bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rectal cancer approach strategies after neoadjuvant treatment - a systematic review and network meta-analysis
Authors: Meng Cong , Shu Wenlong , Sun Liting , Wu Si , Wei Pengyu , Gao Jiale , Shi Jinyao , Li Yang , Yang Zhengyang , Yao Hongwei , Zhang Zhongtao 
Published: February 2025

Background and Aims:
An increasing number of patients with rectal cancer who respond well to neoadjuvant chemoradiotherapy (nCRT) are being considered for organ preservation programs. However, due to the lack of high-level evidence, the survival outcomes of the organ preservation programs are still full of controversy and uncertainty.

Methods:
To assess the effects of total mesorectal excision surgery (TME), watch-and-wait (W&W) and local excision (LE) on long-term outcomes after nCRT, we searched PubMed, Embase, and Web of Science for articles published between 1 January 2010, and 1 December 2023.

Results:
We found 7029 pieces of literature, of which 26 studies met the inclusion criteria, and recruited 2778 participants in the network meta-analysis. Risk of bias assessment showed that most included studies had a low risk of bias. Low-certainty evidence suggests that the TME group was significantly superior to all other interventions for the 2-year local regrowth rate. (W&W group [OR, 0.20; 95% CI, 0.12–0.35], LE group compared with TME group [3.00; 1.60 to 5.80]). There was no significant difference in the 2-year local regrowth rate between W&W and LE group (OR, 0.60; 95% CI, 0.32 to 1.20). There was high to moderate certainty evidence that at three years, the W&W group had a significant advantage in overall survival compared with the TME group (OR, 0.37; 95% CI, 0.09 to 0.95). After five years, no significant difference in overall survival was found between the three treatment modalities.

Conclusions:
We concluded that TME achieved the most significant reduction in 2-year local regrowth rates. However, the W&W strategy and LE demonstrated non-inferiority to TME in long-term survival outcomes.
A novel alpha-synuclein K58N missense variant in a patient with Parkinson’s disease
Authors: Al-Azzani Mohammed , Weber Sandrina , Ramalingam Nagendran , Ramón Maria , Shvachiy Liana , Mestre Gonçalo , Zech Michael , Sicking Kevin , Ibáñez de Opakua Alain , Jayanthi Vidyashree , Amaral Leslie , Agarwal Aishwarya , Chandran Aswathy , Chaves Susana R. , Winkelmann Juliane , Trenkwalder Claudia , Schwager Maike , Pauli Silke , Dettmer Ulf , Fernández Claudio O. , Lautenschläger Janin , Zweckstetter Markus , Busnadiego Ruben Fernandez , Mollenhauer Brit , Outeiro Tiago Fleming 
Published: February 2025

AbstractMutations and multiplications in the SNCAgene, encoding alpha-synuclein (aSyn), are associated with familial forms of Parkinson’s disease (PD). We report the identification of a novelSNCAmissense mutation (NM_000345.4, cDNA 174G>C; protein K58N) in a PD patient using whole exome sequencing, and describe comprehensive molecular and cellular analysss of the effects of this novel mutation. The patient exhibited typical sporadic PD with early onset and a benign disease course. Biophysical studies revealed that the K58N substitution causes local structural effects, disrupts binding to membranes, and enhances aSyn in vitro aggregation. K58N aSyn produces fewer inclusions per cell, and fails to undergo condensate formation. The mutation increases the cytoplasmic distribution of the protein, and has minimal effect on the dynamic reversibility of serine-129 phosphorylation. In total, the identification of this novel mutation advances our understanding of aSyn biology and pathobiology.
Predicting antibody kinetics and duration of protection against SARS-CoV-2 following vaccination from sparse serological data
Authors: Deichmann Julia , Barda Noam , Canetti Michal , Peretz Yovel , Ottolenghi Yael , Lustig Yaniv , Regev-Yochay Gili , Lipsitch Marc 
Published: February 2025

AbstractVaccination against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) generates an antibody response that shows large inter-individual variability. This variability complicates the use of antibody levels as a correlate of protection and the evaluation of population- and individual-level infection risk without access to broad serological testing. Here, we applied a mathematical model of antibody kinetics to capture individual anti-SARS-CoV-2 IgG antibody trajectories and to identify factors driving the humoral immune response. Subsequently, we evaluated model predictions and inferred the corresponding duration of protection for new individuals based on a single antibody measurement, assuming sparse access to serological testing. We observe a reduced antibody response in older and in male individuals, and in individuals with autoimmune diseases, diabetes and immunosuppression, using data from a longitudinal cohort study conducted in healthcare workers at Sheba Medical Center, Israel, following primary vaccination with the BNT162b2 COVID-19 vaccine. Our results further suggest that model predictions of an individual’s antibody response to vaccination can be used to predict the duration of protection when serological data is limited, and could serve as a tool to estimate infection risk over time on both the population and individual level.
The effects of human presence, restraint, and stressed neighbors on corticosterone levels in domesticated budgerigars (Melopsittacus undulatus)
Authors: Reichard Dustin G. , Summers Kelly V. 
Published: February 2025

AbstractLimiting stress during interactions between captive animals and humans is important for effective husbandry. One physiological change during the vertebrate stress response is the release of glucocorticoid hormones. Here, we measured plasma corticosterone in female domesticated budgerigars (Melopsittacus undulatus) to test whether human presence, restraint, or removal and return of a newly stressed neighbor increases corticosterone. The presence of humans for 15 minutes at the beginning of the experiment did not significantly elevate corticosterone above baseline levels, suggesting that birds that acclimate to humans are minimally affected by their presence. However, at the end of the experiment after multiple blood sampling events, the same human presence test significantly elevated corticosterone above baseline and human presence levels measured at the beginning of the experiment. Thus, repeated blood sampling could cause progressively stronger stress responses to human presence. Restraint-induced corticosterone levels were significantly higher than all other treatments, indicating that human handling activates the stress response. After stressed birds were returned home, corticosterone levels of their neighbors were significantly higher than baseline at 25- and 45-minutes post-return. However, the 25- and 45-minute corticosterone levels were not significantly different from each other, or levels induced by human presence at the beginning or end of the experiment. This outcome suggests that social transmission of stress was limited across the sampled time frame. These data highlight the importance of evaluating the costs and benefits of different human-animal interactions in captivity, including in domesticated species that are more tolerant of forced proximity to humans.Research HighlightsHuman presence only elevated plasma corticosterone after multiple blood sampling events.Restraint significantly increased corticosterone levels relative to all other treatments.Minimal evidence for social transmission of stress.
Posttranscriptional activity of the eukaryotic translation initiation factor eIF4E contributes to HoxA9-driven leukemogenesis
Authors: Zhou Fang , Culjkovic-Kraljacic Biljana , Bach Christian , Feng Li , Mishima Yuta , Borden Katherine L. B. , Tenen Daniel G 
Published: February 2025

AbstractHoxA9, a homeodomain-containing transcription factor, is mis-expressed in over half of acute myeloid leukemia (AML) cases, and is associated with poor prognosis. Previous studies indicated that HoxA9 binds to the eukaryotic translation initiation factor eIF4E in primary specimens and that HoxA9 stimulated the RNA export and translation efficiency of selected RNAs via eIF4E. However, the relevance of this to its leukemogenic transformation capacity was unknown. Here, we used a double point mutation (HoxA9AA) to disrupt the physical and functional interaction between eIF4E and HoxA9 while retaining the HoxA9 transcriptional signature. Surprisingly, the mutation dramatically increased AML latency from a median of 90 to 280 days and resulted in incomplete penetrance. Re-transplantation of bone marrow cells from leukemic animals demonstrated even more pronounced differences in disease kinetics and penetrance with all animals succumbing to disease by day 60 in the wildtype group, while some HoxA9AA mice never developed leukemia. Collectively, these findings uncover a novel, transcription-independent mechanism of HoxA9-driven leukemogenesis through eIF4E and positions eIF4E as a potential therapeutic target AML patients expressing high levels of HoxA9.Key PointsA double point mutation in HoxA9 disrupted the physical and functional interaction between eIF4E and HoxA9 while retaining the HoxA9 transcriptional signature.Eukaryotic translation initiation factor eIF4E contributes to HoxA9-driven leukemogenesis and is important for the maintenance of acute myeloid leukemia.
Oral Metformin May Exacerbate Diabetic Neuropathy: A Two-Sample Mendelian Randomization Study
Authors: Wang Xiaoyong , Wu Yujuan , Ma Ningning , Chen Jueying , Chen Yuanjin , Shi Jiaoling 
Published: February 2025

AbstractObjectiveGiven the important role of metformin in diabetes treatment and the uncertainty regarding its relationship with diabetic neuropathy, this study aims to assess the causal relationship between metformin and diabetic neuropathy using Mendelian randomization.MethodsInstrumental variables were derived from publicly available genome-wide association study datasets. Two study cohorts were assigned: a training cohort (exposure ID: ukb-a-159) and a testing cohort (ID: ukb-b-14609), with the outcome ID being finn-b-DM_NEUROPATHY for both.The primary analysis used inverse variance weighting (IVW) for Mendelian randomization, supplemented by weighted median (WMed), weighted mode (WM), simple mode (SM), and MR Egger regression (MER). To test for heterogeneity, pleiotropy, and publication bias, we conducted leave-one-out sensitivity analyses, MR Egger regression, and further assessed with funnel plots.ResultsMendelian randomization analysis showed a significant positive causal relationship between metformin and diabetic neuropathy in both the training set (IVW: logOR 14.73, 95% CI [9.60, 19.86], p=1.78E-08) and the testing set (IVW: logOR 15.83, 95% CI [11.10, 20.56], p=5.54E-11). The WMed, WM, SM, and MER models all consistently supported this conclusion, with no evidence of pleiotropy or heterogeneity, indicating robust results.ConclusionFrom an epidemiological perspective, this study reveals a significant positive correlation between metformin use and diabetic neuropathy through Mendelian randomization analysis. This finding not only provides new insights into the field of diabetes treatment but also suggests that the use of metformin may be associated with the potential side effect of increased risk of diabetic neuropathy.
Heterogeneous constraint and adaptation across the malaria parasite life cycle
Authors: Perkins Sarah A. , Neafsey Daniel E. , Early Angela M. 
Published: February 2025

AbstractEvolutionary forces vary across genomes, creating disparities in how traits evolve. In organisms with complex life cycles, it is unclear how intrinsic differences among discrete life stages impact evolution. We looked for life history-driven changes in patterns of adaptation inPlasmodium falciparum, a malaria-causing parasite with a multi-stage life cycle. Categorizing genes based on their expression in different life stages, we compared patterns of between- and within- species polymorphism across stages by estimating nonsynonymous to synonymous substitution rate ratios (dN/dS) and mean pairwise nucleotide diversity (𝞹NS/𝞹S). Considering these alongside estimates of Tajima’sD, fixation probability, adaptive divergence proportion and rate, andFST, we looked for changes in the drift-selection balance in life stages subject to transmission bottlenecks and changes in ploidy. We observed signals of reduced selection efficacy in genes exclusively expressed in sporozoites, the parasite form transmitted from mosquitoes to humans and often targeted by vaccines and monoclonal antibodies. We discuss implications for how parasites evolve to resist therapeutics and consider functional, molecular, and population genetic factors that could contribute to these patterns.
The Protective Role of Intestinal Alkaline Phosphatase in Inflammatory Bowel Disease-Associated Non-Alcoholic Fatty Liver Disease
Authors: Liu Yang , Lv Hao , Zhang Haonan , Yu Shou , He Qiao , Cao Gang 
Published: February 2025

AbstractBackgroundInflammatory bowel disease (IBD) is a chronic and progressive inflammatory condition characterized by weight loss as a prominent feature. Non-alcoholic fatty liver disease (NAFLD), typically linked to obesity and metabolic dysregulation, is increasingly recognized as being influenced by the gut-liver axis. Notably, IBD patients exhibit a heightened susceptibility to NAFLD, although the underlying mechanisms remain poorly understood. Intestinal alkaline phosphatase (IAP), an endogenous enzyme, plays a critical role in preventing intestinal bacterial translocation. We hypothesized that IAP may serve as a potential therapeutic agent for mitigating IBD-associated NAFLD.MethodsAn IBD model was established using three cycles of 2% dextran sulfate sodium (DSS) administration. Mice were subsequently treated with L-phenylalanine or IAP. The activity of stool IAP, gut microbiota composition, hepatic lipid accumulation, inflammatory markers, and gut microbiome diversity were assessed.ResultsDSS treatment markedly reduced IAP levels. Suppression of IAP significantly increased gut permeability and exacerbated hepatic inflammation and lipid deposition. Conversely, IAP supplementation restored these parameters, improved gut microbial diversity, and normalized microbiota composition. However, IAP failed to ameliorate hepatic inflammation and lipid accumulation in Toll-like receptor 4 (TLR4) knockout mice.ConclusionDeficiency in endogenous IAP contributes to the onset of NAFLD in the context of IBD. Oral IAP supplementation enhances gut barrier integrity, stabilizes gut microbiota, and prevents NAFLD development in IBD through a TLR4-dependent mechanism.
Cost-effectiveness of human papillomavirus self-sampling in the Swedish cervical screening program
Authors: Östensson Ellinor , Borgfeldt Christer , Pedersen Kine , Hellman Kristina , Sy Stephen , Lei Jiayao , Burger Emily A. , Clements Mark S. 
Published: February 2025

AbstractBackgroundIn Sweden, the cervical cancer screening programme is based on primary human papillomavirus (HPV) testing with either clinician-collected cervical sampling or home-based vaginal self-sampling. We assessed the effectiveness and cost-effectiveness of primary HPV clinician-collected sampling and primary HPV self-collected sampling for unvaccinated cohorts of Swedish women.MethodsA model-based analysis was performed to project long-term costs and quality-adjusted life-years (QALYs). Screening strategies included no screening, 18 clinician-collected strategies and 36 self-sampling strategies, with variations in the screening frequency, start age and follow-up management. We estimated incremental cost-effectiveness ratios benchmarked against willingness-to-pay (WTP) thresholds of €50,000 and €100,000 per QALY gained.ResultsCompared with the 2022 recommendations (with primary clinician-collected HPV testing from ages 23 with 5-yearly screening to age 50 and 7-yearly screening through to age 64), self-sampling at the same intensity would lead to similar effectiveness and a 36% reduction in costs. Among the clinician-collected sampling strategies, the optimal strategies involved primary HPV testing from age 25 with 10-yearly screening with extended genotyping (at €50,000 per QALY gained), or 7- and 10-yearly screening for €100,000. Across all strategies, the optimal strategies included primary self-sampling from age 25 with direct referral to colposcopy for HPV-16/18/45 with 7- and 10-yearly screening at €50,000 per QALY gained, and 5- and 7-yearly screening for €100,000 per QALY gained. These results were sensitive to the assumed accuracy of self-sampling compared with clinician-collected sampling.ConclusionsTransitioning from clinician-collected cervical sampling to vaginal HPV self-sampling is likely to be cost-effective for unvaccinated women in Sweden.Highlights-For an analysis restricted to clinician-collected sampling, the 2022 Swedish population-based recommendations (primary HPV testing from age 23 with 5-yearly screening to age 50 and 7-yearly screening between ages 50 and 64 years) were on the cost-efficiency frontier, however longer screening intervals were optimal.-For all of the considered strategies, the optimal strategies were primary vaginal self-sampling from age 25 years with direct referral to colposcopy for HPV 16, 18 and 45 with seven- and ten-yearly screening at €50,000 per QALY gained, and with five- and seven-yearly screening at €100,000 per QALY gained.
Nuclear CK1δ as a Critical Determinant of PER:CRY Complex Dynamics and Circadian Period
Authors: Serrano Fidel E. , Marzoll Daniela , Ruppert Bianca , Diernfellner Axel C. R. , Brunner Michael 
Published: February 2025

AbstractThe mammalian circadian clock is governed by a feedback loop in which the transcription activator CLOCK:BMAL1 induces expression of its inhibitors, PERs and CRYs, which form a complex with CK1δ, the main circadian kinase. The spatiotemporal dynamics of this feedback mechanism and the precise role of CK1δ remain incompletely understood. Using an inducible cell system, we demonstrate that nuclear CK1δ is a key determinant of circadian period. The availability of CK1δ is limited due to rapid degradation and export of unassembled active kinase. Our findings reveal that active CK1δ promotes cytoplasmic localization of the PER2:CRY1 complex and triggers the dissociation of CRY1, which subsequently accumulates in the nucleus. We propose that late in the circadian cycle, cytoplasmic PER:CRY:CK1δ complexes may serve as a reservoir, gradually releasing CRY1 into the nucleus. This mechanism ensures rebinding of CLOCK:BMAL1 to DNA and prolonged attenuation of transcriptional activity after the degradation of PER proteins.
Modeling Epithelial Morphogenesis and Cell Rearrangement during Zebrafish Epiboly: Tissue Deformation, Cell-Cell Coupling, and the Mechanical Response to Stress
Authors: Minsuk Sharon B. , Sego T. J. , Umulis David M. , Mullins Mary C. , Glazier James A. 
Published: February 2025

AbstractMorphogenesis in early development involves complex and extreme deformations in response to intra- and intercellular forces. Zebrafish epiboly, the spreading of the blastoderm to cover and engulf the large yolk cell, is a key early event that sets the stage for gastrulation, but is poorly understood. The enveloping layer (EVL), the thin squamous outer epithelium of the blastoderm, bound at its edges to the yolk cell by tight junctions, plays a central role. The marginal EVL cells receive through their tight junctions, forces generated in the yolk cell, and propagate those forces through the rest of the EVL; and the resulting EVL expansion is required for epiboly of the deep cells within the blastoderm. However, we don’t know how these exogenous forces are generated and regulated; several alternative force generation mechanisms have been proposed. In order to model their relative contributions, we need a mechanical model of the EVL capable of responding to such forces and undergoing the drastic deformation of epiboly. The expanding EVL more than doubles its surface area and experiences significant shear as it deforms from a thin cap at the pole to become a complete sphere, necessarily requiring extensive internal rearrangement. We constructed an agent-based model of the EVL and its response to exogenous forces using the center-based simulation framework, Tissue Forge. Our model captures the large viscoelastic deformation of the EVL by cell rearrangement, and incorporates algorithmic strategies to accommodate these dynamic changes while maintaining tissue cohesion. Features observed in living embryos, such as the straightening of the initially ragged leading edge, also emerge in the model. We identified two key components required for realistic epiboly in the model: first, a mechanism to enable tissue remodeling by cell rearrangement without tearing the tissue, and second, a regulatory negative feedback on the forces driving EVL expansion, to synchronize the advancement of the EVL margin. We discuss the implications of these findings for the behavior of living EVL and the mechanisms that drive epiboly.
Nurturing sustainability: the interplay among digital marketing communication, online customer experience and sustainable purchase intention
Authors: Thakur Anand , Singla Kavita , Singla Kamini , Ansari Alisha , Mishra Ankita , Kaur Simran , Kaur Parwinder 
Published: February 2025

Purpose
This study aims to delve into the underlying factors that play a pivotal role in shaping effective digital marketing communication (DMC) to promote sustainability. Further, it explores the mediating effect of online customer experience (OCE) on the dynamic relationship between DMC and sustainable purchase intention (SPI) and the moderating impact of social media marketing activities (SMMAs) on the relationship between DMC and OCE.

Design/methodology/approach
Based on single cross-sectional survey, 300 responses from green apparel users are analyzed by using partial least squares-structural equation modeling to corroborate the relationships among DMC, OCE, SMMAs and SPI.

Findings
Perceived usefulness, ease of use, web attractiveness, hedonic motivation and subjective norms significantly impact DMC, which in turn positively influences OCE and SPI. Further, OCE significantly mediates the relationship between DMC and SPI, highlighting the crucial role of OCE. The moderation analysis shows that interactivity negatively moderates the DMC-OCE relationship, suggesting that excessive interactivity may diminish the OCE, while personalization and trendiness do not have significant moderating effects.

Practical implications
The findings provide valuable insights for marketers to align their DMC strategies with sustainable business initiatives to create a seamless online experience, thereby fostering SPI in the contemporary digital era.

Originality/value
While previous studies have examined aspects of these relationships separately, this study integrates them into a cohesive framework to provide a more holistic understanding of how digital marketing strategies can promote sustainability.