bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ligand distances as key predictors of pathogenicity and function in NMDA receptors
Authors: Montanucci Ludovica , Brünger Tobias , Bhattarai Nisha , Boßelmann Christian M , Kim Sukhan , Allen James P , Zhang Jing , Klöckner Chiara , Krey Ilona , Fariselli Piero , May Patrick , Lemke Johannes R , Myers Scott J , Yuan Hongjie , Traynelis Stephen F , Lal Dennis 
Published: November 2024

Abstract
Genetic variants in the genes GRIN1, GRIN2A, GRIN2B, and GRIN2D, which encode subunits of the N-methyl-D-aspartate receptor (NMDAR), have been associated with severe and heterogeneous neurologic and neurodevelopmental disorders, including early onset epilepsy, developmental and epileptic encephalopathy, intellectual disability, and autism spectrum disorders. Missense variants in these genes can result in gain or loss of the NMDAR function, requiring opposite therapeutic treatments. Computational methods that predict pathogenicity and molecular functional effects of missense variants are therefore crucial for therapeutic applications. We assembled 223 missense variants from patients, 631 control variants from the general population, and 160 missense variants characterized by electrophysiological readouts that show whether they can enhance or reduce the function of the receptor. This includes new functional data from 33 variants reported here, for the first time. By mapping these variants onto the NMDAR protein structures, we found that pathogenic/benign variants and variants that increase/decrease the channel function were distributed unevenly on the protein structure, with spatial proximity to ligands bound to the agonist and antagonist binding sites being a key predictive feature for both variant pathogenicity and molecular functional consequences. Leveraging distances from ligands, we developed two machine-learning based predictors for NMDA variants: a pathogenicity predictor which outperforms currently available predictors and the first molecular function (increase/decrease) predictor. Our findings can have direct application to patient care by improving diagnostic yield for genetic neurodevelopmental disorders and by guiding personalized treatment informed by the knowledge of the molecular disease mechanism.
Genetic analysis implicates ERAP1 and HLA as risk factors for severe Puumala virus infection
Authors: Haapaniemi Hele , Strausz Satu , Tervi Anniina , Jones Samuel E , Kanerva Mari ,   FinnGen, Estonian Biobank Research Team, Abner Erik , Fors Connolly Anne-Marie , Ollila Hanna M 
Published: November 2024

Abstract
Puumala virus (PUUV) infections can cause severe illnesses such as Hemorrhagic Fever with Renal Syndrome in humans. However, human genetic risk factors contributing to disease severity are still poorly understood. Our goal was to elucidate genetic factors contributing to PUUV infections and understand the biological mechanisms underlying individual vulnerability to PUUV infections. Leveraging data from the FinnGen study, we conducted a genome-wide association study on severe Hemorrhagic Fever with Renal Syndrome caused by PUUV with 2227 cases. We identified associations at the Human Leukocyte Antigen (HLA) locus and ERAP1 with severe PUUV infection. HLA molecules are canonical mediators for immune recognition and response. ERAP1 facilitates immune system recognition and activation by cleaving viral proteins into smaller peptides which are presented to the immune system via HLA class I molecules. Notably, we identified that the lead variant (rs26653, OR = 0.84, P = 2.9 × 10–8) in the ERAP1 gene was a missense variant changing amino acid arginine to proline. From the HLA region, we showed independent and significant associations with both HLA class I and II genes. Furthermore, we showed independent associations with four HLA alleles with severe PUUV infection using conditional HLA fine mapping. The strongest association was found with the HLA-C*07:01 allele (OR = 1.54, P = 4.0 × 10−24) followed by signals at HLA-B*13:02, HLA-DRB1*01:01, and HLA-DRB1*11:01 alleles (P &lt; 5 × 10−8). Our findings suggest an association of viral peptide processing with ERAP1 and antigen presentation through HLA alleles that may contribute to the development of severe PUUV disease.
Analysis of genotype effects and inter-individual variability in iPSC-derived trisomy 21 neural progenitor cells
Authors: Lee Sarah E , Baxter Laura L , Duran Monica I , Morris Samuel D , Mosley Iman A , Fuentes Kevin A , Pennings Jeroen L A , Guedj Faycal , Bianchi Diana W 
Published: November 2024

Abstract
Trisomy of human chromosome 21 (T21) gives rise to Down syndrome (DS), the most frequent live-born autosomal aneuploidy. T21 triggers genome-wide transcriptomic alterations that result in multiple atypical phenotypes with highly variable penetrance and expressivity in individuals with DS. Many of these phenotypes, including atypical neurodevelopment, emerge prenatally. To enable in vitro analyses of the cellular and molecular mechanisms leading to the neurological alterations associated with T21, we created and characterized a panel of genomically diverse T21 and euploid induced pluripotent stem cells (iPSCs). We subsequently differentiated these iPSCs to generate a panel of neural progenitor cells (NPCs). Alongside characterizing genotype effects from T21, we found that T21 NPCs showed inter-individual variability in growth rates, oxidative stress, senescence characteristics, and gene and protein expression. Pathway enrichment analyses of T21 NPCs identified vesicular transport, DNA repair, and cellular response to stress pathways. These results demonstrate T21-associated variability at the cellular level and suggest that cell lines from individuals with DS should not solely be analyzed as a homogenous population. Examining large cohorts of genetically diverse samples may more fully reveal the effects of aneuploidy on transcriptomic and phenotypic characteristics in T21 cell types.
A panel of genomically diverse T21 and euploid induced pluripotent stem cells (iPSCs) were created and subsequently differentiated into neural progenitor cells (NPCs). T21 NPCs showed reduced growth, increased oxidative stress, and inter-individual variability in gene and protein expression. This inter-individual variability suggests that studies with large cohorts of genetically diverse T21 samples may more fully reveal the effects of aneuploidy.
Biologics and Oral Small Molecules Are Not Associated With Increased Major Adverse Cardiovascular Events or Venous Thromboembolism in Inflammatory Bowel Disease
Authors: Qapaja Thabet , Abu-Rumaileh Mohammed , Alsabbagh Alchirazi Khaled , Gharaibeh Ahmad , Naser Ahmad , Hamid Osama , Alayan Dina , Regueiro Miguel 
Published: November 2024

Abstract

Background
Biologics and oral small molecules (OSM) effectively treat inflammatory bowel disease (IBD), but some are linked to higher risks of major adverse cardiovascular events (MACE) and venous thromboembolism (VTE). This study evaluates the MACE and VTE risks in IBD patients treated with biologics or OSM.

Methods
Using the TrinNetX multi-institutional database, we examined MACE and VTE in adult IBD patients on biologics and compared them to IBD patients not on biologics. We also compared IBD patients on OSM to those not on OSM. We performed 1:1 propensity score matching. MACE (myocardial infarction [MI], stroke, and all-cause mortality) and VTE were assessed from 30 days to 3 years after drug prescription.

Results
After matching, IBD patients on biologics had reduced risk of MI, stroke, and all-cause mortality at 1 year, compared to those not on biologics (P &lt; .05). No significant difference in VTE was observed (P = .5). At 3 years, biologic-treated patients had lower risks of MI, stroke, all-cause mortality, and VTE (P &lt; .05). Inflammatory bowel disease patients on OSM showed no significant differences in MI, stroke, or VTE at 1 and 3 years, but had lower all-cause mortality (P &lt; .05). In older IBD patients with at least 1 cardiovascular risk factor, OSM usage showed no significant difference in MI, stroke, or VTE risk compared to nonusers; however, all-cause mortality was decreased at 3 years (P &lt; .05).

Conclusions
Inflammatory bowel disease patients treated with biologics or OSM were not at increased risk of MACE or VTE. Although further studies and longer follow-up periods are needed to confirm these findings, our results provide reassurance regarding the safety of these medications in IBD.
A re-assessment of Palaeotanyrhina (Hemiptera: Heteroptera) elucidates the phylogeny of Leptopodoidea
Authors: Rédei Dávid 
Published: November 2024

Abstract
A morphologically unusual fossil true bug genus, Palaeotanyrhina Poinar, Brown & Kóbor, 2022, placed into Cimicomorpha: Reduvioidea by its authors, is revisited based on an inclusion in mid-Cretaceous Burmese amber. The original description is supplemented with additional details and corrections. It is demonstrated that the placement of Palaeotanyrhina into Cimicomorpha was based on misinterpretations of the morphology of the holotype, and the genus is a member of the infraorder Leptopodomorpha. A phylogenetic analysis is provided for fossil and extant taxa of Leptopodomorpha. Parvilepta Yu, Zhuo & Chen, 2023, Cretaleptus Sun & Chen, 2019, Macrolepta Yu, Zhuo & Chen, 2023 (currently members of Leptopodidae: Leptosaldinae) and Palaeoleptus Poinar, 2009 (the type genus of Palaeoleptidae) are demonstrated to be phylogenetically closely related to Palaeotanyrhina. All the above mentioned genera are recognized to represent stem-group members of Leptopodomorpha: Leptopodidae: Leptopodinae: Leptopodini, and accordingly, they are transferred to the latter tribe. The following new subjective synonyms are proposed: Leptopodidae: Leptopodinae: Leptopodini Brullé, 1836 = Palaeoleptidae Poinar, 2009, syn. nov. = Palaeotanyrhinidae Poinar, Brown & Kóbor, 2022, syn. nov. Based on the analytic results, the subfamilies Leptosaldinae and Leptopodinae of Leptopodidae and the tribes Leotichiini and Leptopodini of Leptopodinae are considered valid, redefined, and a list of their included genera and species are provided. Arguments are provided in support of the placement of Leptosaldinea Popov & Heiss, 2016, formerly placed into Leptosaldinae, into the infraorder Dipsocoromorpha.
Archives of cyanobacterial traits: insights from resurrected Nodularia spumigena from Baltic Sea sediments reveal a shift in temperature optima
Authors: Medwed Cynthia , Karsten Ulf , Romahn Juliane , Kaiser Jérôme , Dellwig Olaf , Arz Helge , Kremp Anke 
Published: November 2024

Abstract
Cyanobacterial blooms in the Baltic Sea proliferated in recent decades due to rising sea surface temperatures, resulting in significant ecological impacts. To elucidate their current success, we examined ecophysiological, biochemical, and morphological traits of recent and ~33-year-old strains of Nodularia spumigena using a resurrection approach. The ability of many cyanobacteria to form dormant stages that can persist in anoxic sediments for decades provides a unique opportunity to study adaptive traits to past environmental conditions. A short sediment core from the Eastern Gotland Basin was processed to isolate strains of N. spumigena buried in 1987 ± 2 and 2020 ± 0.5 Common Era. Sequencing was used for species identification, followed by characterization of cell morphometry, carbon, nitrogen, and chlorophyll a content. Photosynthetic performance was evaluated by using pulse-amplitude modulated fluorimetry and oxygen optodes to assess light and temperature requirements. Our results revealed trait changes in N. spumigena over the past 3 decades: Temperature optimum for photosynthesis shifted from 15.3–21.1°C, which is consistent with the past and present local SST. Recent strains exhibited increased carbon, nitrogen, and chlorophyll a content despite decreased cell volume. The demonstrated adaptability of N. spumigena to increasing temperature suggests that this species will thrive in a warmer climate in the future. These insights will aid modeling efforts aimed at understanding and managing consequences of future cyanobacterial blooms in the Baltic Sea ecosystem.
Vancomycin combined with piperacillin/tazobactam increases the risk of acute kidney injury compared with vancomycin plus other anti-pseudomonal beta-lactams: a systematic review and network meta-analysis
Authors: Pan Kunming , Li Ranyi , Li Yanli , Ding Xiaoqiang , Li Xiaoyu , Lv Qianzhou 
Published: November 2024

Abstract

Objective
To explore whether vancomycin plus piperacillin/tazobactam actually increases nephrotoxicity compared with other anti-pseudomonal beta-lactams (BLs).

Methods
PubMed, Embase, Web of Science, Cochrane, CNKI, Wanfang and VIP were searched from inception to October 2023. The primary outcomes were acute kidney injury (AKI) as defined as acute increase in serum creatinine of 0.3 mg/dL or 50% and severe Stage 2–3 AKI.

Results
We included 70 studies (76 638 patients). Network meta-analysis indicated that vancomycin plus piperacillin/tazobactam was associated with significantly higher AKI risk than vancomycin plus cefepime (OR 2.55, 95% CI 2–3.28), vancomycin plus meropenem (OR 2.26, 95% CI 1.71–3.02) and vancomycin plus other uncommonly used BLs (OR 2.47, 95% CI 1.87–3.29). Also, vancomycin + piperacillin/tazobactam was associated with significantly higher Stage 2–3 AKI risk than vancomycin + cefepime (OR 2.22, 95% CI 1.34–3.62), vancomycin + meropenem (OR1.96, 95% CI 1.22–3.25) and vancomycin + uncommonly used BLs (OR 2.81, 95% CI 1.66–4.91). Vancomycin plus piperacillin/tazobactam did not result in a significant difference in the incidence of receiving dialysis treatment, mortality, length of stay and time to AKI. Subgroup analyses of studies conducting propensity score matching demonstrated vancomycin + piperacillin/tazobactam was associated with significantly higher AKI rates than vancomycin + cefepime (OR 2.19, 95% CI 1.38–3.47) and vancomycin + meropenem (OR 1.38, 95% CI. 1.18–1.60). Subgroup analysis of critically ill patients and children indicated that vancomycin + piperacillin/tazobactam was associated with significantly higher AKI rates.

Conclusions
Vancomycin + piperacillin/tazobactam significantly increased the risk of AKI and severe Stage 2–3 AKI compared with vancomycin plus other BLs. More prospective studies are needed.
An integrative approach to the taxonomy of Oxymycterus paramensis (Rodentia, Cricetidae) and related nominal forms
Authors: Jayat J Pablo , Torres Ricardo , D’Elía Guillermo , de Oliveira João A , Ortiz Pablo E , Teta Pablo 
Published: November 2024

Abstract
Oxymycterus includes 17 species of small- to medium-sized sigmodontine rodents. The taxonomy of this genus has been widely studied, but several unresolved issues persist. One example of this is the Paramo Hocicudo, Oxymycterus paramensis, which over its extended latitudinal range has been associated with several nominal forms that have not been evaluated with an integrative approach. Based on phylogenetic analyses of the Cytb gene, qualitative and quantitative morphological characters, and environmental niche modeling, we reexamined the taxonomic status of the nominal forms akodontius, jacentior, and paramensis while considering the recently recognized species O. willkaurco. The phylogenetic reconstruction guided subsequent analysis of morphological variation and the development of the niche models. Considering the results in an integrative framework, we observed congruence among phylogenetic, species distribution models, and environmental niche models (a proxy indicating different environmental preferences), which support the recognition of 2 species within the concept of O. paramensis s.l. At the same time, we did not observe congruent support for this taxonomic hypothesis from morphological evidence, with the absence of diagnostic qualitative or quantitative characters differentiating the 2 taxa. Considering that some lines of evidence suggest the interruption of gene flow, we see more support for recognizing existing names for 2 taxa at the species level: O. paramensis, endemic to Bolivia; and O. akodontius (which has priority over jacentior), distributed from southern Bolivia to northwestern Argentina. However, we recommend more detailed studies to test the taxonomic scenario advanced here.
Spatial stress analysis in an elastic parallelepiped
Authors: Tokovyy Yuriy , Yuzvyak Mykola 
Published: November 2024

Abstract
The direct integration method is extended onto the 3D analysis of an elastic rectangular parallelepiped subject to arbitrary force loadings on its sides. By making use of the equilibrium equations, the integral-form expressions are derived for the stress-tensor components through the introduced Vihak functions. These expressions were efficiently used to reduce the original sets of the local boundary conditions to the equivalent sets of the integral conditions for the Vihak functions. In such a manner, the original problems are managed to be reduced to the auxiliary boundary value problems for the governing integro-differential equations with accompanying integral conditions for the Vihak functions. For solving the auxiliary problems for the key functions, special semi-analytical algorithms are suggested in engaging a specific approach for the separation of variables by making use of the complete systems of orthogonal eigen- and associated functions. This allows for determining the Vihak key functions and, consequently, the stress-tensor components in the form of explicit analytical dependencies on the applied force loadings. The solution is quite beneficial for both theoretical and practical implementations. It was shown by the numerical evidence that the solutions are efficient for the analysis of stress fields in the entire domain including edges and corners.
Postcritical discourse analysis: examining the case of the student well-being discourse
Authors: Schwimmer Marina 
Published: November 2024

Abstract
This article examines how the critical tradition initiated by Nietzsche and pursued through poststructuralism might be compatible with what is currently being described as postcritique. It does so by looking at the example of critical discourse analysis (CDA). The first section gives some indications about the state of the methodology currently known as critical discourse analysis and introduces what a ‘postcritical’ reaction could look like. The second section focuses on a concrete example and presents the main critical literature about the student well-being discourse, showing that it generally limits itself to a debunking attitude. The third section explores how the affirmative and creative dimension of critique, its ‘postcritical’ dimension, has been and could be put forward to contribute to what could be called a postcritical discourse analysis methodology
A model estimating the level of floral transition in olive trees exposed to warm periods during winter
Authors: Smoly Ilan , Elbaz Haim , Engelen Chaim , Wechsler Tahel , Elbaz Gal , Ben-Ari Giora , Samach Alon , Friedlander Tamar 
Published: November 2024

Abstract
Rising winter temperatures jeopardize the fruit yield of trees that require a prolonged and sufficiently cold winter to flower. Predicting the exact risk to different crop varieties is the first step in mitigating the harmful effects of climate change. This work focused on olive (Olea europaea)—a traditional crop in the Mediterranean basin in which flowering depends on the sufficiency of cold periods and the lack of warm ones during the preceding winter. A satisfactory quantitative model forecasting its expected flowering under natural temperature conditions is still lacking. The effect of different temperature regimes on olive flowering level and flowering gene expression was tested empirically. A modified ‘dynamic model’ describing the response of a putative flowering factor to the temperature signal was constructed. The crucial component of the model was an unstable intermediate, produced and degraded at temperature-dependent rates. The model accounts for the number of both cold and warm hours and also for their sequence. Empirical flowering and temperature data were applied to fit the model parameters, using numerical constrained optimization techniques; the model outcomes were successfully validated. The model accurately predicted low-to-moderate flowering under winters with warm periods and properly accounted for the effects of warm periods during winter.
Digital Dark Field—Higher Contrast and Greater Specificity Dark Field Imaging Using a 4DSTEM Approach
Authors: MacLaren Ian , Fraser Andrew T , Lipsett Matthew R , Ophus Colin 
Published: November 2024

Abstract
A new method for dark field imaging is introduced, which uses scanned electron diffraction (or 4DSTEM—4-dimensional scanning transmission electron microscopy) datasets as its input. Instead of working on simple summation of intensity, it works on a sparse representation of the diffraction patterns in terms of a list of their diffraction peaks. This is tested on a thin perovskite film containing structural ordering resulting in additional superlattice spots that reveal details of domain structures, and is shown to give much better selectivity and contrast than conventional virtual dark field imaging. It is also shown to work well in polycrystalline aggregates of CuO nanoparticles. In view of the higher contrast and selectivity, and the complete exclusion of diffuse scattering from the image formation, it is expected to be of significant benefit for characterization of a wide variety of crystalline materials.
The impact of the cosmological constant on past and future star formation
Authors: Sorini Daniele , Peacock John A , Lombriser Lucas 
Published: November 2024

ABSTRACT
We present an extended analytical model for cosmic star formation, with the aim of investigating the impact of cosmological parameters on the star formation history within the $\Lambda$CDM paradigm. Constructing an ensemble of flat $\Lambda$CDM models where the cosmological constant varies between $\Lambda = 0$ and $10^5$ times the observed value, $\Lambda _{\rm obs}$, we find that the fraction of cosmic baryons that are converted into stars over the entire history of the universe peaks at $\sim$ 27 per cent for $0.01 \lesssim \Lambda /\Lambda _{\rm obs} \lesssim 1$. We explain, from first principles, that the decline of this asymptotic star formation efficiency for lower and higher values of $\Lambda$ is driven, respectively, by the astrophysics of star formation, and by the suppression of cosmic structure formation. However, the asymptotic efficiency declines slowly as $\Lambda$ increases, falling below 5 per cent only for $\Lambda \gt 100 \, \Lambda _{\rm obs}$. Making the minimal assumption that the probability of generating observers is proportional to this efficiency, and following Weinberg in adopting a flat prior on $\Lambda$, the median posterior value of $\Lambda$ is $539 \, \Lambda _{\rm obs}$. Furthermore, the probability of observing $\Lambda \le \Lambda _{\rm obs}$ is only 0.5 per cent. Although this work has not considered recollapsing models with $\Lambda \lt 0$, the indication is thus that $\Lambda _{\rm obs}$ appears to be unreasonably small compared to the predictions of the simplest multiverse ensemble. This poses a challenge for anthropic reasoning as a viable explanation for cosmic coincidences and the apparent fine-tuning of the Universe: either the approach is invalid or more parameters than $\Lambda$ alone must vary within the ensemble.