bluuebunny/crossref_metadata_2025_split huggingface dataset:
Exploring the tolerable region for HiBiT tag insertion in the hepatitis B virus genome
Authors: Murayama Asako , Igarashi Hitomi , Yamada Norie , Aly Hussein Hassan , Toyama Masaaki , Isogawa Masanori , Shimakami Tetsuro , Kato Takanobu 
Published: September 2024

ABSTRACT

A cell culture system that allows the reproduction of the hepatitis B virus (HBV) life cycle is indispensable to exploring novel anti-HBV agents. To establish the screening system for anti-HBV agents, we exploited the high affinity and bright luminescence (HiBiT) tag and comprehensively explored the regions in the HBV genome where the HiBiT tag could be inserted. The plasmids for the HiBiT-tagged HBV molecular clones with a 1.38-fold HBV genome length were prepared. The HiBiT tag was inserted into five regions: preS1, preS2, hepatitis B e (HBe), hepatitis B X (HBx), and hepatitis B polymerase (HB pol). HiBiT-tagged HBVs were obtained by transfecting the prepared plasmids into sodium taurocholate cotransporting polypeptide-transduced HepG2 (HepG2/NTCP) cells, and their infectivity was evaluated in human primary hepatocytes and HepG2/NTCP cells. Among the evaluated viruses, the infection of HiBiT-tagged HBVs in the preS1 or the HB pol regions exhibited a time-dependent increase of the hepatitis B surface antigen (HBsAg) level after infection to HepG2/NTCP cells as well as human primary hepatocytes. Immunostaining of the hepatitis B core (HBc) antigen in infected cells confirmed these viruses are infectious to those cells. However, the time-dependent increase of the HiBiT signal was only detected after infection with the HiBiT-tagged HBV in the preS1 region. The inhibition of this HiBiT-tagged HBV infection in human primary hepatocytes and HepG2/NTCP cells by the preS1 peptide could be detected by measuring the HiBiT signal. The infection system with the HiBiT-tagged HBV in HepG2/NTCP cells facilitates easy, sensitive, and high-throughput screening of anti-HBV agents and will be a useful tool for assessing the viral life cycle and exploring antiviral agents.

IMPORTANCE
Hepatitis B virus (HBV) is the principal causative agent of chronic hepatitis. Despite the availability of vaccines in many countries, HBV infection has spread worldwide and caused chronic infection. In chronic hepatitis B patients, liver inflammation leads to cirrhosis, and the accumulation of viral genome integration into host chromosomes leads to the development of hepatocellular carcinoma. The currently available treatment strategy cannot expect the eradication of HBV. To explore novel anti-HBV agents, a cell culture system that can detect HBV infection easily is indispensable. In this study, we examined the regions in the HBV genome where the high affinity and bright luminescence (HiBiT) tag could be inserted and established an HBV infection system to monitor infection by measuring the HiBiT signal by infecting the HiBiT-tagged HBV in sodium taurocholate cotransporting polypeptide-transduced HepG2 (HepG2/NTCP) cells. This system can contribute to screening for novel anti-HBV agents.
PhoPQ-mediated lipopolysaccharide modification governs intrinsic resistance to tetracycline and glycylcycline antibiotics in
Escherichia coli
Authors: Choi Byoung Jun , Choi Umji , Ryu Dae-Beom , Lee Chang-Ro 
Published: September 2024

ABSTRACT

Tetracyclines and glycylcycline are among the important antibiotics used to combat infections caused by multidrug-resistant Gram-negative pathogens. Despite the clinical importance of these antibiotics, their mechanisms of resistance remain unclear. In this study, we elucidated a novel mechanism of resistance to tetracycline and glycylcycline antibiotics via lipopolysaccharide (LPS) modification. Disruption of the
Escherichia coli
PhoPQ two-component system, which regulates the transcription of various genes involved in magnesium transport and LPS modification, leads to increased susceptibility to tetracycline, minocycline, doxycycline, and tigecycline. These phenotypes are caused by enhanced expression of phosphoethanolamine transferase EptB, which catalyzes the modification of the inner core sugar of LPS. PhoPQ-mediated regulation of EptB expression appears to affect the intracellular transportation of doxycycline. Disruption of EptB increases resistance to tetracycline and glycylcycline antibiotics, whereas the other two phosphoethanolamine transferases, EptA and EptC, that participate in the modification of other LPS residues, are not associated with resistance to tetracyclines and glycylcycline. Overall, our results demonstrated that PhoPQ-mediated modification of a specific residue of LPS by phosphoethanolamine transferase EptB governs intrinsic resistance to tetracycline and glycylcycline antibiotics.

IMPORTANCE

Elucidating the resistance mechanisms of clinically important antibiotics helps in maintaining the clinical efficacy of antibiotics and in the prescription of adequate antibiotic therapy. Although tetracycline and glycylcycline antibiotics are clinically important in combating multidrug-resistant Gram-negative bacterial infections, their mechanisms of resistance are not fully understood. Our research demonstrates that the
E. coli
PhoPQ two-component system affects resistance to tetracycline and glycylcycline antibiotics by controlling the expression of phosphoethanolamine transferase EptB, which catalyzes the modification of the inner core residue of lipopolysaccharide (LPS). Therefore, our findings highlight a novel resistance mechanism to tetracycline and glycylcycline antibiotics and the physiological significance of LPS core modification in
E. coli
.
Deep marine records of Deccan Trap volcanism before the Cretaceous–Paleogene (K–Pg) mass extinction
Authors: Sinnesael Matthias , Percival Lawrence M.E. , Schulz Toni , Vellekoop Johan , Goderis Steven , Daems Kato , Gao Yue , Leermakers Martine , Montanari Alessandro , Coccioni Rodolfo , Koeberl Christian , Claeys Philippe 
Published: September 2024

Abstract
The Cretaceous–Paleogene boundary is marked by a large impact and coeval mass extinction event that occurred 66 m.y. ago. Contemporaneous emplacement of the volcanic Deccan Traps also affected global climate before, during, and after the mass extinction. Many questions remain about the timing and eruption rates of Deccan volcanism, its precise forcing of climatic changes, and its signature in the marine geochemical sedimentary proxy record. Here, we compile new and existing mercury (Hg) concentration and osmium isotope (187Os/188Os) records for various stratigraphic sections worldwide. Both geochemical proxies have been suggested to reflect past variations in Deccan volcanic activity. New data from deep marine pelagic carbonate records are compared to contemporaneous records from shallower marine sites correlated through high-resolution cyclostratigraphic age models. The robustness of the proxy records is evaluated on a common timeline and compared to two different Deccan eruption history scenarios. Results show that the global 187Os/188Os signal is clearly reproducible, while the global Hg record does not form a consistent pattern. Moreover, the deep marine sections investigated do not record clear variations in the Hg cycle, particularly in the latest Cretaceous, prior to the extinction event. A detailed reevaluation of the precise depth of the redistribution of impactor-sourced platinum group elements does not exclude the possibility of a minor drop in 187Os/188Os corresponding with a pulse of Deccan volcanism ~50,000 years before the Cretaceous–Paleogene boundary. Simple Os isotope mass balance modeling indicates that the latest Cretaceous was marked by significant levels of basalt weathering. CO2 sequestration during this weathering likely overwhelmed the emission of Deccan volatiles, thereby contributing to the end of the late Maastrichtian warming.
Mercury evidence of Emeishan volcanism driving the mid-Capitanian (Middle Permian) extinction
Authors: Huang Hu , Deng Changzhou , Grasby Stephen E. , Cawood Peter A. , Hou Mingcai , Yang Chenchen , Feng Mingshi , Xiong Fuhao , Zhong Hanting , Yin Runsheng 
Published: September 2024

Abstract
The mid-Capitanian (Middle Permian) extinction has been widely attributed to the eruption of the Emeishan large igneous province. Here, we investigate the nature and timing of this link by determining Hg concentrations and isotopic compositions of limestones from the Xiongjiachang section of southwestern China, where Emeishan basalts directly overlie sediments recording the mid-Capitanian extinction horizon. Results show an initial Hg-enrichment interval ~2.2 m below the mid-Capitanian extinction horizon. Positive Δ199Hg values in the Hg-enrichment interval suggest enhanced volcanic Hg influx into the ocean via atmospheric Hg(II) deposition. The late stage of the mid-Capitanian extinction interval has lower Δ199Hg values, which indicates enhanced input of terrestrial Hg due to ecosystem collapse and soil erosion. The results of this study provide evidence that the Emeishan large igneous province eruption occurred earlier than the mid-Capitanian extinction, and establish a more reasonable temporal link between Emeishan large igneous province volcanism and the mid-Capitanian extinction.
Sex disparities in gallstone disease: insights from the MAUCO prospective population-based cohort study
Authors: Rodriguez Gatta Danae , Huidobro Laura , Petermann-Rocha Fanny , Van de Wyngard Vanessa , Godoy Franco , Cid Vicente , Garrido Macarena , Cook Paz , Roa Juan Carlos , Vargas Claudio , Araya Juan Carlos , Cortes Sandra , Cruz Francisco , Koshiol Jill , Arrese Marco , Ferreccio Catterina 
Published: September 2024

Objective
To investigate factors associated with the prevalence and incidence of gallstone disease (GSD) in women and men of the MAUCO population-based prospective cohort.

Design
8948 MAUCO participants (aged 38–74 years) underwent abdominal ultrasound at baseline (2015–2019); 4385 received follow-up ultrasound at years 2 or 4. Factors associated with prevalent GSD were assessed using Poisson multiple regression and with incident GSD using Cox regression models.

Results
GSD prevalence was 40.4% in women (13.1% gallstones, 27.3% cholecystectomies) and 17.1% in men (8.9% gallstones, 8.2% cholecystectomies). In men, GSD prevalence rate ratio (PRR) by age in >64 years was 3.85 (95% CI 3.00 to 4.94), doubling that of women’s PRR 1.78 (95% CI 1.57 to 2.01). In women, waist circumference and diabetes were stronger GSD factors; a higher number of children and worse metabolic and socioeconomic conditions were also highlighted. GSD men had higher cardiovascular disease and a family history of GSD and gallbladder cancer. 198 GSD cases developed during follow-up, with incidence increasing by 2% (95% CI 1.005% to 1.03%) per each centimetre above the ideal waist circumference, statistically significant only in women. In men, age was the strongest factor for incidence, followed by a family history of GSD and low high-density lipoprotein increased incidence risk.

Conclusions
GSD burden was high in this population; a third of women had their gallbladder removed, which may pose them at risk of other health problems. Abdominal obesity was the only preventable GSD risk factor, highlighting the need for effective public health policies promoting obesity reduction.
Asthma control in severe asthma and occupational exposures to inhalable asthmagens
Authors: Walters Gareth I , Reilly Christopher , Le Moual Nicole , Huntley Christopher C , Hussein Hanan , Marsh Julie , Bahron Ali , Krishna Mamidipudi Thirumala , Mansur Adel H 
Published: September 2024

IntroductionWork-related asthma accounts for ≥25% of asthma in working-age populations, though the relationship between work exposures and symptoms is frequently missed, leading to poor health and employment outcomes. We hypothesised that inhalable exposures at work are associated with poor asthma control in severe asthma (SA).MethodsWe searched the Birmingham (UK) Regional NHS SA Service clinical database (n=1453 records; 1 March 2004 to 1 March 2021) and undertook a cross-sectional study using baseline data collected at diagnosis. We included all employed patients aged 16–64 with documented current occupation (n=504), and collected socio-demographic, general health and asthma-specific data, including Asthma Control Questionnaire 7 (ACQ7) score. The Occupational Asthma Specific Job-Exposure Matrix (OAsJEM) was employed to determine the likelihood of exposure to respiratory sensitisers, irritants, cleaning agents and detergents; associations between exposures and ACQ7 were investigated using binary and multinomial regression.ResultsFrequently reported occupations were care assistants (7%) and nurses (6%); 197/504 (39%) patients were exposed to an asthmagen, including respiratory sensitisers (30%), airway irritants (38%) and cleaning products/disinfectants (29%). ACQ7 score was available for 372/504 (74%) patients, of whom 14% had adequate control (ACQ7=0–1.5). After adjustment for major confounders there were no significant associations between inhaled asthmagens and ACQ7 score (either as binary or multinomial outcomes).ConclusionJEM-determined workplace exposures to inhaled asthmagens are not associated with asthma control in SA; 29–39% of patients may have current exposure to workplace asthmagens. Routine collection of lifetime occupational data including current job role and level of exposure, in the national asthma registry, would give further insights into this relationship.
Nuclear translocation of plasma membrane protein ADCY7 potentiates T cell-mediated antitumour immunity in HCC
Authors: Chen Jianan , Jiang Youhai , Hou Minghui , Liu Chunliang , Liu Erdong , Zong Yali , Wang Xiang , Meng Zhengyuan , Gu Mingye , Su Yu , Wang Hongyang , Fu Jing 
Published: September 2024

BackgroundThe potency of T cell-mediated responses is a determinant of immunotherapy effectiveness in treating malignancies; however, the clinical efficacy of T-cell therapies has been limited in hepatocellular carcinoma (HCC) owing to the extensive immunosuppressive microenvironment.ObjectiveHere, we aimed to investigate the key genes contributing to immune escape in HCC and raise a new therapeutic strategy for remoulding the HCC microenvironment.DesignThe genome-wide in vivo clustered regularly interspaced short palindromic repeats (CRISPR) screen library was conducted to identify the key genes associated with immune tolerance. Single-cell RNA-seq (scRNA-seq), flow cytometry, HCC mouse models, chromatin immunoprecipitation and coimmunoprecipitation were used to explore the function and mechanism of adenylate cyclase 7 (ADCY7) in HCC immune surveillance.ResultsHere, a genome-wide in vivo CRISPR screen identified a novel immune modulator-ADCY7. The transmembrane protein ADCY7 undergoes subcellular translocation via caveolae-mediated endocytosis and then translocates to the nucleus with the help of leucine-rich repeat-containing protein 59 (LRRC59) and karyopherin subunit beta 1 (KPNB1). In the nucleus, it functions as a transcription cofactor of CCAAT/enhancer binding protein alpha (CEBPA) to induceCCL5transcription, thereby increasing CD8+T cell infiltration to restrain HCC progression. Furthermore, ADCY7 can be secreted as exosomes and enter neighbouring tumour cells to promote CCL5 induction. Exosomes with high ADCY7 levels promote intratumoural infiltration of CD8+T cells and suppress HCC tumour growth.ConclusionWe delineate the unconventional function and subcellular location of ADCY7, highlighting its pivotal role in T cell-mediated immunity in HCC and its potential as a promising treatment target.
Impact of margin thermal ablation after endoscopic mucosal resection of large (≥20 mm) non-pedunculated colonic polyps on long-term recurrence
Authors: O’Sullivan Timothy , Mandarino Francesco Vito , Gauci Julia L , Whitfield Anthony M , Kerrison Clarence , Elhindi James , Neto do Nascimento Catarina , Gupta Sunil , Cronin Oliver , Sakiris Anthony , Prieto Aparicio Juan Francisco , Arndtz Sophie , Brown Gregor , Raftopoulos Spiro , Tate David , Lee Eric Y , Williams Stephen J , Burgess Nicholas , Bourke Michael J 
Published: September 2024

Background and aimsThe efficacy of colorectal endoscopic mucosal resection (EMR) is limited by recurrence and the necessity for conservative surveillance. Margin thermal ablation (MTA) after EMR has reduced the incidence of recurrence at the first surveillance colonoscopy at 6 months (SC1). Whether this effect is durable to second surveillance colonoscopy (SC2) is unknown. We evaluated long-term surveillance outcomes in a cohort of LNPCPs that have undergone MTA.MethodsLNPCPs undergoing EMR and MTA from four academic endoscopy centres were prospectively recruited. EMR scars were evaluated at SC1 and in the absence of recurrence, SC2 colonoscopy was conducted in a further 12 months. A historical control arm was generated from LNPCPs that underwent EMR without MTA. The primary outcome was recurrence at SC2 in all LNPCPs with a recurrence-free scar at SC1.Results1152 LNPCPs underwent EMR with complete MTA over 90 months until October 2022. 854 LNPCPs underwent SC1 with 29/854 (3.4%) LNPCPs demonstrating recurrence. 472 LNPCPs free of recurrence at SC1 underwent SC2. 260 LNPCPs with complete SC2 follow-up formed the control arm from January 2012 to May 2016. Recurrence at SC2 was significantly less in the MTA arm versus controls (1/472 (0.2%) vs 9/260 (3.5%); p<0.001)).ConclusionLNPCPs that have undergone successful EMR with MTA and are free of recurrence at SC1 are unlikely to develop recurrence in subsequent surveillance out to 2 years. Provided the colon is cleared of synchronous neoplasia, the next surveillance can be potentially extended to 3–5 years. Such an approach would reduce costs and enhance patient compliance.
A Bi-Population Competition Adaptive Interior Search Algorithm Based on Reinforcement Learning for Flexible Job Shop Scheduling Problem
Authors: Jiang Tianhua , Liu Lu 
Published: September 2024

In this paper, a bi-population competition adaptive interior search algorithm (BCAISA) based on a reinforcement learning strategy is proposed for the classical flexible job shop scheduling problem (FJSP) to optimize the makespan. First, the scheduling solution is represented using a machine-job-based two-segment integer encoding method, and various heuristic rules are then applied to generate the initial population. Secondly, a bi-population mechanism is introduced to partition the population into two distinct sub-populations. These sub-populations are specifically tailored for machine assignment and operation permutation, employing different search strategies respectively, aiming to facilitate an efficient implementation of parallel search. A competition mechanism is introduced to facilitate the information exchange between the two sub-populations. Thirdly, the ISA is adapted for the discrete scheduling problem by discretizing a series of search operators, which include composition optimization, mirror search, and random walk. A Q-learning-based approach is proposed to dynamically adjust a key parameter, aiming to strike a balance between the capacity for global exploration and local exploitation. Finally, extensive experiments are conducted based on 10 well-known benchmark instances of the FJSP. The design of the experiment (DOE) method is employed to determine the algorithm’s parameters. Based on the computational results, the effectiveness of four improvement strategies is first validated. The BCAISA is then compared with fifteen published algorithms. The comparative data demonstrate that our algorithm outperforms other algorithms in 50% of benchmark instances. Additionally, according to the relative percentage deviation (RPD) from the state-of-the-art results, the BCAISA also exhibits superior performance. This highlights the effectiveness of our algorithm for solving the classical FJSP. To enhance the practical application, the scope of the ISA will be broadened in future work to more complex problems in real-world scenarios.
A further generalization of sums of higher derivatives of the Riemann zeta function
Authors: Pearce-Crump Andrew 
Published: September 2024

We obtain a full asymptotic for the sum of [Formula: see text], where [Formula: see text] denotes the nth derivative of the Riemann zeta function, X is a positive real number, and [Formula: see text] denotes a nontrivial zero of the Riemann zeta function. The sum is over the zeros with imaginary parts up to a height T, as [Formula: see text]. We also specify what the asymptotic formula becomes when X is a positive integer, highlighting the differences in the asymptotic expansions as X changes its arithmetic nature.
Enabling Adaptive Sampling for Intra-Window Join: Simultaneously Optimizing Quantity and Quality
Authors: Tang Xilin , Zhang Feng , Zhang Shuhao , Liu Yani , He Bingsheng , He Bingsheng , Du Xiaoyong , Du Xiaoyong 
Published: September 2024

>Sampling is one of the most widely employed approximations in big data processing. Among various challenges in sampling design, sampling for join is particularly intriguing yet complex. This perplexing problem starts with a classical case where the join of two Bernoulli samples shrinks its output size quadratically and exhibits a strong dependency on the input data, presenting a unique challenge that necessitates adaptive sampling to guarantee both the quantity and quality of the sampled data. The community has made strides in achieving this goal by constructing offline samples and integrating support from indexes or key frequencies. However, when dealing with stream data, due to the need for real-time processing and high-quality analysis, methods developed for processing static data become unavailable. Consequently, a fundamental question arises: Is it possible to achieve adaptive sampling in stream data without relying on offline techniques?
To address this problem, we propose FreeSam, which couples hybrid sampling with intra-window join, a key stream join operator. Our focus lies on two widely used metrics: output size, ensuring quantity, and variance, ensuring quality. FreeSam enables adaptability in both the desired quantity and quality of data sampling by offering control on the two-dimensional space spanned by these metrics. Meanwhile, adjustable trade-offs between quality and performance make FreeSam practical for use. Our experiments show that, for every 1% increase in latency limitation, FreeSam can yield a 3.83% increase in the output size while maintaining the level of the estimator's variance. Additionally, we give FreeSam a multi-core implementation and ensure predictability of its latency through both an analytic model and a neural network model. The accuracy of these models is 88.05% and 96.75% respectively.
Reducing the Carbon Impact of Generative AI Inference (Today and in 2035)
Authors: Chien Andrew A. , Lin Liuzixuan , Nguyen Hai , Rao Varsha , Sharma Tristan , Wijayawardana Rajini 
Published: September 2024

Generative AI, exemplified in ChatGPT, Dall-E 2, and Stable Diffusion, are exciting new applications consuming growing quantities of computing. We study the compute, energy, and carbon impacts of generative AI inference. Using ChatGPT as an exemplar, we create a workload model and compare request direction approaches (Local, Balance, CarbonMin), assessing their power use and carbon impacts.
Our workload model shows that for ChatGPT-like services, inference dominates emissions, in one year producing 25x the carbon-emissions of training GPT-3. The workload model characterizes user experience, and experiments show that carbon emissions-aware algorithms (CarbonMin) can both maintain user experience and reduce carbon emissions dramatically (35%). We also consider a future scenario (2035 workload and power grids), and show that CarbonMin can reduce emissions by 56%. In both cases, the key is intelligent direction of requests to locations with low-carbon power. Combined with hardware technology advances, CarbonMin can keep emissions increase to only 20% compared to 2022 levels for 55x greater workload. Finally we consider datacenter headroom to increase effectiveness of shifting. With headroom, CarbonMin reduces 2035 emissions by 71%.