bluuebunny/crossref_metadata_2025_split huggingface dataset:
Eye features and retinal photoreceptors of the nocturnal aardvark (Orycteropus afer, Tubulidentata)
Authors: Peichl Leo , Meimann Sonja , Solovei Irina , Gügel Irene L. , Geiger Christina , Schauerte Nicole , Goździewska-Harłajczuk Karolina , Klećkowska-Nawrot Joanna E. , Wibbelt Gudrun , Haverkamp Silke 
Published: November 2024

AbstractThe nocturnal aardvarkOrycteropus aferis the only extant species in the mammalian order Tubulidentata. Previous studies have claimed that it has an all-rod retina. In the retina of one aardvark, we found rod densities ranging from 124,000/mm² in peripheral retina to 214,000/mm² in central retina; the retina of another aardvark had 182,000 – 245,000 rods/mm². This is moderate in comparison to other nocturnal mammals. With opsin immunolabelling we found that the aardvark also has a small population of cone photoreceptors. Cone densities ranged from 300 to 1,300/mm² in one animal, and from 1,100 to 1,600/mm² in the other animal, with large local variations and no large central-peripheral density gradient. Overall, cones comprised 0.25-0.9% of the photoreceptors. Both typical mammalian cone opsins, longwave-sensitive (L) and shortwave-sensitive (S), were present. However, there was colocalization of the two opsins in many cones across the retina (35 – 96% dual pigment cones). Pure L cones and S cones formed smaller populations. This probably results in poor colour discrimination. Thyroid hormones, important regulators of cone opsin expression, showed normal blood serum levels. The relatively low rod density and hence a relatively thin retina may be related to the fact that the aardvark retina is avascular and its oxygen and nutrient supply have to come from the choriocapillaris by diffusion. In contrast to some previous studies, we found that the aardvark eye has a reflective tapetum lucidum with features of a choroidal tapetum fibrosum, in front of which the retinal pigment epithelium is unpigmented. The discussion considers these findings from a comparative perspective.
Heterogeneous Effects of Src Inhibition on Determinants of Metastasis in Preclinical Models of Human Bladder Cancer
Authors: Aragaki Kai , Wehrenberg Bryan , Hayashi Yujiro , McConkey David J. 
Published: November 2024

ABSTRACTBackgroundPast work in preclinical models of solid tumors have implicated SRC in invasion and metastasis, but also demonstrated it inhibited bladder cancer metastasis.ObjectiveDetermine if the role of SRC in metastasis is dependent on bladder cancer molecular subtype membership.MethodsWe analyzed large public datasets, performedin vitroinvasion and migration assays using small-molecule and doxycycline inducible SRC knock-down constructs, andin vivoexperimental metastasis assays.ResultsLooking at large public datasets, we found SRC is upregulated in luminal papillary muscle invasive bladder cancer. Using the consensus classifier on RNA expression from 30 cell lines, we demonstrated that chemical SRC antagonists inhibited migration in luminal papillary cells but had little effect in basal/squamous lines. Conditional SRC knockdown inhibited migration in luminal papillary RT112 cells, whereas it increased migration and reduced proliferation in luminal papillary UM-UC6 cells. Regardless, these effects did not affect levels or sites of experimental metastasisin vivo.ConclusionsThe results support the conclusion that SRC’s biological effects in bladder cancer are not primarily involved in promoting invasion and metastasis. Further work is required to define SRC’s roles in luminal papillary bladder cancers.
Genomic Diversity inPorphyromonas: Evidence ofP. catoniaeCommensality in Lungs
Authors: Velo-Suarez Lourdes , Moalic Yann , Guilloux Charles-Antoine , Ame Jacky , Lamoureux Claudie , Gouriou Stéphanie , Le Berre Rozenn , Beauruelle Clémence , Héry-Arnaud Geneviève 
Published: November 2024

2.AbstractData on the genomics ofPorphyromonasspecies other thanPorphyromonas gingivalis(POTG), particularly within pulmonary environments, are scarce. In this study, we conducted whole genome sequencing (WGS) on pulmonary isolates of POTG, specificallyP. catoniae(n=3),P. pasteri(n=1), andP. uenonis(n=2), from people with cystic fibrosis. These genomic analyses were complemented with antimicrobial susceptibility tests for these strains.We compared the genomic sequences of these pulmonary isolates with those of previously characterizedPorphyromonasspecies. Our study revealed a distinct clade differentiation between non-pigmented and pigmentedPorphyromonasspecies. Interestingly, unlikeP. gingivalis, the pulmonary POTG strains lacked known virulence genes, except a putative hemolysin gene. Regarding antibiotic resistance, notable resistances were limited to vancomycin inP. catoniaeand clindamycin inP. uenonis.These findings support the hypothesis that POTG species may predominantly behave as commensals in the lung environment rather than as pathogens.3.Impact statementPorphyromonasconstitutes a prevalent genus of anaerobic bacteria within the respiratory tract. Despite its ubiquity, the precise taxonomic delineation ofPorphyromonasspecies implicated in respiratory conditions needs to be better defined, as most microbiome analyses report results only at the genus level. Consequently, data about these pulmonary species often default to associations withPorphyromonas gingivalis, a well-characterized oral pathogen. In this study, we sequenced the complete genomes of sixPorphyromonasstrains isolated from the airway microbiota of people with cystic fibrosis (CF) to enhance the representation and identification ofPorphyromonasother thangingivalis(POTG) species. Our phylogenomic analysis aimed to elucidate the diversity within pulmonary POTG. Notably, genomes of the commensal speciesPorphyromonas catoniaeisolated from CF patients did not harbor virulence genes typically associated withP. gingivalis. Additionally, phenotypic resistance profiling against nine clinically relevant antibiotics revealed low resistance levels, notwithstanding the frequent antibiotic treatments administered to CF patients. Our findings provide compelling evidence for the non-pathogenic role of these POTG species in the pulmonary environment.4.Data summarySixPorphyromonasgenomes generated in this study are available in the Sequence Read Archive and GenBank databases under BioProject accession PRJEB75658.The raw data set generated during the current study is available in the European Nucleotide Archive (repository with the project accession number.The authors confirm that all supporting data, code, and protocols have been provided within the article or through supplementary data files.
Predicting Chronic Obstructive Pulmonary Disease (COPD) Diagnosis Using Primary Care Variables and Machine Learning Algorithms
Authors: Santos Dheiver Francisco 
Published: November 2024

AbstractChronic Obstructive Pulmonary Disease (COPD) affects many adults over the age of 50. Part of its incidence in the population is attributed to work and exposure to risk factors such as silica dust, and anticipating the diagnosis can prevent its worsening. This study aims to identify patients at higher risk of having a positive COPD diagnosis using variables routinely collected in primary care. A total of 120,294 participants from the UK Biobank database, recruited between 2006 and 2010, were analyzed. Of these, 1,837 (1.5%) had a positive COPD diagnosis. A total of 20 variables, including demographic data, laboratory tests, habits, and symptoms, were selected to build predictive models of COPD using five machine learning algorithms (artificial neural networks, extra trees, random forests, catboost, and extreme gradient boosting). Additionally, a subset of 7,628 participants with a history in the construction and mining industries was selected to train a specialized model. Among them, 248 (3.25%) had a positive diagnosis. Data were randomly divided, with 70% allocated for training the models and 30% for performance testing. Both models showed good predictive performance. The general model achieved an AUC of 0.847, sensitivity of 0.786, and specificity of 0.765. In the specialist model, an AUC of 0.830, sensitivity of 0.773, and specificity of 0.773 were obtained. The five main predictive variables were chronic cough, age, history of asthma, sputum production, and tobacco exposure. The results demonstrate that it is possible to predict the individual risk of COPD diagnosis using variables commonly collected in primary care.
Leveraging Electronic Health Records to Investigate Sex Differences in Oral Diseases and Conditions
Authors: Fetchko E. , Sangalli L. , Letra A. 
Published: November 2024

ABSTRACTObjectivesSexual dimorphism has been shown to influence disease predisposition and/or progression, however, studies addressing sex-based differences in dental, oral, and craniofacial (DOC) diseases and conditions are scarce. This study aimed to identify DOC diseases and conditions likely influenced by sexual dimorphism using two large data repositories.MethodsRetrospective study of medical/dental record data obtained from adult participants (>18 years old) in the NIHAll of UsResearch Program (n=254,700) and the BigMouth Data Repository (n ≈ 4.7 million). The number of males and females presenting each selected DOC disease concept in each database was recorded. Sex-specific association analysis for each concept was performed using chi-square tests (α ≦ 0.0002). Female-to-male odds ratio (OR) and confidence intervals were also calculated.ResultsThe initial search inAll of Usand BigMouth yielded 216 and 243 DOC concepts, respectively. Eighty-seven of 216 dental concepts identified inAll of Ushad sex-stratified data. Of these, significant sex-related differences were found for 61/87 concepts (70%), with 33 concepts (54%) showing female bias and 28 (46%) showing male bias (P≦ 0.0002). Higher female bias was noted for ‘diseases of oral soft tissues’, ‘disorders of tooth development and eruption’, and ‘diseases of pulpal/periapical tissues’, whereas higher male bias was noted for ‘gingival and periodontal diseases’, ‘dental caries’, and ‘malignant tumor of oral cavity’(P≦ 0.0002). Analysis of BigMouth data showed sex bias for 90/230 (39%) concepts investigated, of which 87 (97%) showed female bias and 3 (3%) showed male bias (P≦ 0.0002). Discordant sex bias results among the databases were noted for 8 concepts.ConclusionsThis study provides evidence of sex bias in numerous DOC diseases and conditions in the populations studied. Additional studies in other populations and considering sociodemographic factors might provide further insight into the role of sexual dimorphism in DOC diseases.
Association Between Glucagon-like Peptide-1 Receptor Agonist Use and Perioperative Aspiration: A Systematic Review and Meta-Analysis
Authors: Elkin Jasmin , Rele Siddharth , Sumithran Priya , Hii Michael , Thuraisingam Sharmala , Spelman Tim , Phan Tuong , Choong Peter , Dowsey Michelle , Shadbolt Cade 
Published: November 2024

SummaryBackgroundGlucagon-like peptide-1 receptor agonists (GLP-1 RAs) are known to slow gastric emptying, however the association between GLP-1 RA use and perioperative aspiration risk is not known. This systematic review and meta-analysis aimed to summarise the evidence on whether GLP-1 RA exposure is associated with (1) pulmonary aspiration in patients undergoing procedures requiring anaesthesia or sedation, or (2) increased residual gastric contents among fasted patients.MethodsA search of MEDLINE, EMBASE, Web of Science, and Cochrane CentralClinicalTrials.govand WHO ICTRP registries (updated 13 Jan 2025), and citation tracking of included studies was performed (14 Jan 2025). Studies assessing perioperative pulmonary aspiration or residual gastric contents among fasted patients who were using any form of GLP-1 RA were included. Data was extracted independently and in duplicate. Pooled odds ratios (ORs) were estimated for each outcome using random effect meta-analysis. Certainty of the evidence for each outcome was assessed using the Grading of Recommendations Assessment, Development, and Evaluation framework.ResultsOf 9,010 screened studies, 28 observational studies were included in the analysis. In a meta-analysis of 9 studies involving 304,060 individuals and 481 cases of aspiration, GLP-1RA exposure was not associated with pulmonary aspiration (OR, 1.04; 95% CI, 0.87-1.25, low certainty evidence). In a meta-analysis of 18 studies involving 165,522 individuals and 3,831 cases of residual gastric contents, GLP-1RA exposure was positively associated with residual gastric contents despite appropriate fasting (OR, 5.96; 95% CI, 3.96-8.98, low certainty evidence). In a meta-analysis of 5 studies involving 1,706 individuals and 208 cases of residual gastric contents, withholding at least one dose of GLP-1 RA prior to a procedure was associated with a lower odds of residual gastric contents (OR, 0.51; 95% CI, 0.33-0.81, very low certainty evidence). No studies measured the association between the time since last dose of GLP-1 RA and pulmonary aspiration.ConclusionsPatients using GLP-1RAs are at heightened risk of presenting to surgery with residual gastric contents, though the available evidence does not indicate that this translates to an elevated risk of aspiration. Further research is needed to evaluate the risks and benefits of different strategies for managing these medications during the perioperative period.
Attention bias at baseline does not moderate the effect of attention bias modification for depressive symptoms
Authors: Hagen Hallvard Solbø , Røssberg Jan Ivar , Harmer Catherine J. , Jonassen Rune , Landrø Nils Inge , Bø Ragnhild 
Published: November 2024

AbstractBackgroundClinical trials of Attention Bias Modification for depressive symptoms have consistently produced small effect sizes and mixed results. Therefore, identifying subpopulations for whom this intervention works has been called for. Considering the intended mechanism behind Attention Bias Modification, change of attentional bias, the level of bias at baseline may moderate its efficacy.MethodsParticipants with a history of depression (N=301) were randomized to receive two daily sessions of either Attention Bias Modification or sham for 14 days. A response-based attention bias score was calculated, and a moderator analysis was run at post-intervention and 1-month follow-up measured by change in Hamilton Depression Rating Scale and Beck Depression Inventory II, respectively.ResultsBaseline attention bias did not significantly moderate the effect of Attention Bias Modification on any of the time points or depression measures.ConclusionsBaseline attentional bias was not found useful for characterizing subgroups more likely to benefit from ABM for depressive symptoms.
A CRISPR-Cas9 assisted analysis of single-cell microbiomes for identifying rare bacterial taxa in phycospheres of diatoms
Authors: Schulte-Hillen Ruben , Giesler Jakob K. , Mock Thomas , Belshaw Nigel , John Uwe , Harder Tilmann , Kühne Nancy , Neuhaus Stefan , Wohlrab Sylke 
Published: November 2024

AbstractPrimary production in aquatic systems is governed by interactions between microalgae and their associated bacteria. Most of our knowledge about algal microbiomes stems from natural mixed communities or isolated algal monocultures, which therefore does neither address the role of genotypic diversity among the algal host cells nor do they reveal how this host diversity impacts the assembly process of associated bacteria. To overcome this knowledge gap, we developed a single-cell 16S sequencing approach in combination with CRISPR-Cas9 guided depletion of host 16S contaminations from the chloroplast. The validity of this novel method was tested by comparing bacterial communities of 144 single-cells across three genotypes of the Arctic marine diatomThalassiosira gravidagrown under different environmental conditions. From these, 62 single-cells were additionally sequenced after CRISPR-Cas9 treatment. Due to the improved sequencing depth, bacterial richness associated with individual diatom cells was increased by up to 56%. By applying this CRISPR-Cas9 treatment we not only revealed intraspecific host-genotype associations but also rare bacterial taxa that were not detected by standard 16S rRNA gene metabarcoding. Thus, the CRISPR-Cas9 assisted single-cell approach developed in this study advances our understanding on how the intraspecific diversity among algal hosts impacts the assembly process of their associated bacteria. This knowledge is essential to understand the co-evolution and adaptation of species in algal microbiomes.
Programmable protein degraders enable selective knockdown of pathogenic β-catenin subpopulationsin vitroandin vivo
Authors: Ye Tianzheng , Alamgir Azmain , Robertus Cara M. , Colina Darianna , Monticello Connor , Donahue Thomas Connor , Hong Lauren , Vincoff Sophia , Goel Shrey , Fekkes Peter , Camargo Luis Miguel , Lam Kieu , Heyes James , Putnam David , Alabi Christopher A. , Chatterjee Pranam , DeLisa Matthew P. 
Published: November 2024

ABSTRACTAberrant activation of Wnt signaling results in unregulated accumulation of cytosolic β-catenin, which subsequently enters the nucleus and promotes transcription of genes that contribute to cellular proliferation and malignancy. Here, we sought to eliminate pathogenic β-catenin from the cytosol using designer ubiquibodies (uAbs), chimeric proteins composed of an E3 ubiquitin ligase and a target-binding domain that redirect intracellular proteins to the proteasome for degradation. To accelerate uAb development, we leveraged a protein language model (pLM)-driven algorithm called SaLT&PepPr to computationally design “guide” peptides with affinity for β-catenin, which were subsequently fused to the catalytic domain of a human E3 called C-terminus of Hsp70-interacting protein (CHIP). Expression of the resulting peptide-guided uAbs in colorectal cancer cells led to the identification of several designs that significantly reduced the abnormally stable pool of free β-catenin in the cytosol and nucleus while preserving the normal membrane-associated subpopulation. This selective knockdown of pathogenic β-catenin suppressed Wnt/β-catenin signaling and impaired tumor cell survival and proliferation. Furthermore, one of the best degraders selectively decreased cytosolic but not membrane-associated β-catenin levels in livers of BALB/c mice following delivery as a lipid nanoparticle (LNP)-encapsulated mRNA. Collectively, these findings reveal the unique ability of uAbs to selectively eradicate abnormal proteinsin vitroandin vivoand open the door to peptide-programmable biologic modulators of other disease-causing proteins.
Cholesterol metabolism and intrabacterial potassium homeostasis are intrinsically related inMycobacterium tuberculosis
Authors: Chen Yue , Hagopian Berge , Tan Shumin 
Published: November 2024

SUMMARYPotassium (K+) is the most abundant intracellular cation, but much remains unknown regarding how K+homeostasis is integrated with other key bacterial biology aspects. Here, we show that K+homeostasis disruption (CeoBC K+uptake system deletion) impedesMycobacterium tuberculosis(Mtb) response to, and growth in, cholesterol, a critical carbon source during infection, with K+augmenting activity of the Mtb ATPase MceG that is vital for bacterial cholesterol import. Reciprocally, cholesterol directly binds to CeoB, modulating its function, with a residue critical for this interaction identified. Finally, cholesterol binding-deficient CeoB mutant Mtb are attenuated for growth in lipid-rich foamy macrophages andin vivocolonization. Our findings raise the concept of a role for cholesterol as a key co-factor, beyond its role as a carbon source, and illuminate how changes in bacterial intrabacterial K+levels can act as part of the metabolic adaptation critical for bacterial survival and growth in the host.
Processing reliant on granule cells is essential for motor learning but dispensable for many cerebellar-dependent behaviors
Authors: Lee Joon-Hyuk , Guo Chong , Wu Shuting , Norton Aliya , Seo Soobin , Yao Zhiyi , Regehr Wade G. 
Published: November 2024

AbstractCerebellar dysfunction leads to motor, learning, emotional, and social deficits. It is assumed that these deficits arise from impaired processing of mossy fiber inputs that activate granule cells (GCs) that in turn excite Purkinje cells (PCs). However, high-frequency spontaneous PC firing might also influence behaviors. To clarify how the cerebellum regulates behaviors, we compared the effects of disrupting either GC signaling, which selectively perturbs cerebellar processing, or PC signaling, which disrupts cerebellar processing and spontaneous PC firing. We find that both GC and PC signaling are required for eyeblink conditioning and vestibulo-ocular reflex (VOR) learning. However, disrupting PC signaling impairs baseline VOR, anxiety, and social behaviors, but abolishing GC signaling does not. This establishes that cerebellar processing is essential for motor learning, but is not required for many cerebellum-dependent behaviors. This suggests that such behaviors could be rescued by elevating firing in downstream targets, as shown previously for social deficits.
De novodesign of triosephosphate isomerases using generative language models
Authors: Romero-Romero Sergio , Braun Alexander E. , Kossendey Timo , Ferruz Noelia , Schmidt Steffen , Höcker Birte 
Published: November 2024

AbstractThe design of proteins with tailored functions is of immense interest to biotechnology, medicine, and the chemical industry. While protein design is rapidly evolving with the use of AI techniques, the design of complex enzymes remains a challenge. Here, we present the use of two large language models (LLMs), ZymCTRL and ProtGPT2, for the generation of de novo enzymes that catalyze the triosephosphate isomerase (TIM) reaction. Natural TIM enzymes are obligatory oligomers that catalyze a multi-step isomerization reaction near the diffusion limit. This makes TIM an ideal target to assess the generative ability of protein language models. Newly generated sequences were filtered to obtain a set of twelve candidates from each approach for experimental validation. Multiple constructs from both language models exhibit the intended function in vivo through their ability to complement a TIM-deficient E. coli strain. In-depth characterization of the best-behaving artificial enzyme reveals behavior and catalytic efficiency close to its natural counterparts. These findings support the use of conditional and fine-tuned unconditional LLMs for the generation of complex enzymes.