bluuebunny/crossref_metadata_2025 huggingface dataset:
Elevated Platelet‐to‐Lymphocyte Ratio as a Predictor of All‐Cause and Cardiovascular Mortality in Hypertensive Individuals
Authors: Xu Rui , Chen Ling , Yan Changshun , Xu Hong , Cao Guiqiu
Published: January 2025

The platelet‐to‐lymphocyte ratio (PLR) has been proposed as a promising inflammatory biomarker, with potential implications for cardiovascular prognosis. However, its association with mortality outcomes in hypertensive individuals is not fully elucidated. This investigation sought to clarify the linkage between PLR and both overall and cardiovascular mortality in hypertensive individuals. Data from 15 483 hypertensive adults in the NHANES (2005–2018) were analyzed. Mortality data, including all‐cause and cardiovascular deaths, were sourced from the National Death Index (NDI) up to December 31, 2019. The linkage between PLR and mortality risk was depicted using restricted cubic spline (RCS) models. Cox proportional hazards regression models assessed the independent association of PLR with mortality risk, with adjustments incrementally applied: Model 1 without adjustments; Model 2 adjusted for age and sex; Model 3 adjusted further for age, gender, race, marital status, diabetes, alcohol intake, smoking status, body mass index (BMI), history of cardiovascular disease (CVD), high‐density lipoprotein cholesterol (HDL), low‐density lipoprotein cholesterol (LDL), total cholesterol (TC), triglyceride (TG), and creatinine (CR). Over a median follow‐up of 79 months, there were 2820 all‐cause deaths and 758 cardiovascular deaths. The multivariate Cox analysis showed that those in the highest PLR quartile had significantly elevated risks of all‐cause mortality (Model 1: HR = 1.28, 95% CI 1.16–1.42, p < 0.001; Model 2: HR = 1.14, 95% CI 1.03–1.26, p = 0.014; Model 3: HR = 1.16, 95% CI 1.05–1.29, p = 0.004)and cardiovascular mortality (Model 1: HR = 1.59, 95% CI 1.30–1.94, p < 0.001; Model 2: HR = 1.38, 95% CI 1.13–1.68, p = 0.001; Model 3: HR = 1.47, 95% CI 1.20–1.80, p < 0.001). The study reveals a U‐shaped relationship between PLR and all‐cause mortality, alongside a linear association with cardiovascular mortality. A PLR threshold of 118.83 has been identified as indicative of an adverse prognosis for all‐cause mortality. Elevated PLR independently predicts heightened risks of both all‐cause and cardiovascular mortality among hypertensive patients.
Exploring the Role of the Pharmacist in the Prevention and Management of Hypertensive Disorders in Pregnancy in Ashanti Region, Ghana
Authors: Boachie‐Ansah Pauline , Anto Berko Panyin , Marfo Afia Frimpomaa Asare , Dassah Edward Tieru , Asiamah Morrison , Mozu Ivan Eduku , Adomako Nana Ofori , Oppong Kwaku Gyamfi
Published: January 2025

Hypertensive disorders in pregnancy (HDPs) are a leading cause of poor maternal and birth outcomes worldwide. Prompt management of these disorders is usually recommended to optimize outcomes. Administration of pharmacotherapeutic agents is critical in the prevention and management of these disorders. The services of the pharmacist are required to maximize the benefits of drug therapy during prevention and management. There is a paucity of data on the effectiveness of pharmacist‐led interventions in the management of these disorders in Ghana.

This study investigated the effect of a pharmacist‐led intervention on knowledge, adherence to antihypertensive medication, and blood pressure (BP) control among pregnant women.

A quasi‐experimental study was conducted. The study was carried out among pregnant women with moderate to high risk of developing HDPs and seeking antenatal care at a university hospital in Kumasi, Ghana. The pharmaceutical care model comprising health education, counseling, and medication administration reminders was provided fortnightly to study participants till delivery. Differences in pre‐ and post‐intervention median scores were compared using the Wilcoxon signed‐rank test.

The mean age was 35.7 years (± 1.2). The overall median knowledge and adherence scores increased significantly after the intervention by 11 versus 17 (p < 0.001) and 5 versus 9 (p < 0.001), respectively. Pharmaceutical intervention increased the proportion of mothers who were adherent by 68.9% (95% CI, 53.9–83.8%; p < 0.001). The commonest side effect of the two first‐line antihypertensives (nifedipine and methyldopa) was headache. About 91% of the women delivered vaginally, and almost all (97.8%) of all deliveries were live births.

Pharmacist‐led interventions had a positive impact on the knowledge of HDPs and adherence to antihypertensive medication in the study setting. Thus, incorporating pharmaceutical care into antenatal care would be worthwhile.
CN7:1h Alleviates Inflammation, Apoptosis and Extracellular Matrix Degradation in Osteoarthritis by Modulating the NF‐κB and mTOR Pathways
Authors: Wang Chih‐Chien , Lu Jeng‐Wei , Wu Ya‐Wun , Chu You‐Hsiang , Ho Yi‐Jung , Liu Feng‐Cheng , Peng Yi‐Jen
Published: January 2025

Osteoarthritis (OA) is a degenerative joint disease with a complex aetiology, which includes inflammation, cellular growth dysregulation and extracellular matrix (ECM) degradation. This study investigated the therapeutic potential of a small‐molecule compound, 2‐amino‐4‐(3,4,5‐trimethoxyphenyl)‐4H‐benzo[h]chromene‐3‐carbonitrile (CN7:1h) in modulating these critical biochemical pathways in OA. Cellular models and rat models of OA were used to explore the impact of CN7:1h on the nuclear factor kappa light chain enhancer of activated B cells (NF‐κB) and mechanistic target of rapamycin (mTOR) signalling pathways. Parameters such as autophagy, apoptosis and ECM preservation were evaluated. CN7:1h demonstrated a non‐cytotoxic profile at a concentration as high as 140 μM as confirmed by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) assay. At a concentration of 5 μM, CN7:1h was shown to inhibit the activation of NF‐κB and mTOR pathways. CN7:1h was also shown to promote autophagy and reduce apoptosis in cellular models. In rat models, CN7:1h facilitated cartilage repair and demonstrating the therapeutic efficacy of this compound. In conclusion, CN7:1h is a promising bioactive compound for the modulation of key biochemical pathways with therapeutic benefits in degenerative conditions, such as OA. Its high bioavailability and lack of cytotoxicity make CN7:1h an excellent candidate for further research aimed at clinical applications.
LPCAT1, the Enzyme Responsible for Converting LPC to PC, Promotes OPC Differentiation In Vitro
Authors: Shang Qi , Zhang Xin , Pu Yingyan , Lin Junjian , Ma Peng , Pan Yuchen , Zhao Ming , Sun Dingya , Cao Li
Published: January 2025

Myelin is the key structure for high‐speed information transmission and is formed by oligodendrocytes (OLs) which are differentiated from oligodendrocyte precursor cells (OPCs) in the central nervous system. Lipid is the main component of myelin and the role of lipid metabolism‐related molecules in myelination attach increasing attention. Lysophosphatidylcholine acyltransferase 1 (LPCAT1) mediates the conversion of lysophosphatidylcholine (LPC) to phosphatidylcholine (PC), and its role in myelination draws our interest as LPC is a classical demyelination inducer and PC is a major component of myelin. In this work, LPCAT1 is found expressed in the oligodendrocyte lineage cells during myelination. In vitro experiments showed that the expression level of LPCAT1 gradually increased along with the differentiation process from OPCs to OLs, and over‐expression and interference experiments showed that LPCAT1 promoted OPCs differentiation without affecting their proliferation or apoptosis. Mechanistically, the undertaker of LPCAT1's pro‐differentiation role is not PC, but the phosphorylated mTOR which is a key regulator in OPCs differentiation. RNA sequencing analysis showed LPCAT1 promoted the expression of ZBTB20 which is an important transcription factor related to lipid metabolism and regulates mTOR phosphorylation. In vivo, complex myelin tomacula involving multiple axons was formed after conditionally knocking out LPCAT1 in oligodendrocyte lineage cells, but no obvious myelin thickness abnormalities were observed. Our results indicate that LPCAT1 is an important regulator of myelination, and lipid metabolism‐related molecules may be new valuable targets for the treatment of diseases with myelin abnormalities.
How Nurses' Interventions Promote Health Literacy in Patients With Non‐Communicable Diseases: A Systematic Review
Authors: Boumendil Karima , Yakubu Nana‐Ayisha , Al Wachami Nadia , Arraji Maryem , Iderdar Younes , Mourajid Yassmine , Bouchachi Fatima Zahra , Chahboune Mohamed
Published: January 2025

Background

More than one‐third of all diseases in the world are non‐communicable diseases (NCDs), and poorer health outcomes are linked to low health literacy (HL), in which nurses have a significant role to play. Various studies have confirmed that there is an association between HL and NCDs. However, less is known about how nurses can intervene in the development of HL in patients with NCDs. This systematic review was carried out to explore, in a comprehensive way, nursing interventions that could promote HL in patients with NCDs.

Methods

A systematic review (PROSPERO registration number: CRD370625) was carried out on five databases (PubMed MEDLINE, Web of Science, Scopus, ScienceDirect and JSTOR). Sequences that provided information for our study topic were retrieved and analysed following PRISMA guidelines for systematic reviews.

Results

In total, 1915 titles and abstracts were screened, 71 articles were assessed in full‐text screening and 25 studies were included in the review. Around 23 different nurse‐led intervention strategies were identified, but only 11 major ones were explored in detail. The majority of them prioritised communication (teach‐back), self‐management programs, counselling and education. In the majority of the trials, a significant positive outcome was discovered. Both nurses and patients needed to devote time and attention to the complex nurse‐led HL interventions.

Conclusion

Nurses' HL interventions have shown promise in promoting HL and other health outcomes in people with NCDs, but they need to be tailored to fit specific patients. Nursing programs should include more than just patient teaching strategies.

Relevance to Clinical Practice

Nurses' HL efforts hold potential for enhancing HL in NCD patients, provided they are customised to individual needs.
Crops, Culture and Complexity
Authors: Ang James B.
Published: January 2025

This study shows that traditional farming practices have a persistent effect on shaping cultural traits that influence modern‐day economic complexity. Societies with a legacy of growing more labour‐intensive crops tend to develop interdependence, creating a culture of collectivism. Conversely, societies with a history of farming less labour‐intensive crops tend to develop independent traits, leading to a culture of individualism. The dichotomy in these farming legacies gives rise to the individualism–collectivism cleavage, which may explain variation in the level of economic complexity. Using information on land suitability to construct measures of individualism‐ and collectivism‐enhancing environments, this paper finds that societies with a more individualist orientation tend to develop stronger innovative capabilities. This enables them to produce and export a wide range of sophisticated products, resulting in a high level of economic complexity. However, societies imbued with collectivistic cultures tend to have a less complex economic structure.
Use of immunoglobulin G homeostatic set point and recovery time in plasmapheresis donor safety monitoring: A retrospective observational cohort study
Authors: Warner Janet V. , Drinkwater Michael J. , Chu Gerard J. , Kelly Shane , McComish Jeremy S.
Published: January 2025

Background and Objectives

Serum immunoglobulin G (IgG) and total protein are used to monitor plasmapheresis donor safety. However, there is a lack of information from large donor cohorts to determine the best use of these measurements.

Materials and Methods

We identified 230,144 plasmapheresis donors making their first donation between 1 July 2020 and 31 March 2024. IgG and total protein were measured prior to the first donation and then annually, following our donor safety monitoring protocol. We considered individuals who had not donated for 12 months to estimate intra‐individual biological variability of IgG. We compared four models to predict which donors would develop IgG < 6 g/L.

Results

The IgG reference interval for the cohort was 7.67–15.6 g/L. IgG declines 5%–11% after the age of 45 years. The intra‐individual biological variability of IgG (5.2%) is small, indicating that there is homeostatic set point for individual IgG. IgG is reduced by plasmapheresis but recovers to recruitment level after 12 weeks. When plasma is donated every 2–3 weeks, mean IgG plateaus 1 g/L below recruitment concentration. IgG at recruitment is the best predictor of which donors will have IgG < 6 g/L after a year of donations. Total protein is a low‐value test in this context.

Conclusion

Plasmapheresis is safe and sustainable for almost every donor, at the 2‐weekly frequency allowed in Australia. The donors most likely to experience unacceptably low IgG are those with very low recruitment IgG levels. These donors could be recommended 12‐week intervals between donations or other donation types.
Similitude laws for the vibroacoustic response of fluid-loaded plates under a turbulent boundary layer excitation
Authors: Plouseau-Guédé Xavier , Berry Alain , Maxit Laurent , Meyer Valentin
Published: January 2025

The theory of similitudes provides simple laws by which the response of one system (usually of small size) can be used to predict the response of another system (usually larger). This paper establishes the exact conditions and laws of similitude for the vibrations and acoustic radiation of a panel immersed in a heavy fluid and excited by a turbulent boundary layer. Previous work on vibroacoustic similitude had not considered the problem of a panel radiating in heavy fluid, for which the radiation impedance of the structure must be scaled. The scaling parameters studied here are the dimensions and thickness of the structure, its material properties, the properties of the acoustic domain, and the convective velocity of the turbulent boundary layer. The corresponding scaling laws are derived analytically and verified numerically; in particular, material properties of scaled panels can be determined with simple geometrical constructions on the diagram of Ashby.
Estimating in vivo power deposition density in thermotherapies based on ultrasound thermal strain imaging
Authors: Yin Chuhao , Su Huajin , Xie Yuting , Tu Juan , Zhang Dong , Kong Xiangqing , Guo Xiasheng
Published: January 2025

In thermal therapies, accurate estimation of in-tissue power deposition density (PDD) is essential for predicting temperature distributions over time or regularizing temperature imaging. Based on our previous work on ultrasound thermometry, namely, multi-thread thermal strain imaging (MT-TSI), this work develops an in vivo PDD estimation method. Specifically, by combining the TSI model infinitesimal echo strain filter with the bio-heat transfer theory (the Pennes equation), a finite-difference time-domain model is established to allow online extraction of the PDD. An alternating-direction implicit method is adopted to ensure numerical stability and computational efficiency in implementing the model. Based on simulations, the accuracy and effectiveness of the model are examined by comparing a preset PDD distribution with the estimated one. Then, TSI results are obtained from ultrasound data acquired in in vivo experiments; with the PDD estimated from that, TSI distributions are then “predicted” using a validated numerical procedure. The two TSI results are compared to verify the self-consistency of the proposed method. A simplified and more efficient protocol for obtaining an “equivalent spherical PDD” is also discussed.
Startup flow with and without wall slip in a pipe plugged with weakly compressible complex fluids—A new insight
Authors: Sanyal Aniruddha , Shinde Sachin Balasaheb , Kumar Lalit
Published: January 2025

The present article explains the nontrivial synergetic effect of wall slip, compressibility, and thixotropy in a pressurized flow startup operation of various structured fluids. Opposite to intuition, experimental and numerical simulations suggest that the wall slip (adhesive failure) facilitates gel degradation (cohesive failure), revealing a new flow startup mechanism. The irreversible thixotropic rheological model, along with the static slip-based model, is utilized to describe the structural degradation kinetics in the bulk phenomenon and the near-wall phenomenon, respectively. The near-wall transient variations in axial velocity or strain evolution and the initial pressure propagation mechanism along the axis of the circular pipe explain the essence of the aforementioned synergy. Finally, a comparative study of the effect of wall slip on the pressure propagation mechanisms and startup flow of generalized Newtonian fluids, viscoelastic based thixotropic fluids, and viscoelastic solids is also performed. Wall slip can convert no-steady-state thixotropic elasto-viscoplastic flow cases into a steady-state fluid flow, whereas it causes viscoelastic solids to move with a slip velocity. Additionally, our study revealed that stick-slip phenomena occur at an acoustic time scale. It requires a compressive wave to travel with information of stick position to the outlet and again back to the inlet, concomitantly causing the release of additional fluid, thereby converting the stick to a slip regime. Conventionally, stick-slip phenomena were mainly associated with nonlinearity. Hence, our study opened a new direction. Finally, concomitant with the experimental observations, we found that stick-slip phenomena disappear when the fluid is uniformly compressed and a steady state is reached.
One-dimensional nanosonosensitizer boosted multiple branches of immune responses against MHC-deficient immune-evasive urologic tumor
Authors: Yang Wei , Di Sichen , Yang Zihuan , Cao Jianwei , Fu Qingqiao , Ren Hongze , Cheng Hui , Xie Yujie , Jia Wencong , Dai Xinyue , Yu Meihua , Chen Yu , Cui Xingang
Published: January 2025

Cancer immunotherapies rely on CD8
+
cytolytic T lymphocytes (CTLs) in recognition and eradication of tumor cells via antigens presented on major histocompatibility complex class I (MHC-I) molecules. However, we observe MHC-I deficiency in human and murine urologic tumors, posing daunting challenges for successful immunotherapy. We herein report an unprecedented nanosonosensitizer of one-dimensional bamboo-like multisegmented manganese dioxide@manganese–bismuth vanadate (BMMBV) to boost multiple branches of immune responses targeting MHC-I–deficient tumors. BMMBV markedly augments sonodynamic activity contributed by manganese heteroatoms in the lattice of bismuth vanadate with narrowing bandgaps. Under sonoirradiation, BMMBV enhances tumor antigen spreading and emission of adjuvant signals, which potentiate dendritic cell maturation, thereby eliciting high aptitude of CTLs. This therapy substantially up-regulates MHC expression on tumor cells, which are reversely sensitive to CTLs. Alongside, extensive innate immune cells complement the cytolytic activity of CTLs for eliminating mouse urologic tumors. This study offers a reinforced strategy against antigen-loss immune-evasive tumor.
A multi-analytical study of the Montelirio beaded attires: Marine resources, sumptuary crafts, and female power in copper age Iberia
Authors: Sanjuán Leonardo García , Ramírez-Cruzado Samuel , Díaz-Guardamino Marta , Rodríguez José Antonio Lozano , Romero Teodosio Donaire , Vargas José Ángel Afonso , Rodríguez-Rellán Carlos , Nieto Verónica Balsera , Cáceres Puro Luis M. , Wheatley David W. , Earle Timothy , Cintas-Peña Marta , Jiménez Juan Manuel Vargas , Flores Álvaro Fernández , Triviño Miriam Luciañez , Cárdenas-Párraga Juan , Merino María Martínez , Guinea Fernando Muñiz
Published: January 2025

Excellent indicators of technology, social organization, exchange patterns, and even beliefs, beads are a topic of research in their own right. Findings made between 2010 and 2011 at the Montelirio tholos burial, part of the Valencina Copper Age mega-site, in south-western Spain, revealed what amounts to the largest single-burial ever-documented assemblage of beads. Furthermore, the Montelirio beads were part of unparalleled beaded attires worn by some of the people buried in the grave, mostly females. A multi-analytical study undertaken over the past 5 years—including a meticulous quantification of the collection, the characterization of the raw materials, radiocarbon dating and chronometric statistical modeling, morphometric analysis, phytolith analysis, experimental work and contextual analysis—reveals several previously unidentified aspects of these remarkable creations. This includes the role of the attires as sumptuary attributes heavily loaded of symbolism, used by a selected group of women of high social significance.
Dispersive heterodyne cavity ring-down spectroscopy exploiting eigenmode frequencies for high-fidelity measurements
Authors: Cygan Agata , Wójtewicz Szymon , Jóźwiak Hubert , Kowzan Grzegorz , Stolarczyk Nikodem , Bielska Katarzyna , Wcisło Piotr , Ciuryło Roman , Lisak Daniel
Published: January 2025

Measuring low light absorption with combined uncertainty <1 per mil (‰) is crucial for many applications. Popular cavity ring-down spectroscopy can provide ultrahigh precision, below 0.01‰, but its accuracy is often worse than 5‰ due to inaccuracies in light intensity measurements. To eliminate this problem, we exploit optical frequency information carried by the ring-down cavity electromagnetic field. Instead of measuring only the decaying light intensity, we perform heterodyne detection of ring-downs followed by Fourier analysis to provide exact frequencies of optical cavity modes and a high-fidelity dispersive spectrum of a gas sample from them. We demonstrate the sub–per-mil accuracy of our method, confirmed by the best ab initio results for CO line intensity and for HD line shape, and the long-term repeatability of our dispersion measurements at 10
−4
level. We see potential for our approach in atmospheric remote sensing, isotope ratio metrology, thermometry, and establishment of primary gas standards.
Room-temperature continuous-wave pumped exciton polariton condensation in a perovskite microcavity
Authors: Song Jiepeng , Ghosh Sanjib , Deng Xinyi , Li Chun , Shang Qiuyu , Liu Xinfeng , Wang Yubin , Gao Xiaoyue , Yang Wenkai , Wang Xianjin , Zhao Qing , Shi Kebin , Gao Peng , Xing Guichuan , Xiong Qihua , Zhang Qing
Published: January 2025

Microcavity exciton polaritons (polaritons) as part-light part-matter quasiparticles garner considerable attention for Bose-Einstein condensation at elevated temperatures. Recently, halide perovskites have emerged as promising room-temperature polaritonic platforms because of their large exciton binding energies and superior optical properties. However, currently, inducing room-temperature nonequilibrium polariton condensation in perovskite microcavities requires optical pulsed excitations with high excitation densities. Here, we demonstrate continuous-wave optically pumped polariton condensation with an exceptionally low threshold of ~0.53 W cm
−2
and a narrow linewidth of ~0.5 meV. Polariton condensation is unambiguously demonstrated by characterizing the nonlinear behavior and coherence properties. We also unveil the trapping potential landscape strategy to facilitate polariton relaxation and accumulation. Our findings lay the foundation for the next-generation energy-efficient polaritonic devices operating at room temperature.
Tensor networks enable the calculation of turbulence probability distributions
Authors: Gourianov Nikita , Givi Peyman , Jaksch Dieter , Pope Stephen B.
Published: January 2025

Predicting the dynamics of turbulent fluids has been an elusive goal for centuries. Even with modern computers, anything beyond the simplest turbulent flows is too chaotic and multiscaled to be directly simulatable. An alternative is to treat turbulence probabilistically, viewing flow properties as random variables distributed according to joint probability density functions (PDFs). Such PDFs are neither chaotic nor multiscale, yet remain challenging to simulate due to their high dimensionality. Here, we overcome the dimensionality problem by encoding turbulence PDFs as highly compressed “tensor networks” (TNs). This enables single CPU core simulations that would otherwise be impractical even with supercomputers: for a 5 + 1 dimensional PDF of a chemically reactive turbulent flow, we achieve reductions in memory and computational costs by factors of

O

(

10
6

)

and

O

(

10
3

)

, respectively, compared to standard finite-difference algorithms. A future path is opened toward something heretofore thought infeasible: directly simulating high-dimensional PDFs of both turbulent flows and other chaotic systems that can usefully be described probabilistically.
Motion Hologram: Jointly optimized hologram generation and motion planning for photorealistic 3D displays via reinforcement learning
Authors: Dong Zhenxing , Ling Yuye , Li Yan , Su Yikai
Published: January 2025

Holography is capable of rendering three-dimensional scenes with full-depth control and delivering transformative experiences across numerous domains, including virtual and augmented reality, education, and communication. However, traditional holography presents 3D scenes with unnatural defocus and severe speckles due to the limited space bandwidth product of the spatial light modulator (SLM). Here, we introduce Motion Hologram, a holographic technique that accurately portrays photorealistic and speckle-free 3D scenes. This technique leverages a single hologram and a learnable motion trajectory, which are jointly optimized within a deep reinforcement learning framework. Specifically, we experimentally demonstrated that the proposed technique could achieve a 4- to 5-dB PSNR improvement of focal stacks in comparison with traditional holography and could successfully depict speckle-free, high-fidelity, and full-color 3D displays using only a commercial SLM. We believe that the proposed method promises a prospective form of holographic displays that will offer immersive viewing experiences for audiences.
The case against machine vision for the control of wearable robotics: Challenges for commercial adoption
Authors: Ghonasgi Keya , Kaveny Kyle J. , Langlois David , Sigurðarson Leifur D. , Swift Tim A. , Wheeler Jason , Young Aaron J.
Published: January 2025

Deploying machine vision for wearable robot control faces challenges in terms of usability, reliability, privacy, and costs.
AGER-dependent macropinocytosis drives resistance to KRAS-G12D–targeted therapy in advanced pancreatic cancer
Authors: Li Changfeng , Liu Yuanda , Liu Chang , Chen Fangquan , Xie Yangchun , Zeh Herbert J. , Yu Chunhua , Liu Jiao , Tang Daolin , Kang Rui
Published: January 2025

Pancreatic ductal adenocarcinoma (PDAC) driven by the
KRAS-G12D
mutation presents a formidable health challenge because of limited treatment options. MRTX1133 is a highly selective and first-in-class KRAS-G12D inhibitor under clinical development. Here, we report that the advanced glycosylation end product–specific receptor (AGER) plays a key role in mediating MRTX1133 resistance in PDAC cells. The up-regulation of AGER within cancer cells instigates macropinocytosis, facilitating the internalization of serum albumin and subsequent amino acid generation. These amino acids are then used to synthesize the antioxidant glutathione, leading to resistance to MRTX1133 treatment due to the inhibition of apoptosis. The underlying molecular mechanism involves AGER’s interaction with diaphanous-related formin 1 (DIAPH1), a formin protein responsible for driving Rac family small GTPase 1 (RAC1)–dependent macropinosome formation. The effectiveness and safety of combining MRTX1133 with pharmacological inhibitors of the AGER-DIAPH1 complex (using RAGE299) or macropinocytosis (using EIPA) were confirmed in patient-derived xenografts, orthotopic models, and genetically engineered mouse PDAC models. This combination therapy also induces high-mobility group box 1 (HMGB1) release, resulting in a subsequent antitumor CD8
+
T cell response in immunocompetent mice. Collectively, the study findings underscore the potential to enhance the efficacy of KRAS-G12D blockade therapy by targeting AGER-dependent macropinocytosis.
Prior vaccination prevents overactivation of innate immune responses during COVID-19 breakthrough infection
Authors: Chan Leslie , Pinedo Kassandra , Stabile Mikayla A. , Hamlin Rebecca E. , Pienkos Shaun M. , Ratnasiri Kalani ,   Stanford COVID-19 Biobank, Yang Samuel , Blomkalns Andra L. , Nadeau Kari C. , Pulendran Bali , O’Hara Ruth , Rogers Angela J. , Holmes Susan P. , Blish Catherine A. , Ranganath Thanmayi , Zhao Nancy Q. , Wilk Aaron J. , Vergara Rosemary , McKechnie Julia L. , de la Parte Lauren , Dantzler Kathleen Whittle , Ty Maureen , Kathale Nimish , Martínez-Colón Giovanny J. , Rustagi Arjun , Ivison Geoff , Pi Ruoxi , Lee Madeline J. , Brewer Rachel E. , Hollis Taylor , Baird Andrea , Ugur Michele , Tal Michal C. , Bogusch Drina , Nahass Georgie , Haider Kazim , Thi Tran Kim Quyen , Simpson Laura , Din Hena N. , Roque Jonasel , Mann Rosen , Chang Iris , Do Evan , Fernandes Andrea , Lyu Shu-Chen , Zhang Wenming , Manohar Monali , Krempski James W. , Visweswaran Anita , Zudock Elizabeth J. , Jee Kathryn , Kumar Komal , Newberry Jennifer A. , Quinn James V. , Schreiber Donald , Ashley Euan A.
Published: January 2025

At this stage in the COVID-19 pandemic, most infections are “breakthrough” infections that occur in individuals with prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. To refine long-term vaccine strategies against emerging variants, we examined both innate and adaptive immunity in breakthrough infections. We performed single-cell transcriptomic, proteomic, and functional profiling of primary and breakthrough infections to compare immune responses from unvaccinated and vaccinated individuals during the SARS-CoV-2 Delta wave. Breakthrough infections were characterized by a less activated transcriptomic profile in monocytes and natural killer cells, with induction of pathways limiting monocyte migratory potential and natural killer cell proliferation. Furthermore, we observed a female-specific increase in transcriptomic and proteomic activation of multiple innate immune cell subsets during breakthrough infections. These insights suggest that prior SARS-CoV-2 vaccination prevents overactivation of innate immune responses during breakthrough infections with discernible sex-specific patterns and underscore the potential of harnessing vaccines in mitigating pathologic immune responses resulting from overactivation.
Population pharmacokinetics and pulmonary modeling of eravacycline and the determination of microbiological breakpoint and cutoff of PK/PD
Authors: Ji Xi-wei , Mak Wen Yao , Xue Feng , Yang Wen-yu , Kuan Isabelle Hui-San , Xiang Xiao-qiang , Li Yun , Zhu Xiao
Published: January 2025

Eravacycline is a broad-spectrum fluorocycline currently approved for complicated intra-abdominal infections (cIAIs). In lung-infection models, it is effective against methicillin-resistant
Staphylococcus aureus
(MRSA) and tetracycline-resistant MRSA. As such, we aimed to develop a population pharmacokinetic/pharmacodynamic (PK/PD) model to evaluate eravacycline’s pulmonary distribution and kinetics. Data were extracted from a Phase I study (
NCT01989949
) which assessed the bronchopulmonary disposition of intravenous eravacycline to construct the population PK model that could adequately describe the drug’s pulmonary kinetics. Eravacycline lung PK was best described by a three-compartment model with allometric scaling, with the epithelial lining fluid (ELF) component parameterized as the ELF distribution ratio (

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, unbound concentration in ELF over central compartment). The estimated ELF distribution ratio was 8.26 (95% confidence interval = 6.8–9.8). Besides allometrically scaled weight, no other significant covariate was found. MIC
90
was 0.5 mg/L (
Escherichia coli
), 2 mg/L (
Klebsiella pneumoniae
), 0.5 mg/L (
Acinetobacter baumannii
), and 0.12 mg/L (
S. aureus
). At the approved cIAI dosage or higher (1 mg/kg or 1.5 mg/kg q12h), a PK/PD cutoff value of 2 mg/L was appropriate for
E. coli
, while a lower value of 1 mg/L was selected for
K. pneumoniae
,
A. baumannii
, and
S. aureus
. For lower doses, the cutoff value was reduced to 0.5 mg/L for
K. pneumoniae
,
A. baumannii
, and
S. aureus
. The study showed eravacycline was widely distributed into the lungs with promising antibacterial efficacy, thus justifying further investigations into its uses for pulmonary infections.
Proinflammatory synergy between protease and superantigen streptococcal pyogenic exotoxins
Authors: Johnson Anders F. , Bushman Summer D. , LaRock Doris L. , Díaz Juan Manuel , McCormick John K. , LaRock Christopher N.
Published: January 2025

Streptococcal pyogenic exotoxins (Spe proteins) secreted by
Streptococcus pyogenes
(group A
Streptococcus
, GAS) are responsible for scarlet fever and streptococcal toxic shock syndrome. Most Spes are superantigens that cause excessive inflammation by activating large numbers of T cells. However, Streptococcal pyogenic exotoxin B (SpeB) is an exception, which is pro-inflammatory through its protease activity. Prior work shows that SpeB has the potential to cleave bacterial proteins. If cleavage of superantigens results in their inactivation, this gives the possibility that these two classes of exotoxins work at cross-purposes. We examined SpeB cleavage of the 11 major GAS superantigens and found that lability was not specific to structure, conservation, or, when compared to orthologous superantigens from
Staphylococcus aureus
, species of origin. We further show that rather than strictly antagonizing superantigen activity through degradation, SpeB can synergistically enhance superantigen-induced inflammation. For SpeB-labile superantigens, such as SmeZ, this is limited due to degradation, but for protease-resistant superantigens like SpeA, activity remains synergistic even at high protease concentrations. These findings suggest two modes by which proteases like SpeB may post-translationally regulate superantigens: positively, as a force amplifier that cooperatively increases inflammation, and negatively, through degradation that could act as a rheostat-like mechanism to limit excessive immune activation. Both mechanisms may contribute to the pathogenesis of GAS and other superantigen-producing pathogens.

IMPORTANCE

Streptococcus pyogenes
produces both superantigen and protease virulence factors to subvert host immunity. However, its major protease is highly promiscuous and would potentially limit superantigen activity through its degradation. We profile the sensitivity of the streptococcal superantigens to degradation by the protease SpeB, providing evidence that many are highly resistant. Furthermore, we show that these important toxins can have synergistic proinflammatory activity. This provides insight into diseases like scarlet fever and toxic shock syndrome caused by these toxins and suggests anti-inflammatories that may be therapeutically useful.
LitR and its quorum-sensing regulators modulate biofilm formation by
Vibrio fischeri
Authors: Fung Brittany L. , Visick Karen L.
Published: January 2025

Quorum sensing controls numerous processes ranging from the production of virulence factors to biofilm formation. Biofilms, communities of bacteria that are attached to one another and/or a surface, are common in nature, and when they form, they can produce a quorum of bacteria. One model system to study biofilms is the bacterium
Vibrio fischeri
, which forms a biofilm that promotes the colonization of its symbiotic host. Many factors promote
V. fischeri
biofilm formation
in vitro
, including the symbiosis polysaccharide (SYP) and cellulose, but the role of quorum sensing is currently understudied. Recently, a quorum-sensing-dependent transcription factor, LitR, was shown to negatively influence
V. fischeri
biofilm formation in the context of a biofilm-overproducing strain. To better understand the importance of LitR, we identified conditions in which the impact of LitR on biofilm formation could be observed in an otherwise wild-type strain and then investigated its role and the roles of upstream quorum regulators in biofilm phenotypes. In static conditions, LitR and its upstream quorum regulators, including autoinducer synthases LuxS and AinS, contributed to control over biofilms that were both SYP and cellulose dependent. In shaking liquid conditions, LitR and AinS contributed to control over biofilms that were primarily cellulose dependent. LitR modestly inhibited cellulose transcription in a manner that depended on the transcription factor VpsR. These findings expand our understanding of LitR and the quorum-sensing pathway in the physiology of
V. fischeri
and illuminate negative control mechanisms that prevent robust biofilm formation by wild-type
V. fischeri
under laboratory conditions.

IMPORTANCE

Quorum sensing is a key regulatory mechanism that controls diverse phenotypes in numerous bacteria, including
Vibrio fischeri
. In many microbes, quorum sensing has been shown to control biofilm formation, yet in
V. fischeri
, the link between quorum sensing and biofilm formation has been understudied. This study fills that knowledge gap by identifying roles for the quorum sensing-controlled transcription factor, LitR, and its upstream quorum-sensing regulators, including the autoinducer synthases AinS and LuxS, in inhibiting biofilm formation under specific conditions. It also determined that LitR inhibits the transcription of genes required for cellulose biosynthesis. This work thus expands our understanding of the complex control over biofilm regulation.
Perturbation of
Pseudomonas aeruginosa
peptidoglycan recycling by anti-folates and design of a dual-action inhibitor
Authors: Yaeger Luke N. , Sychantha David , Luong Princeton , Shekarriz Shahrokh , Goncalves Océane , Dobrin Annamaria , Ranieri Michael R. , Lamers Ryan P. , Harvey Hanjeong , diCenzo George C. , Surette Michael , Côté Jean-Phiippe , Magolan Jakob , Burrows Lori L.
Published: January 2025

Peptidoglycan (PG) is an important bacterial macromolecule that confers cell shape and structural integrity, and is a key antibiotic target. Its synthesis and turnover are carefully coordinated with other cellular processes and pathways. Despite established connections between the biosynthesis of PG and the outer membrane, or PG and DNA replication, links between PG and folate metabolism remain comparatively unexplored. Folate is an essential cofactor for bacterial growth and is required for the synthesis of many important metabolites. Here we show that inhibition of folate synthesis in the important Gram-negative pathogen
Pseudomonas aeruginosa
has downstream effects on PG metabolism and integrity that can manifest as the formation of a subpopulation of round cells that can undergo explosive lysis. Folate inhibitors potentiated β-lactams by perturbation of PG recycling, reducing expression of the AmpC β-lactamase. Supporting this mechanism, folate inhibitors also synergized with fosfomycin, an inhibitor of MurA, the first committed step in PG synthesis that can be bypassed by PG recycling. These insights led to the design of a dual-active inhibitor that overcomes NDM-1 metallo-β lactamase-mediated meropenem resistance and synergizes with the folate inhibitor, trimethoprim. We show that folate and PG metabolism are intimately connected, and targeting this connection can overcome antibiotic resistance in Gram-negative pathogens.

IMPORTANCE

To combat the alarming global increase in superbugs amid the simultaneous scarcity of new drugs, we can create synergistic combinations of currently available antibiotics or chimeric molecules with dual activities, to minimize resistance. Here we show that older anti-folate drugs synergize with specific cell wall biosynthesis inhibitors to kill the priority pathogen,
Pseudomonas aeruginosa
. Anti-folate drugs caused a dose-dependent loss of rod cell shape followed by explosive lysis, and synergized with β-lactams that target D,D-carboxypeptidases required to tailor the cell wall. Anti-folates impaired cell wall recycling and subsequent downstream expression of the chromosomally encoded β-lactamase, AmpC, which normally destroys β-lactam antibiotics. Building on the anti-folate-like scaffold of a metallo-β-lactamase inhibitor, we created a new molecule, MLLB-2201, that potentiates β-lactams and anti-folates and restores meropenem activity against metallo-β-lactamase-expressing
Escherichia coli
. These strategies are useful ways to tackle the ongoing rise in dangerous bacterial pathogens.
The high-osmolarity glycerol (HOG) pathway in
Candida auris
Authors: Yaakoub Hajar , Courdavault Vincent , Papon Nicolas
Published: January 2025

The emerging fungal pathogen
Candida auris
is known for its strong skin tropism and resilience against antifungal and disinfection treatment, posing a significant challenge for healthcare units. Although efforts to identify the effectors of its unique pathogenic behavior have been insightful, the role of the high-osmolarity glycerol (HOG) pathway in this context remains unexplored. The study by Shivarathri and co-workers (R. Shivarathri, M. Chauhan, A. Datta, D. Das et al., mBio 15:e02748-24, 2024,
https://doi.org/10.1128/mbio.02748-24
) sought to address this gap. This report indeed advances our understanding of the critical role of the HOG pathway in
C. auris
pathogenicity by emphasizing its involvement in skin colonization, biofilm formation, and evasion of phagocyte attack.
Complete genome sequence of a carbon tetrachloride-degrading bacterium,
Pseudomonas
sp. strain Stari2
Authors: Stari Leonardo , Jittayasotorn Thiti , Inoue Chihiro , Chien Mei-Fang
Published: January 2025

This article reports on the complete genome of
Pseudomonas
sp. strain Stari2, which was shown to have the ability to degrade carbon tetrachloride (CCl
4
) in aerobic conditions. A single circular sequence of 6,310,573 bp, a GC content of 60.3%, and 5,680 coding sequences were obtained.
In silico
analysis revealed an average nucleotide identity of 94.06% to its closest species.
Draft genome sequencing of a multidrug-resistant
Klebsiella pneumoniae
strain MBBL2 isolated from mastitic cow milk
Authors: Rahman Md. Morshedur , Siddique Naim , Arafat Kh. Yeashir , Das Ziban Chandra , Islam Tofazzal , Hoque M. Nazmul
Published: January 2025

Milk from cows with mastitis is a primary source of bacteria harboring antibiotic resistance genes (ARGs), including
Klebsiella pneumoniae
. We present the genome sequence of
K. pneumoniae
strain MBBL2 isolated from mastitic cow milk, which contains numerous ARGs and virulence-associated genes potentially pathogenic to humans.
Draft genome sequencing of multidrug-resistant
Escherichia coli
strains isolated from mastitic cow milk
Authors: Rahman Md. Morshedur , Siddique Naim , Arafat Kh. Yeashir , Homa Syeda Fowzia , Das Ziban Chandra , Islam Tofazzal , Hoque M. Nazmul
Published: January 2025

Escherichia coli
is an important antibiotic-resistant pathogen in mastitis, with broader public health implications. We report the genomes of two
E. coli
strains, MBBL4 and MBBL5, isolated from mastitic cow milk. The draft genomes, covering 4.6 Mbp each, revealed 57.5% GC content and 100× sequencing depth.
Erratum to: Currents and Tides in the Fram Strait and Greenland Sea
Authors: Morozov E. G. , Frey D. I.
Published: January 2025

An Erratum to this paper has been published: https://doi.org/10.1134/S000143702406002X
Light Stimulation of Sulfide Oxidation in the Black Sea Anoxic Water Column
Authors: Dubinin A. V. , Rimskaya-Korsakova M. N. , Dubinina E. O. , Demidova T. P. , Semilova L. S. , Berezhnaya E. D. , Zologina E. N. , Ocherednik O. A.
Published: January 2025

Elemental sulfur is a common product of hydrogen sulfide oxidation in the photic zone of meromictic basins due to the anoxigenic oxidation of hydrogen sulfide by photosynthetic bacteria. The photic zone in the Black Sea is limited to 50–60 m, which is much higher than the upper limit of the hydrogen sulfide zone interface, which is at a depth of 90–100 m in the center of the sea. In peripheral areas of the Black Sea, the depth of the redox interface reaches 150–170 m, where, as expected, photoautotrophic bacteria are rare and in an inactive state. A study of the distribution of elemental sulfur in the Black Sea anoxic zone showed that waters from depths of 180–300 m are light sensitive. This leads to a sharp increase in sulfur concentrations up to 11.3 µmol/kg with background values of 0.15–0.18 µmol/kg under strictly anaerobic conditions. It was found that such a significant increase in elemental sulfur is associated with the activity of photoautotrophic bacteria. The conditions for the existence of photoautotrophic bacteria at depths of 180–300 m in the Black Sea in the absence of light remain unclear.
Structure of Finite Groups Isospectral to the Automorphism Group of the Second Sporadic Janko Group
Authors: Zhurtov A. Kh. , Lytkina D. V. , Mazurov V. D.
Published: January 2025

We prove that every solvable chief factor of a finite group whose set
of element orders coincides with that of the automorphism group of
the second sporadic Janko group is a 2-group of order 
$ 2^{4} $
,
$ 2^{6} $
, or 
$ 2^{20} $
.
Simpson-Golabi-Behmel syndrome type 1 in a neonate with central hepatoblastoma
Authors: Rahiman Emine A , Bhat Vasudev , Kumar Naveena , Mathai Sheila Samanta
Published: January 2025

We report a neonate evaluated for hepatomegaly during hospitalisation and was diagnosed to have hepatoblastoma, an uncommon childhood malignancy. The presence of dysmorphism, macrosomia and congenital heart defect led to the suspicion of congenital overgrowth conditions. The genetic evaluation revealed a pathogenic variant, conclusive of Simpson-Golabi-Behmel syndrome type 1 (SGBS1). The child was treated with neoadjuvant chemotherapy followed by central hepatectomy and is currently in remission. We discuss the predisposing syndromes for hepatoblastoma, as the neonatal onset of malignancy in the setting of dysmorphism and congenital anomalies led us to the molecular diagnosis. Children with multisystem involvement require interdisciplinary care, which is detailed. The role of neoadjuvant chemotherapy in facilitating extensive liver resection and the use of technological advancement like intraoperative imaging that can aid definitive resection is discussed. Long-term follow-up for surveillance of primary cancers is crucial in the comprehensive care of cancer-predisposing conditions, the recommendations of which are listed.
Cardioembolic stroke caused by atrial myxoma
Authors: Devlin Kate , McGreal-Bellone Aimée , O'Driscoll Anne
Published: January 2025

A woman in her early 60s presented with multiple transient neurological symptoms over the course of 20 months, including transient loss of power to her right lower limb. Initial workup with CT brain scan, carotid dopplers and ECG revealed no abnormality; however, MRI of the brain suggested recent ischaemic events in separate cortical territories. Subsequent transoesophageal echocardiogram revealed a large mobile mass histologically confirmed to be an atrial myxoma. This case highlights the challenges in diagnosing atrial myxomas and the importance of thorough workup including cardiac imaging for suspected cerebrovascular events. It also underscores the role of brain MRI when clinical suspicion for a cerebrovascular event persists despite a normal CT scan.