bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

ABSTRACTDrug-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

AbstractChronic 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.HighlightsUtilization of QbD to screen and optimize critical factors for the development of CLDevelopment of proof of concept using the curcumin and luciferase siRNA as the small molecule and oligonucleotide candidates for efficient cell viability and transfectionEvaluation of cell internalization and gene knockdown in a luciferase-expressing chondrocyte cell line to prove the model efficacyIn 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

AbstractInfluenza 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.
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

AbstractObjectivesIn 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.MethodsThis 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.ResultsFrom 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.ConclusionsNVX-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

AbstractFunctional 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 PointsGradient count used in Procrustes alignment impacts identification accuracy and differential identifiability obtained using the principal gradientThe 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

AbstractEgress 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

ABSTRACTMany 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

AbstractOur 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

SummaryIn 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

AbstractFamilial 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.
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
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

PurposeThe study aims to understand the association between subjective well-being, psychological well-being, work satisfaction and engagement amongst middle-level hospitality managers.Design/methodology/approachThe 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.FindingsEvidently, 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/valueGiven 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.