bluuebunny/crossref_metadata_2025 huggingface dataset:
Development of a dynamic counterfactual risk stratification strategy for newly diagnosed acute myeloid leukemia patients treated with venetoclax and azacitidine
Authors: Islam Nazmul , Dale Justin L. , Reuben Jamie S. , Sapiah Karan , Coates James W. , Markson Frank R. , Zhang Jingjing , Wu Lezhou , Gasparetto Maura , Stevens Brett M. , Staggs Sarah E. , Showers William M. , Ransom Monica R. , Desai Jairav , Kulkarni Ujjwal V. , Engel Krysta L. , Jordan Craig T. , Boyiadzis Michael , Smith Clayton A.
Published: November 2024

Objective

The objective of this study was to develop a flexible risk model (RM) stratification strategy for Acute Myeloid Leukemia (AML) that is specific for the new standard of care venetoclax plus azacitidine (ven/aza), captures disease heterogeneity, and addresses a range of real-world data issues.

Materials and Methods

A series of tunable RMs based on a dynamic counterfactual machine learning (ML) strategy that utilized next generation sequencing, cytogenetics, flow cytometry, and other features of the diagnostic AML samples were developed and tested on a single institutional cohort of 316 newly diagnosed patients treated initially with ven/aza.

Results

Favorable, Intermediate, and Adverse risk groups were identified in a series of novel RMs derived using ML models for overall survival (OS) and event free survival (EFS). Most, but not all models, demonstrated equitable patient distribution into the different risk categories (∼20%-40% in each group) with significant separation between categories (Log-Rank based p-values <0.001), and with predictability computed by survival AUC values in the ∼0.60-0.70 range.

Discussion and Conclusion

The general strategy employed here is specific for AML patients treated with ven/aza, is based on a wide range of diagnostic AML pathology features, considers feature interactions, addresses data missingness, sparsity, and the confounding effects of allogeneic hematopoietic cell transplant. It is also readily tunable through simple coding and context specific parameter updates, and adaptable to reflect different use case needs. This strategy represents a new approach to developing more effective RMs for AML and possibly other diseases as well.
Risk of hypothyroidism in meat-eaters, fish-eaters, and vegetarians: A population-based prospective study
Authors: Candussi Catharina J. , Bell William , Thompson Alysha S. , Knüppel Sven , Gaggl Martina , Světnička Martin , Gojda Jan , Cassidy Aedín , Weikert Cornelia , Córdova Reynalda , Kühn Tilman
Published: November 2024

Background

Globally, plant-based diets are gaining in popularity. Whilst their cardiometabolic benefits are well-documented, there is a lack of studies examining the associations between plant-based diets and risk of hypothyroidism.

Methods

We analysed data from the UK Biobank cohort. Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for incident hypothyroidism across vegans, vegetarians, pescatarians, poultry eaters, low meat eaters, and high meat eaters aged 40-69 years. Ancillary to this, we carried out logistic regression analysess to evaluate associations between the diet groups and prevalent hypothyroidism (according to International Classification of Diseases (ICD) codes at baseline.

Results

We included 494,437 individuals from the UK Biobank, of which 231,906 followed a high-meat, 236,510 a low-meat, 5,662 a poultry-based, 11,286 a pescatarian, 8,654 a vegetarian, and 419 a vegan diet. During a median (SD) follow-up of 12.7 (± 3.2) years, 24,240 participants developed hypothyroidism. In multivariable Cox regression models without adjustment for body mass index (BMI), none of the diets were significantly associated with the risk of hypothyroidism. However, there was a tendency for a higher risk of hypothyroidism among vegetarians compared to people following a high-meat diet (HR: 1.08, 95% CI: 0.98 - 1.19). After controlling for BMI the association for vegetarians (HR = 1.18, 95% CI 1.07 – 1.30) became stronger and statistically significant. Furthermore, we observed a positive association between a vegetarian (OR: 1.37, 95% CI: 1.14 - 1.63) and a poultry diet (OR: 1.35, 95% CI: 1.10 1.63) with hypothyroidism prevalence.

Conclusion

In the present study, we found a moderately higher risk of hypothyroidism among vegetarians, after controlling for BMI, a potential collider. This slightly higher risk of hypothyroidism among vegetarians, requires further investigation, taking iodine status and thyroid hormone levels into account.
Diagnostic value of PIVKA-II + AFP and PIVKA-II AFP-L3 in hepatocellular carcinoma: a systematic review and meta-analysis
Authors: Ibn Awadh Abdulrahman , Ajeebi Mariam , Alharbi Shaikhah , Alanazi Khulud , Alzahrani Ahmed , Alkhenizan Abdullah
Published: November 2024

Background

The most promising serum biomarkers for hepatocellular carcinoma (HCC) patients include PIVKA-II, AFP, and AFP-L3. Nevertheless, the effectiveness of combining biomarkers is still up for debate. This meta-analysis aimed to evaluate the diagnostic accuracy of PIVKA-II+AFP and PIVKA-II+AFP-L3.

Methods

Following a systematic search of the literature in PubMed, Medline, Web of Science, Scopus, the Cochrane Library, Embase, Google Scholar and CINAHL, thirty relevant papers were found. Pooled sensitivity, specificity, and diagnostic odds ratio (DOR) were evaluated using a random-effects model.

Results

The pooled sensitivity, specificity and DOR values of PIVKA-II+AFP were 0,79, 0,83, and 24,95, respectively; which were slightly lower to those of PIVKA-II+AFP-L3 (0,77, 0,88, and 29,73, respectively) except for sensitivity. Furthermore, PIVKA-II+AFP-L3 presented higher diagnostic accuracy (AUC=0,923) than did PIVKA-II+AFP (AUC=0,895). Neither threshold effects nor continent or etiology of HCC were found to be sources of heterogeneity. Interestingly, we demonstrated proof of publication bias for DOR values using Egger’s regression test (p < 0,05) and funnel plots. Sensitivity analysis proved the strong reliability of this meta-analysis.

Conclusion

The combined assay of PIVKA-II+AFP-L3 seemed to be more adequate than PIVKA-II+AFP for the diagnosis of HCC. Hence, diagnostic tests combining many biomarkers will be clinically significant for HCC decision-making processes.
Limitations and Enhancements in Genomic Language Models: Dynamic Selection Approach
Authors: Qiu Shibo
Published: November 2024

Genomic Language Models (GLMs), which learn from nucleotide sequences, are crucial for understanding biological principles and excel in tasks such as sequence generation and classification. However, state-of-the-art models vary in training methods, architectures, and tokenization techniques, resulting in different strengths and weaknesses. We propose a multi-model fusion approach with a dynamic model selector that effectively integrates three models with distinct architectures. This fusion enhances predictive performance in downstream tasks, outperforming any individual model and achieving complementary advantages. Our comprehensive analysis reveals a strong correlation between model performance and motif prominence in sequences. Nevertheless, overreliance on motifs may limit the understanding of ultra-short core genes and the context of ultra-long sequences.Importantly, based on our in-depth experiments and analyses of the current three leading models, we identify unresolved issues and suggest potential future directions for the development of genomic models.The code, data, and pre-trained model are available at https://github.com/Jacob-S-Qiu/glm\_dynamic\_selection.
Identification of novel drug-drug interactions: towards precision medicine in women’s reproductive health
Authors: Garcia-Acero Pablo , Henarejos-Castillo Ismael , Sebastian-Leon Patricia , Parraga-Leo Antonio , Garcia-Velasco Juan Antonio , Diaz-Gimeno Patricia
Published: November 2024

Drug-drug interactions (DDIs) may occur when two or more drugs are taken together, leading to undesired side effects or potential synergistic effects. Most clinical effects of drug combinations have not been assessed in clinical trials. Therefore, predicting DDIs can provide better patient management, avoid drug combinations that can negatively affect patient care, and exploit potential synergistic combinations to improve current therapies in women healthcare. For this purpose, a DDI prediction model was built to describe relevant drug combinations affecting reproductive treatments. Approved drug features (chemical structure of drugs, side effects, targets, enzymes, carriers and transporters, pathways, protein-protein interactions, and interaction profile fingerprints) were obtained. A unified predictive score revealed unknown DDIs between reproductive and commonly used drugs and their associated clinical effects on reproductive health. The performance of the prediction model was validated using known DDIs.

This prediction model accurately predicted known interactions (AUROC = 0.9876) and identified 2,991 new DDIs between 192 drugs used in different female reproductive conditions and other drugs used to treat unrelated conditions. These DDIs included 836 between drugs used for in-vitro fertilization. Most new DDIs involved estradiol, acetaminophen, bupivacaine, risperidone, and follitropin. Follitropin, bupivacaine, and gonadorelin had the highest discovery rate (42%, 32%, and 25% respectively). Some were expected to improve current therapies (n=23), while others would cause harmful effects (n=11). We also predicted twelve DDIs between oral contraceptives and HIV drugs that could compromise their efficacy. Overall, these results show the importance of DDIs studies to personalize female reproductive therapies.
A QbD strategy to develop curcumin and siRNA co-loaded lipoplexes to combat osteoarthritis-related inflammation and oxidative stress
Authors: Ranamalla Saketh Reddy , Porfire Alina , Licarete Emilia , Tefas Lucia , Parvathaneni Rohith Pavan , Varghese Oommen. P. , Sesarman Alina , Focsan Monica , Tudoran Lucian Barbu , Tomuta Ioan , Banciu Manuela
Published: November 2024

Chronic knee and lower back pain due to osteoarthritis (OA) has a global prevalence and impacts human well-being by impairing mobility. Oxidative stress and inflammation are key factors in OA pathogenesis and progression. Non-viral gene delivery through liposomes is a promising approach for repairing damaged cartilage tissues. Our study focuses on developing co-loaded lipoplexes for efficient co-delivery of curcumin and therapeutic siRNA. Curcumin downregulates many inflammatory cytokines, scavenges free radicals, and upregulates collagen and aggrecan, therefore reducing pain and helping with regeneration. Quality by Design (QbD) principles guided the development of curcumin-loaded cationic liposomes (CL), which were further used as vectors for therapeutic siRNA in the design of the co-loaded lipoplexes. QbD steps involved risk assessment, Design of Experiments (DoE), and selection of the optimal vector, i.e., optimum curcumin-loaded cationic liposomes (Opt-CL), which would ensure the best transfection efficiency for therapeutic siRNA. The efficiency of Opt-CL was evaluated in both the primary chondrocytes and cell lines, which were induced by oxidative stress and inflammatory conditions. The Opt-CL successfully reduced the oxidative stress levels in both. The Opt-CL were complexed with the IL-6 and IL-8 siRNA to form co-loaded lipoplexes, which efficiently reduced the inflammation in the chondrocytes. These co-loaded lipoplexes effectively transfected chondrocytes with no toxicity and are promising for further testing in OA models. The study has yielded an optimal non-viral vector that could serve as a platform for the incorporation of other lipophilic drugs and negatively charged oligonucleotides for various ailments.

Highlights

Utilization of QbD to screen and optimize critical factors for the development of CL

Development of proof of concept using the curcumin and luciferase siRNA as the small molecule and oligonucleotide candidates for efficient cell viability and transfection

Evaluation of cell internalization and gene knockdown in a luciferase-expressing chondrocyte cell line to prove the model efficacy

In chondrocytes, the optimized formulation demonstrated the reduction of inflammation and oxidative stress.
Future Sequon Finder - A novel approach for predicting future N-linked glycosylation sequons on viral surface proteins
Authors: Bryan Shane P. , Zand Martin S.
Published: November 2024

Influenza viruses are known to evade host immune responses by shielding vulnerable surface protein epitopes via N-linked glycosylation. A program titledFuture Sequon Finderwas developed to predict the locations in which glycan binding sites are most likely to emerge in future influenza hemagglutinin proteins. The predictive modeling approach considers how closely sites in currently circulating strains resemble glycosylation sequons genetically, the surface accessibility of those sites, and the site-specific mutation frequency of the amino acids within those sites that would need to change to generate a glycosylation sequon. The efficacy of this model is tested using historic human H1N1 and H3N2 influenza strains along with swine H1N1 strains. Through this analysis, it is revealed that glycosylation addition events in influenza hemagglutinin proteins are almost always the result of single nucleotide mutation events. It is also revealed that site-specific mutation frequency and surface accessibility are powerful predictors of which sites will become glycosylated in human influenza viruses when considered with the genetic composition of the sites in question. Having been designed to incorporate these factors, the program successfully predicted almost every historic sequon addition event and, in the case of the human strains, ranked them highly among falsely predicted sequons. After demonstrating the model’s power with historical data, the program is used to predict future HA glycosylation sequon locations based on currently circulating human influenza viruses.
Whole Exome Sequencing Uncovers Key Genetic Variants in Congenital Tooth Agenesis: An Integrative Omics Approach
Authors: Ranjan Prashant , Devi Chandra , Verma Neha , Bansal Rajesh , Srivastava Vinay Kumar , Das Parimal
Published: November 2024

This study investigates the genetic underpinnings of congenital tooth agenesis (CTA) using a multiomics approach, integrating whole exome sequencing (WES) and RNA expression analysis. WES was used to analyze the genetic basis of CTA in six affected individuals one with syndromic and five with non-syndromic CTA alongside three healthy and two internal controls. We identified both known and novel variants in candidate genes (EDA, WNT10A, PAX9, TSPEAR) and assessed the functional impacts of novel variants (WNT10A (A135S), and compound heterozygous TSPEAR (L219P, I419Lfs*150)) using RT PCR, while bioinformatics tools were applied to both known and novel variants. RT-PCR indicated disrupted EDA and WNT10A signaling in novel candidate genes WNT10A and TSPEAR. Computational analysis showed deleterious effects for six variants, with gene ontology, protein disorder, localization, and post-translational modifications suggesting significant functional changes. Molecular dynamics simulations predicted that these variants could impact protein stability and function. Additionally, WES analysis revealed 21 genes consistently present in all patients (MAF less than equal to 20%), including novel variants in OR4F21 (K310R, F44L) and LCORL (L1734P). Two variants, OR4F21 (K310R) and MRTFB (A135A), appeared in all cases. Furthermore, 391 genes were shared among three patients, 204 among four, and 98 among five. Integrating multiomic data from the GEO database identified 18 upregulated and 15 downregulated genes, with variants linked to systemic conditions such as autism, Alzheimer, congenital heart disease (CHD), ALS (amyotrophic lateral sclerosis), and cancer. Our findings provide insights into CTA molecular mechanisms, identifying potential biomarkers and therapeutic targets. Further validation could improve diagnosis and treatment strategies for CTA.
Real-world effectiveness of NVX-CoV2373 and BNT162b2 mRNA COVID-19 vaccination in South Korea
Authors: Gwak Eunseon , Choe Seung-Ah , Kim Kyuwon , Bolormaa Erdenetuya , Fix Jonathan , Vadivale Muruga , Rousculp Matthew D. , Choe Young June
Published: November 2024

Abstract

Objectives

In February 2022, NVX-CoV2373 became available in South Korea; real-world effectiveness of multiple doses compared with mRNA-based vaccines has not been thoroughly evaluated.

Methods

This retrospective study identified NVX-CoV2373 and BNT162b2 recipients aged ≥12 years from the K-COV-N database. Vaccine groups were propensity score–matched based on demographic characteristics, Seoul capital area residence, income level, comorbidity/disability, prior SARS-CoV-2 infection, and prior vaccination dose/timing. Outcomes were any and severe (intensive-care-unit admission or death within 8 weeks of infection) laboratory-confirmed SARS-CoV-2 infection assessed from 7 days after the third and fourth dose. Adjusted hazard ratios (aHRs) from matched groups measured vaccine effectiveness up to a 180-day risk window.

Results

From February–December 2022, 923,833 NVX-CoV2373 and 1,286,604 BNT162b2 doses were administered. The 180-day risk-window aHRs (95% CI) for NVX-CoV2373 compared with BNT162b2 for any SARS-CoV-2 infection were 0.78 (0.76–0.79) post third dose and 0.86 (0.86–0.87) post fourth dose. The 180-day aHRs (95% CI) for severe infection were 0.73 (0.53–1.00) after the third dose and 1.21 (1.03–1.42) after the fourth dose.

Conclusions

NVX-CoV2373 demonstrated favorable and similar effectiveness against any and severe SARS-CoV-2 infection, respectively, compared with BNT162b2, with evidence of enhanced NVX-CoV2373 durability.
Procrustes Alignment in Individual-level Analyses of Functional Gradients
Authors: Sasse Leonard , Paquola Casey , Dukart Juergen , Hoffstaedter Felix , Eickhoff Simon B. , Patil Kaustubh R.
Published: November 2024

Functional connectivity (FC) gradients provide valuable insights into individual differences in brain organization, yet aligning these gradients across individuals poses challenges. Procrustes alignment is often employed to standardize gradients across multiple subjects, but the choice of the number of gradients used in alignment introduces complexities that may impact individual-level analyses. In this study, we systematically investigate the impact of varying gradient counts in Procrustes alignment on the principal FC gradient, using data from four resting state fMRI datasets, including the Human Connectome Project (HCP-YA), Amsterdam Open MRI Collection (AOMIC) PIOP1 and PIOP2, and Cambridge Centre for Ageing and Neuroscience (Cam-CAN). We find that increasing the number of gradients used in alignment enhances identification accuracy but can reduce differential identifiability, as additional gradients risk introducing nuisance signals such as motion back into the principal gradient. To further probe these effects, machine learning to predict fluid intelligence and age, and a motion prediction analysis, revealing that higher alignment gradient counts may leak information from lower gradients into the principal gradient for individual-level analyses. These findings highlight the trade-off between alignment precision and the potential reintroduction of noise.

Key Points

Gradient count used in Procrustes alignment impacts identification accuracy and differential identifiability obtained using the principal gradient

The magnitude of the Procrustes transformation correlates with motion measures, and this correlation increases with higher gradient count used in alignment.

Gradient count used in Procrustes alignment impacts prediction of fluid intelligence and age
Recruitment of the cellular lipid transport protein CERT toC. psittaciinclusions regulates the timing of bacterial egress
Authors: Scholz Jana , Holland Gudrun , Laue Michael , Banhart Sebastian , Heuer Dagmar
Published: November 2024

Egress of intracellular pathogens is highly regulated and carefully timed. For the zoonotic bacteriumC. psittaci, the predominant egress pathway isChlamydia-containing sphere (CCS) formation, a calcium-dependent sequential mechanism including protease activity, inclusion membrane destabilization, intracellular calcium increase, and plasma membrane blebbing. How egress is regulated to ensure that it takes place only afterC. psittaciintracellular development is thus far unknown. Here, we show thatC. psittacirecruits the cellular ceramide transporter CERT to its inclusion during intracellular development, but this recruitment is reduced at late time points prior to egress. In addition, an early loss of CERT at the inclusion membrane induced by CERT-KO induces premature egress by CCS formation. Complementation of the CERT-KO with different CERT-GFP variants prevents premature egress, except of complementation with a variant lacking the inclusion targeting PH domain, showing that the localization of CERT is critical for CCS formation. The CERT-KO induced premature CCS are formed by the sequential process described for mature CCS, but they contain mostly RBs and are predominantly non-infectious. Thus, our findings suggest that the timing ofC. psittaciegress by CCS formation is regulated by the recruitment of CERT to the inclusion. We propose that CERT stabilizes the chlamydial inclusion by the formation of ER-inclusion membrane contact sites during intracellular development, and the loss of CERT recruitment facilitates inclusion membrane destabilization and CCS formation.
A domain-general process for theta-rhythmic sampling of either environmental information or internally stored information
Authors: Cavanah Paul J. , Fiebelkorn Ian C.
Published: November 2024

Many everyday tasks, such as shopping for groceries, require the sampling of both environmental information and internally stored information. Selective attention involves the preferential processing and sampling of behaviorally important information from the external environment, while working memory involves the preferential processing and sampling of behaviorally important, internally stored information. These essential cognitive processes share neural resources within a large-scale network that includes frontal, parietal, and sensory cortices, and these shared neural resources can lead to between-domain interactions. Previous research has linked external sampling during selective attention and internal sampling during working memory to theta-rhythmic (3–8 Hz) neural activity in higher-order (e.g., frontal cortices) and sensory regions (e.g., visual cortices). Such theta-rhythmic neural activity might help to resolve the competition for shared neural resources by isolating neural activity associated with different functions over time. Here, we used EEG and a dual-task design (i.e., a task that required both external and internal sampling) to directly compare (i) theta-dependent fluctuations in behavioral performance during external sampling with (ii) theta-dependent fluctuations in behavioral performance during internal sampling. Our findings are consistent with a domain-general, theta-rhythmic process for sampling either external information or internal information. We further demonstrate that interactions between external and internal information—specifically, when to-be-detected information matches to-be-remembered information—are not dependent on theta-band activity (i.e., theta phase). Given that these theta-independent ‘match effects’ occur during early processing stages (peaking at 75 ms), we propose that theta-rhythmic sampling modulates external and internal information during later processing stages.
How sturdy is your memory palace? Reliable room representations predict subsequent reinstatement of placed objects
Authors: Masís-Obando Rolando , Norman Kenneth A. , Baldassano Christopher
Published: November 2024

Our autobiographical experiences typically occur within the context of familiar spatial locations. When we encode these experiences into memory, we can use our spatial map of the world to help organize these memories and later retrieve their episodic details. However, it is still not well understood what psychological and neural factors make spatial contexts an effective scaffold for storing and accessing memories. We hypothesized that spatial locations with distinctive and stable neural representations would best support the encoding and robust reinstatement of new episodic memories. We developed a novel paradigm that allowed us to quantify the within-participant reliability of a spatial context (“room reliability”)prior tomemory encoding, which could then be used to predict the degree of successful re-activation of item memories. To do this, we constructed a virtual reality (VR) “memory palace”, a custom-built environment made up of 23 distinct rooms that participants explored using a head-mounted VR display. The day after learning the layout of the environment, participants underwent whole-brain fMRI while being presented with videos of the rooms in the memory palace, allowing us to measure the reliability of the neural activity pattern associated with each room. Participants were taken back to VR and asked to memorize the locations of 23 distinct objects randomly placed within each of the 23 rooms, and then returned to the scanner as they recalled the objects and the rooms in which they appeared. We found that our room reliability measure was predictive of object reinstatement across cortex, and further showed that this was driven not only by the group-level reliability of a room across participants, but also the idiosyncratic reliability of rooms within each participant. Together, these results showcase how the quality of the neural representation of a spatial context can be quantified and used to ‘audit’ its utility as a memory scaffold for future experiences.
In mouse and gut-on-a-chip models, pre-colonoscopy bowel preparation promotes pathogen colonization of the gut and translocation to other organs
Authors: Clayton Charlotte A. , McCallum Giselle , Deng Brian D. , Srinivas Apsara , Sie Claire , Ng Katharine M. , He Jerry Y. , Tertigas Dominique , Porter Imogen , Pepin Deanna M. , Fardeen Touran , Sinha Sidhartha R. , Surette Michael G. , Vallance Bruce A. , Tropini Carolina
Published: November 2024

In the United States, an estimated 14 million colonoscopies are performed yearly, each requiring patients to undergo bowel preparation, a laxative cleansing of the intestine’s luminal contents. Despite the widespread use of bowel preparation, its effects on the gut and susceptibility to pathogens remains poorly understood, particularly for patients with compromised gut health. Using mouse and gut-on-a-chip models, we found that bowel preparation with the laxative polyethylene glycol rapidly alters the gut environment in multiple ways, making it more susceptible to colonization by bothSalmonella, including a non-motile mutant normally unable to invade the gut, and gut pathobionts from an ulcerative colitis microbiota. In addition, bowel preparation promotes the translocation of these bacteria from the mouse gut to extraintestinal organs, such as nearby lymph nodes, the liver, and spleen. These findings suggest that bowel preparation may have clinical implications that are not currently appreciated.
Engineered CRISPR-Base Editors as a Permanent Treatment for Familial Dysautonomia
Authors: Yun Shuqi , Chekuri Anil , Art Jennifer , Kondabolu Krishnakanth , Slaugenhaupt Susan A. , Zeltner Nadja , Kleinstiver Benjamin P. , Morini Elisabetta , Alves Christiano R. R.
Published: November 2024

Familial dysautonomia (FD) is a fatal autosomal recessive congenital neuropathy caused by a T-to-C mutation in intron 20 of theElongator acetyltransferase complex subunit 1(ELP1) gene, which causes tissue-specific skipping of exon 20 and reduction of ELP1 protein. Here, we developed a base editor (BE) approach to precisely correct this mutation. By optimizing Cas9 variants and screening multiple gRNAs, we identified a combination that was able to promote up to 70% on-target editing in HEK293T cells harboring theELP1T-to-C mutation. These editing levels were sufficient to restore exon 20 inclusion in theELP1transcript. Moreover, we optimized an engineered dual intein-split system to deliver these constructsin vivo. Mediated by adeno-associated virus (AAV) delivery, this BE strategy effectively corrected the liver and brainELP1splicing defects in a humanized FD mouse model carrying theELP1T-to-C mutation and rescued the FD phenotype in iPSC-derived sympathetic neurons. Importantly, we observed minimal off-target editing demonstrating high levels of specificity with these optimized base editors. These findings establish a novel and highly precise BE-based therapeutic approach to correct the FD mutation and associated splicing defects and provide the foundation for the development of a transformative, permanent treatment for this devastating disease.
Theory of spin center sensing of diffusion and other surface electric dynamics
Authors: Candido Denis R. , Flatté Michael E.
Published: November 2024

Surface electric dynamics influences the quantum coherence of near-surface spin centers (i.e., T1 and T2 times) through spatial and temporal fluctuations of the surface charge density and the electrostatic potential at the crystal surface that are described by the spectral noise density S(ω). We find that the electric noise's S(ω) dependence on the depth d of a spin center below the surface follows a power law d−γ not solely determined by whether the surface charges move as localized pointlike charges (monopoles) or dipoles. The exponent γ instead reveals the structure of the surface charge and surface potential correlation functions. For surface dynamics originating from diffusion, the spin center's relaxation and decoherence times exhibit a temporal crossover near the correlation time of the fluctuators and thus provide a quantitative fingerprint of the diffusive behavior of charged particles at surfaces.

Published by the American Physical Society
2024
Quantum dissipative effects for a real scalar field coupled to a time-dependent Dirichlet surface in
d+1
dimensions
Authors: Fosco C. D. , Guntsche B. C.
Published: November 2024

We study the dynamical Casimir effect for a real scalar field φ in d+1 dimensions, in the presence of a mirror that imposes Dirichlet boundary conditions and undergoes time-dependent motion or deformation. Using a perturbative approach, we expand in powers of the deviation of the mirror’s surface Σ from a hyperplane, up to fourth order. General expressions for the probability of pair creation induced by motion are derived, and we analyze the impact of space-time dimensionality as well as of the nonlinear effects introduced by the fourth-order terms.

Published by the American Physical Society
2024
Scattering and Bound Observables for Spinning Particles in Kerr Spacetime with Generic Spin Orientations
Authors: Gonzo Riccardo , Shi Canxin
Published: November 2024

We derive the radial action of a spinning probe particle in Kerr spacetime from the worldline formalism in the first-order form, focusing on linear in spin effects. We then develop a novel covariant Dirac bracket formalism to compute the impulse and the spin kick directly from the radial action, generalizing some conjectural results in the literature and providing ready-to-use expressions for amplitude calculations with generic spin orientations. This allows, for the first time, to find new covariant expressions for scattering observables in the probe limit up to O(G6s1s24). Finally, we use the action-angle representation to compute the fundamental frequencies for generic bound orbits, including the intrinsic spin precession, the periastron advance, and the precession of the orbital plane.

Published by the American Physical Society
2024
Propagation of strong electromagnetic waves in tenuous plasmas
Authors: Sobacchi Emanuele , Iwamoto Masanori , Sironi Lorenzo , Piran Tsvi
Published: November 2024

We study the propagation of electromagnetic waves in tenuous plasmas, where the wave frequency ω0 is much larger than the plasma frequency ωP. We show that in pair plasmas, nonlinear effects are weak for a0≪ω0/ωP, where a0 is the wave strength parameter. In electron-proton plasmas, a more restrictive condition must be satisfied, namely, either a0≪1/ωPτ0, where τ0 is the duration of the radiation pulse, or a0≪1. We derive the equations that govern the evolution of the pulse in the weakly nonlinear regime. Our results have important implications for the modeling of fast radio bursts. We argue that (i) millisecond duration bursts with a smooth profile must be produced in a proton-free environment, where nonlinear effects are weaker, and (ii) propagation through an electron-proton plasma near the source can imprint a submicrosecond variability on the burst profile.

Published by the American Physical Society
2024
Quantum enhancement of spoofing detection with squeezed states of light
Authors: Espinoza Tomás P. , Carrasco Sebastian C. , Rogan José , Valdivia Juan Alejandro , Malinovsky Vladimir S.
Published: November 2024

We employ quantum state discrimination theory to establish the ultimate limit for spoofing detection in electromagnetic signals encoded with random quantum states. Our analysis yields an analytical expression for the optimal bound, which we prove can be achieved using a pair of coherent states. Notably, the quantum enhancement persists regardless of photon number, thereby removing the previous constraint to single-photon sources. This breakthrough unlocks new experimental possibilities using standard laser sources. Furthermore, we explore the encoding of squeezed states and demonstrate that the detection probability approaches 100% when the spoofer's capability is restricted to coherent-state generation.

Published by the American Physical Society
2024
Theoretical basis for cell deaths
Authors: Himeoka Yusuke , Horiguchi Shuhei A. , Kobayashi Tetsuya J.
Published: November 2024

Understanding deaths and life-death boundaries of cells is a fundamental challenge in biological sciences. In this study, we present a theoretical framework for investigating cell death. We conceptualize cell death as a controllability problem within dynamical systems, and compute the life-death boundary through the development of “stoichiometric rays.” This method utilizes enzyme activity as control parameters, exploiting the inherent property of enzymes to enhance reaction rates without affecting thermodynamic potentials. This approach facilitates the efficient evaluation of the global controllability of models. We demonstrate the utility of our framework using its application to a toy metabolic model, where we delineate the life-death boundary. The formulation of cell death through mathematical principles provides a foundation for the theoretical study of cellular mortality.

Published by the American Physical Society
2024
Escherichia coli
Maintains pH via the Membrane Potential
Authors: Terradot Guillaume , Krasnopeeva Ekaterina , Swain Peter S. , Pilizota Teuta
Published: November 2024

Maintaining intracellular homeostases is a hallmark of life, and works to maintain multiple interconnected electrophysiological variables, such as a near-neutral pH and a sufficient electrochemical gradient of protons, the so-called proton motive force (PMF). To generate the latter, relies on central metabolism to move protons out of the cell, where in its preferred near-neutral extracellular environments this is not enough to achieve reported physiological PMF values. Using mathematical modeling, we predict that also uses proton-ion antiporters for this purpose. Their principal function, powered by the central-metabolism-enabled proton efflux, is to generate the PMF by moving other ions. Consistently, our model predicts that the strength of the PMF sets the maximal rate at which the antiporters work, and so determines the extracellular pH range for which the two homeostases hold. We further predict that artificially collapsing the PMF destroys the membrane potential. In support and by concurrently measuring the PMF and pH in individual cells of , we show that decreasing the PMF's strength impairs the cells' ability to maintain pH and that they have negligible membrane potential when there is no PMF. Finally, we use our model to predict the previously reported ranges of extracellular pH for which expresses three antiporters, by defining their cost through the rate at which they divert protons from generating ATP. Taken together our results suggest a new perspective on bacterial electrophysiology, where cells use antiporters to generate the plasma membrane potential and thus their PMF.

Published by the American Physical Society
2024
Enhanced Quantum Emission from a Topological Floquet Resonance
Authors: Afzal Shirin , Zimmerling Tyler J. , Rizvandi Mahdi , Taghavi Majid , Esmaeilifar Leili , Hrushevskyi Taras , Kaur Manpreet , Van Vien , Barzanjeh Shabir
Published: November 2024

Entanglement is a valuable resource in quantum information technologies. The practical implementation of entangled photon sources faces obstacles from imperfections and defects inherent in physical systems, resulting in a loss or degradation of entanglement. The topological photonic insulators, however, have emerged as promising candidates, demonstrating an exceptional capability to resist defect-induced scattering, thus enabling the development of robust entangled sources. Despite their inherent advantages, building programmable topologically protected entangled sources remains challenging due to complex device designs and weak material nonlinearity. Here, we present a development in entangled photon-pair generation achieved through a nonmagnetic and tunable anomalous Floquet insulator, utilizing an optical spontaneous four-wave-mixing process. We verify the nonclassicality and time-energy entanglement of the photons generated by our topological system. Our experiment demonstrates a substantial enhancement in nonclassical photon-pair generation compared to devices reliant only on topological edge states. Our results could lead to the development of resilient quantum sources with potential applications in quantum technology.

Published by the American Physical Society
2024
Construction of pyridine-functionalized metal–organic frameworks for the detection of flazasulfuron
Authors: Zhao Xiaoya , Su Boya , Zhao Qian , Lv Wan , Chen Litong , Huang Lixin , Li Xia , Liao Shengyun
Published: November 2024

Two novel Cu-based metal–organic frameworks (MOFs), namely, poly[[aquadichlorido[μ4-4′-(pyridin-4-yl)-[2,2′:6′,2′′-terpyridine]-4,4′′-dicarboxylato][μ3-4′-(pyridin-4-yl)-[2,2′:6′,2′′-terpyridine]-4,4′′-dicarboxylato]tricopper(II)] monohydrate], {[Cu3(C22H12N4O4)2Cl2(H2O)]·H2O}
n
or {[Cu3(PTP)2Cl2(H2O)]·H2O}
n
, (I), and poly[[diaquabis[μ2-4′-(pyridin-3-yl)-[2,2′:6′,2′′-terpyridine]-4,4′′-dicarboxylato]bis(μ2-terephthalato)tricopper(II)] dihydrate], {[Cu3(C22H12N4O4)2(C8H4O4)2(H2O)2]·2H2O}
n
or {[Cu3(BDC)2(MTP)2(H2O)2]·2H2O}
n
, (II), have been synthesized successfully with 4′-(pyridin-4-yl)-[2,2′:6′,2′′-terpyridine]-4,4′′-dicarboxylic acid (H2PTP) and 4′-(pyridin-3-yl)-[2,2′:6′,2′′-terpyridine]-4,4′′-dicarboxylic acid (H2MTP) as the ligands, respectively. Crystal structure analysis reveals that (II) possesses a 2D coordinated layer structure, in which adjacent 2D coordination layers are linked into 3D frameworks through π–π interactions, while the structure of (I) displays dual coordination layers, in which adjacent coordination layers are connected into a 3D framework through hydrogen-bonding interactions. The photophysical properties of the two MOFs were investigated by fluorescence spectroscopy. Complex (II) shows an obvious `turn-on' fluorescence enhancement effect towards flazasulfuron and its potential application for sensing flazasulfuron in water with high selectivity and sensitivity was also investigated in detail.
Photosystem II: light-dependent oscillation of ligand composition at its active site
Authors: Wang Jimin
Published: November 2024

Recently, the conclusions drawn from crystallographic data about the number of oxygen ligands associated with the CaMn4 cofactor in the oxygen-evolving center (OEC) of Thermosynechococcus vulcanus photosystem II (PSII) have been called into question. Here, using OEC-omit, metal ion-omit and ligand-omit electron-density maps, it is shown that the number of oxygen ligands ranges from three in the functional OEC of monomer B following dark adaption (0F), i.e. in its ground state (PDB entry 6jlj/0F and PDB entry 6jlm/0F), to five for both monomers of PSII in photo-advanced states following exposure to one and two flashes of light. For a significant fraction of the 0F OECs in monomer A, the number is four (PDB entry 6jlj/0F). Following one flash it increases to five (PDB entry 6jlk/1F), where it remains after a second flash (PDB entry 6jlj/2F). Following a third flash (3F), it decreases to three (PDB entry 6jlp/3F), suggesting that an O2 molecule has been produced. These observations suggest a mechanism for the reaction that transforms the O atoms of the water molecules bound at the O3 and O1 sites of the OEC into O2.
Well-being, satisfaction and work engagement: an evidence-based study amongst hospitality managers
Authors: Kautish Pradeep , Agarwal Alpana , Rehman Hina , Jabeen Fauzia , Mehmood Khalid
Published: November 2024

Purpose

The study aims to understand the association between subjective well-being, psychological well-being, work satisfaction and engagement amongst middle-level hospitality managers.

Design/methodology/approach

The data were collected from 624 middle-level hospitality managers working in two corporate hotel chains across five north-western states of India. Structural equation modelling (SEM) with a covariance-based approach (CB-SEM) was implemented using SPSS AMOS, adhering to a two-step process that included both measurement and structural models. The application of CB-SEM primarily aimed to (1) evaluate the cascading impacts across constructs and (2) scrutinise the concurrent relationships amongst constructs, with a specific focus on well-being (both psychological and subjective), context-specific job satisfaction and work engagement.

Findings

Evidently, the post-COVID-19 scenario found to be challenging for the hospitality industry. Thus, this empirical research posits that subjective and psychological well-being positively influences work engagement via work satisfaction as a mediator.

Originality/value

Given the people orientation in the hospitality sector, the research contributes to the existing body of literature by assessing the relationships between psychological and subjective well-being, work satisfaction and engagement amongst middle-level hotel managers employed in the corporate chain of hotels in India.
Committees’ diversity and firm performance: evidence from an emerging country
Authors: Tahir Kamran , Riaz Salman , Battisti Enrico , Ha Van Su
Published: November 2024

Purpose

This study aims to investigate the relationship between committee diversity and firm performance among non-financial firms listed on the Pakistan Stock Exchange (PSX).

Design/methodology/approach

This research is based on a comprehensive assessment of secondary data retrieved from annual reports of firms listed on the PSX and publications from the State Bank of Pakistan spanning the period from 2012 to 2021. The study used various statistical models, including pooled regression, fixed effects and random effects, to examine the relationship between diversity among committees and firm performance. Firm-specific variables such as return on assets, return on equity and market price per share were used as proxies for firm performance.

Findings

The results show that the presence of a female head of the committee on company performance does not show any significant correlation with diversity in board committees. This suggests that the investigation into gender diversity and the appointment of women to leadership positions on these committees is not supported by the findings of this particular sample.

Originality/value

To the best of the authors’ knowledge, this study is the first to investigate the impact of committee diversity on firm performance in Pakistan, one of the Next Eleven countries.
Co-opetition strategies with reference quality effect
Authors: Yan Tianyu , Yang Weizhe , He Yanyan , Gou Qinglong
Published: November 2024

Purpose

This study aims to investigate the effect of the reference quality on the optimal production strategy of a component manufacturer (CM), which mainly concerns whether to sell its high quality self-branded products and whether to supply critical components to a competitive original equipment manufacturer (OEM) who produces low quality products.

Design/methodology/approach

The study considers a supply chain comprising an OEM, a CM and a third-party component manufacturer (TCM), who produces components with uncertain quality. The OEM selects a supplier between the CM and the TCM to produce products. Anticipating the OEM’s supplier selection, the CM chooses among three alternative production strategies. For each alternative strategy of the CM, the authors derive the equilibrium solutions between the OEM and the CM with or without the reference quality effect. Then, the authors obtain the effect of the reference quality on the CM by comparing the CM’s optimal strategy between the two situations.

Findings

First, the reference quality has opposite effects on the CM’s production strategy depending on the competition results. A high reference quality effect motivates the CM to solely sell the self-branded products if the OEM can always enter the final product market when purchasing from the TCM, and to sell both self-branded products and components if the OEM cannot enter the market when using the TCM’s low quality components. Second, the reference quality effect motivates the OEM to accept a higher wholesale price from the CM. Third, the reference quality effect can make the CM benefit from a more stable TCM in competition.

Originality/value

This paper first considers the impact of the reference quality effect on the CM’s production strategy. By considering consumers’ behavior in a co-opetitive supply chain, this paper contributes to both literature and practice.
Impact of corporate climate change disclosure on firm performance: empirical evidence from an emerging economy
Authors: Ghose Biswajit , Gogoi Nivaj , Singh Premendra Kumar , Gope Kiran
Published: November 2024

Purpose

This study aims to investigate the impact of corporate climate change disclosure (CCD) on the financial performance of Indian firms.

Design/methodology/approach

The study is grounded in the principles of signalling theory, legitimacy theory and the cost-benefit analysis approach. The sample for the study includes 77 Indian firms from 2018–2019 to 2021–2022. Required data are collected from published annual reports, sustainability reports and the Ace Equity Database. The explanatory variable CCD is measured using content analysis based on the Task Force on Climate-related Financial Disclosures (TCFD) framework. The panel fixed-effects or random-effects models have been considered for hypotheses testing.

Findings

The disclosure level of CCD and its different components is found to be moderate with an average score of 0.364 among top Indian firms. Regression results reveal a significant positive association between CCD on firms’ market-based performance, suggesting its long-term benefits. Besides, additional analysis indicates the differential impact of CCD on financial performance based on firms’ CEO duality status, industry affiliation and pre-COVID and post-COVID period, thus establishing their moderating role in the observed relationship.

Practical implications

The study highlights the necessity of enhancing climate-related disclosure by Indian firms and strategically leveraging the same to boost their financial performance.

Originality/value

Few studies have examined the implications of CCD (based on the TCFD framework) on firm performance. Moreover, exploring the moderating role of CEO duality, industry type and COVID-19 in the CCD and firm performance relationship is a novel empirical contribution.