task Force on Design and Analysis in Oral Health Research—statisticians and trialists from academia and industry—identified the minimum information needed to report and evaluate observational studies and clinical trials in oral health: the OHStat Guidelines. Drafts were circulated to the editors of 85 oral health journals and to Task Force members and sponsors and discussed at a December 2020 workshop attended by 49 researchers. The guidelines were subsequently revised by the Task Force’s writing group. The guidelines draw heavily from the Consolidated Standards for Reporting Trials (CONSORT), Strengthening the Reporting of Observational Studies in Epidemiology (STROBE), and CONSORT harms guidelines and incorporate the SAMPL guidelines for reporting statistics, the CLIP principles for documenting images, and the GRADE indicating the quality of evidence. The guidelines also recommend reporting estimates in clinically meaningful units using confidence intervals, rather than relying on P values. In addition, OHStat introduces 7 new guidelines that concern the text itself, such as checking the congruence between abstract and text, structuring the discussion, and listing conclusions to make them more specific. OHStat does not replace other reporting guidelines; it incorporates those most relevant to dental research into a single document. Manuscripts using the OHStat guidelines will provide more information specific to oral health research.
Blood coagulation factor IX: structural insights impacting hemophilia B therapy
Authors: Bos Mettine H. A. , van Diest Rianne E. , Monroe Dougald M.
Published: July 2024

Coagulation factor IX plays a central role in hemostasis through interaction with factor VIIIa to form a factor X–activating complex at the site of injury. The absence of factor IX activity results in the bleeding disorder hemophilia B. This absence of activity can arise either from a lack of circulating factor IX protein or mutations that decrease the activity of factor IX. This review focuses on analyzing the structure of factor IX with respect to molecular mechanisms that are at the basis of factor IX function. The proteolytic activation of factor IX to form activated factor IX(a) and subsequent structural rearrangements are insufficient to generate the fully active factor IXa. Multiple specific interactions between factor IXa, the cofactor VIIIa, and the physiological substrate factor X further alter the factor IXa structure to achieve the full enzymatic activity of factor IXa. Factor IXa also interacts with inhibitors, extravascular proteins, and cellular receptors that clear factor IX(a) from the circulation. Hemophilia B is treated by replacement of the missing factor IX by plasma-derived protein, a recombinant bioequivalent, or via gene therapy. An understanding of how the function of factor IX is tied to structure leads to modified forms of factor IX that have increased residence time in circulation, higher functional activity, protection from inhibition, and even activity in the absence of factor VIIIa. These modified forms of factor IX have the potential to significantly improve therapy for patients with hemophilia B.
Differential inflammatory conditioning of the bone marrow by acute myeloid leukemia and its impact on progression
Authors: Minciacchi Valentina R. , Karantanou Christina , Bravo Jimena , Pereira Raquel S. , Zanetti Costanza , Krack Theresa , Kumar Rahul , Bankov Katrin , Hartmann Sylvia , Huntly Brian J. P. , Meduri Eshwar , Ruf Wolfram , Krause Daniela S.
Published: July 2024

Inflammation promotes solid tumor progression, but how regulatory mechanisms of inflammation may affect leukemia is less well studied. Using annexin A5 (ANXA5), a calcium-binding protein known for apoptosis, which we discovered to be differentially expressed in the bone marrow microenvironment (BMM) of mice with acute myeloid (AML) vs chronic myeloid leukemia, as a model system, we unravel here a circuit in which AML–derived tumor necrosis factor α (TNF-α) dose-dependently reduces ANXA5 in the BMM. This creates an inflammatory BMM via elevated levels of prostaglandin E2 (PGE2). Via binding to its EP4 receptor, PGE2 increases β-catenin and hypoxia-inducible factor 1α signaling in AML cells, thereby accelerating PGE2-sensitive AML. Human trephine biopsies may show lower ANXA5 expression and higher PGE2 expression in AML than other hematologic malignancies. Furthermore, syngeneic and xenogeneic transplantation models suggest a survival benefit after treatment with the inhibitor of prostaglandin-endoperoxide synthase 2 (cyclooxygenase 2 [COX2]), celecoxib, plus cytarabine in those AML types highly sensitive to PGE2 compared with cytarabine alone. Taken together, TNF-α/ANXA5/NF-κB/COX2/PGE2–mediated inflammation influences AML course in a highly differential and circular manner, and patients with AML with “inflammatory AML” may benefit from antiphlogistic agents as adjunct therapy.
Extrachromosomal circular DNA promotes prostate cancer progression through the FAM84B/CDKN1B/MYC/WWP1 axis
Authors: Jin Wei , Xu Zhenqun , Song Yan , Chen Fangjie
Published: July 2024

Background

Extrachromosomal circular DNA (eccDNA), a kind of circular DNA that originates from chromosomes, carries complete gene information, particularly the oncogenic genes. This study aimed to examine the contributions of FAM84B induced by eccDNA to prostate cancer (PCa) development and the biomolecules involved.

Methods

The presence of eccDNA in PCa cells and the FAM84B transcripts that eccDNA carries were verified by outward and inward PCR. The effect of inhibition of eccDNA synthesis on FAM84B expression in PCa cells was analyzed by knocking down Lig3. The impact of FAM84B on the growth and metastases of PCa cells was verified by Cell Counting Kit-8 (CCK8), EdU, transwell assays, and a xenograft mouse model. Chromatin immunoprecipitation quantitative PCR (ChIP-qPCR) and dual-luciferase reporter assays were carried out to examine the effect of FAM84B/MYC on WWP1 transcription, and a co-immunoprecipitation (Co-IP) assay was conducted to verify the modification of CDKN1B by WWP1. The function of this molecular axis in PCa was explored by rescue assays.

Results

The inhibited eccDNA synthesis significantly downregulated FAM84B in PCa cells, thereby attenuating the growth and metastasis of PCa. FAM84B promoted the transcription of WWP1 by MYC by activating the expression of MYC coterminous with the 8q24.21 gene desert in a beta catenin-dependent approach. WWP1 transcription promoted by MYC facilitated the ubiquitination and degradation of CDKN1B protein and inversely attenuated the repressive effect of CDKN1B on MYC expression. Exogenous overexpression of CDKN1B blocked FAM84B-activated MYC/WWP1 expression, thereby inhibiting PCa progression.

Conclusions

FAM84B promoted by eccDNA mediates degradation of CDKN1B via MYC/WWP1, thereby accelerating PCa progression.
Genetic Dissection of Major Rice QTLs for Strong Culms and Fine Mapping of qWS5 for Breeding Application in Transplanted System
Authors: Bian Zhong , Cao Dongping , Zou Yiting , Xie Dong , Zhuang Wenshu , Sun Zixing , Mou Nana , Sun Yangyang , Zhang Changquan , Li Qianfeng , Liu Qiaoquan , Zhang Lin
Published: July 2024

Background

Rice is one of the major staples that feeds about one half of the global populations, and it is important to identify the genetic loci for the traits related to yield improvement. Lodging will cause severe yield loss when it happens, and stem diameter has been characterized as an important trait for lodging resistance. However, most QTLs for stem diameter have not been finely dissected due to their sensitivity to environmental fluctuation.

Result

In this study, we performed QTL analysis for stem diameter using populations derived from Nipponbare (NIP) and strong culm variety YYP1, and confirmed the single and combined effect of three major QTLs by recombinant inbred lines (RILs). Based on the QTL location, we found that qWS5 is a novel QTL not well characterized before. To finely dissect the novel locus, several recombinant heterogeneous inbred families (HIFs) were selected from the RILs for linkage analysis and their derived nearly isogenic lines (NILs) were subjected to detailed trait investigation throughout different years. The HIF-NILs strategy confined the QTL to about 380 kb region supported by repeated genotype and phenotype data, and it lays the foundation for QTL cloning in the future. In addition, introgression of the QTL to an elite japonica variety SD785 was performed by successive backcrossing, and it confirmed the value of qWS5 in increasing stem diameter and other agronomic traits during rice breeding.

Conclusions

We prove that qWS5 is a novel QTL with relatively stable effect for stem diameter and the QTL can be finely mapped to small region by the HIF-NILs strategy. The result will facilitate the improvement of rice lodging resistance by molecular marker assisted selection breeding.
Unveiling the translational dynamics of lychee (Litchi chinesis Sonn.) in response to cold stress
Authors: Chen Mingming , Dai Shuangfeng , Chen Daming , Chen Haomin , Feng Naijie , Zheng Dianfeng
Published: July 2024

Cold stress poses a significant threat to the quality and productivity of lychee (Litchi chinensis Sonn.). While previous research has extensively explored the genomic and transcriptomic responses to cold stress in lychee, the translatome has not been thoroughly investigated. This study delves into the translatomic landscape of the 'Xiangjinfeng' cultivar under both control and low-temperature conditions using RNA sequencing and ribosome profiling. We uncovered a significant divergence between the transcriptomic and translatomic responses to cold exposure. Additionally, bioinformatics analyses underscored the crucial role of codon occupancy in lychee's cold tolerance mechanisms. Our findings reveal that the modulation of translation via codon occupancy is a vital strategy to abiotic stress. Specifically, the study identifies ribosome stalling, particularly at the E site AAU codon, as a key element of the translation machinery in lychee's response to cold stress. This work enhances our understanding of the molecular dynamics of lychee's reaction to cold stress and emphasizes the essential role of translational regulation in the plant's environmental adaptability.
Cas12a-mediated gene targeting by sequential transformation strategy in Arabidopsis thaliana
Authors: Li Jing , Wei Qi , Cheng Yiqiu , Kong Dali , Kong Zhe , Ke Yongping , Dang Xiaofei , Zhu Jian-Kang , Shimada Hiroaki , Miki Daisuke
Published: July 2024

Gene targeting (GT) allows precise manipulation of genome sequences, such as knock-ins and sequence substitutions, but GT in seed plants remains a challenging task. Engineered sequence-specific nucleases (SSNs) are known to facilitate GT via homology-directed repair (HDR) in organisms. Here, we demonstrate that Cas12a and a temperature-tolerant Cas12a variant (ttCas12a) can efficiently establish precise and heritable GT at two loci in Arabidopsis thaliana (Arabidopsis) through a sequential transformation strategy. As a result, ttCas12a showed higher GT efficiency than unmodified Cas12a. In addition, the efficiency of transcriptional and translational enhancers for GT via sequential transformation strategy was also investigated. These enhancers and their combinations were expected to show an increase in GT efficiency in the sequential transformation strategy, similar to previous reports of all-in-one strategies, but only a maximum twofold increase was observed. These results indicate that the frequency of double strand breaks (DSBs) at the target site is one of the most important factors determining the efficiency of genetic GT in plants. On the other hand, a higher frequency of DSBs does not always lead to higher efficiency of GT, suggesting that some additional factors are required for GT via HDR. Therefore, the increase in DSB can no longer be expected to improve GT efficiency, and a new strategy needs to be established in the future. This research opens up a wide range of applications for precise and heritable GT technology in plants.
Trace of delirium after robotic lower abdominal tumor resection at different end-tidal carbon dioxide: a RCT trial
Authors: Chen Jingwen , Liang Si , Wei Ming , Ma Yue , Bi Tianpeng , Liu Zheng , Song Yang , Chen Hong , Wang Yu
Published: July 2024

Background

Postoperative delirium (POD) often occurs in oncology patients, further increasing the medical and financial burden. Robotic technology in lower abdominal tumors resection reduces surgical trauma but increases risks such as carbon dioxide (CO2) absorption. This study aimed to investigate the differences in their occurrence of POD at different end-tidal CO2 levels.

Method

This study was approved by the Ethics Committee of Affiliated Hospital of He Bei University (HDFY-LL-2022-169). The study was registered with the Chinese Clinical Trials Registry on URL: http://www.chictr.org.cn, Registry Number: ChiCTR2200056019 (Registry Date: 27/08/2022). In patients scheduled robotic lower abdominal tumor resection from September 1, 2022 to December 31, 2022, a comprehensive delirium assessment was performed three days postoperatively using the CAM scale with clinical review records. Intraoperative administration of different etCO2 was performed depending on the randomized grouping after intubation. Group L received lower level etCO2 management (31-40mmHg), and Group H maintained the higher level(41-50mmHg) during pneumoperitoneum. Data were analyzed using Pearson Chi-Square or Wilcoxon Rank Sum tests and multiple logistic regression. Preoperative mental status score, alcohol impairment score, nicotine dependence score, history of hypertension and diabetes, duration of surgery and worst pain score were included in the regression model along with basic patient information for covariate correction analysis.

Results

Among the 103 enrolled patients, 19 (18.4%) developed postoperative delirium. The incidence of delirium in different etCO2 groups was 21.6% in Group L and 15.4% in Group H, respectively, with no statistical differences. In adjusted multivariate analysis, age and during of surgery were statistically significant predictors of postoperative delirium. The breath-hold test was significantly lower postoperatively, but no statistical differences were found between two groups.

Conclusion

With robotic assistant, the incidence of postoperative delirium in patients undergoing lower abdominal tumor resection was not modified by different end-tidal carbon dioxide management, however, age and duration of surgery were positively associated risk factors.
Dapagliflozin, inflammation and left ventricular remodelling in patients with type 2 diabetes and left ventricular hypertrophy
Authors: Dihoum Adel , Brown Alexander JM , McCrimmon Rory J , Lang Chim C , Mordi Ify R
Published: July 2024

Background and Aims

Sodium-glucose co-transporter 2 (SGLT2) inhibitors have beneficial effects in heart failure (HF), including reverse remodelling, but the mechanisms by which these benefits are conferred are unclear. Inflammation is implicated in the pathophysiology of heart failure (HF) and there are some pre-clinical data suggesting that SGLT2 inhibitors may reduce inflammation. There is however a lack of clinical data. The aim of our study was to investigate whether improvements in cardiac remodelling caused by dapagliflozin in individuals with type 2 diabetes (T2D) and left ventricular hypertrophy (LVH) were associated with its effects on inflammation.

Methods

We measured C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin-1β (IL-1β), interleukin 6 (IL-6), and interleukin 10 (IL-10) and neutrophil-to-lymphocyte ratio (NLR) in plasma samples of 60 patients with T2D and left ventricular hypertrophy (LVH) but without symptomatic HF from the DAPA-LVH trial in which participants were randomised dapagliflozin 10 mg daily or placebo for 12 months and underwent cardiac magnetic resonance imaging (CMR) at baseline and end of treatment. The primary analysis was to investigate the effect of dapagliflozin on inflammation and to assess the relationships between changes in inflammatory markers and LV mass and global longitudinal strain (GLS) and whether the effect of dapagliflozin on LV mass and GLS was modulated by baseline levels of inflammation.

Results

Following 12 months of treatment dapagliflozin significantly reduced CRP compared to placebo (mean difference of -1.96; 95% CI -3.68 to -0.24, p = 0.026). There were no significant statistical changes in other inflammatory markers. There were modest correlations between improvements in GLS and reduced inflammation (NLR (r = 0.311), IL-1β (r = 0.246), TNF-α (r = 0.230)) at 12 months.

Conclusions

Dapagliflozin caused a significant reduction in CRP compared to placebo. There were correlations between reductions in inflammatory markers including IL-1β and improvements in global longitudinal strain (but not reduced LV mass). Reductions in systemic inflammation might play a contributory role in the cardiovascular benefits of dapagliflozin.

Trial registration

Clinicaltrials.gov NCT02956811 (06/11/2016).
Assessing seropositivity of MMR antibodies in individuals aged 2–22: evaluating routine vaccination effectiveness after the 2003 mass campaign-a study from Iran’s National Measles Laboratory
Authors: Ghafoori Fateme , Mokhtari-Azad Talat , Foroushani Abbas Rahimi , Farahmand Mohammad , shadab Azade , Salimi Vahid
Published: July 2024

Background and purpose

The seroprevalence of antibodies against measles, mumps, and rubella (MMR) was evaluated 17 years following a mass vaccination campaign in individuals aged 2 to 22 years who had received routine immunization but were not eligible for an extended immunization program.

Methods

Samples were acquired from Iran’s National Measles Laboratory (NML), with individuals showing positive IgM results excluded. Out of the samples collected in 2020, a random selection of 290 serum samples was chosen, representing individuals between the ages of 2 and 22 years from diverse regions in the country. These samples were subjected to analysis using an enzyme-linked immunosorbent assay (ELISA) to quantify specific IgG antibodies against MMR.

Results

The seroprevalence rates of antibodies for measles, mumps, and rubella were determined to be 76.2%, 89.3%, and 76.9%, respectively. Younger age groups exhibited higher seropositivity rates for measles and mumps, whereas the 7- to 11-year-old group demonstrated the highest seropositivity rate for rubella. A reduction in antibody status was observed from younger to older age groups, particularly those aged 17–22.

Conclusion

The study unveiled suboptimal antibody levels for measles and rubella, highlighting the necessity for further investigation and potential adjustments to future vaccination strategies. Moreover, the decline in antibody status post-vaccination can accumulate in seronegative individuals over time, elevating the risk of outbreaks.