bluuebunny/crossref_metadata_2025 huggingface dataset:
Can minor trauma cause asymptomatic cervical spinal cord compression leading to severe cervical spinal cord injury in rats?
Authors: Xu Luchun , Wang Ting , Cao Zheng , Gao Yushan , Jiang Guozheng , Ma Yukun , Song Jiawei , Yang Yongdong , Yu Xing
Published: November 2024

The study aimed to determine whether asymptomatic rats with cervical spinal cord compression (CSCC) experience more severe cervical spinal cord injury (SCI) compared with rats without CSCC under the same degree of minor trauma. Four weeks after the polyvinyl alcohol-polyacrylamide hydrogel was implanted into the C5 vertebral canal, asymptomatic rats were selected based on locomotor function score. Mild cervical SCI was subsequently established based on CSCC. The motor function, morphology, neuron loss, myelin destruction, nerve cell apoptosis, microglia activation, and neuroinflammation were evaluated after SCI. Under the same injury conditions, rats in the CSCC group exhibited more severe motor dysfunction compared with those without CSCC. Similarly, asymptomatic CSCC rats showed significant damage to spinal cord tissue, neurons, and myelin. Finally, compared with rats without CSCC, asymptomatic CSCC rats experienced increased nerve cell apoptosis, microglial activation, and neuroinflammation following the same SCI. In asymptomatic CSCC rats, the same degree of minor trauma resulted in more severe cervical SCI compared with rats without CSCC. This was evidenced by increased nerve cell apoptosis, microglial activation, neuron death, myelin destruction, and a strong neuroinflammatory response, leading to severe motor dysfunction.
Family screening for hypertrophic cardiomyopathy: initial cardiologic assessment, and long-term follow-up of genotype-positive phenotype-negative individuals
Authors: Schoonvelde Stephan A.C. , Alexandridis Georgios M. , Price Laura B. , Schinkel Arend F.L. , Hirsch Alexander , Zwetsloot Peter-Paul , Kammeraad Janneke A.E. , van Slegtenhorst Marjon A. , Verhagen Judith M.A. , de Boer Rudolf A. , Michels Michelle
Published: November 2024

Aims

(i) Investigate the prevalence of hypertrophic cardiomyopathy (HCM) in individuals with pathogenic/likely pathogenic (P/LP) gene variants detected through family cascade testing in relatives, and (ii) evaluate phenotypic progression in genotype-positive phenotype-negative (G+/P-) individuals during follow-up.

Results

From 2000-2023, 273 individuals underwent cardiologic evaluation following P/LP variant detection through family screening. Upon initial evaluation, HCM was diagnosed in 128 (47%) individuals. Comparing with 145 G+/P- individuals, HCM patients were older (48 vs 38 years,p<0.001) and more likely male (57% vs 34%,p<0.001). During follow-up (median 11 years), 14 (11%) of the HCM patients died (two from sudden cardiac death), four (3%) underwent myectomy, 15 (12%) developed atrial fibrillation and 17 (13%) required implantable cardioverter-defibrillator implantation (15 primary prevention, 88%). HCM-related adverse outcomes correlated with younger diagnosis age.

During follow-up (median 8 years), out of the 118 G+/P- subjects, seven (6%) individuals (71% female, diagnosed age 39-77, after median follow-up 6 years) developed HCM (mean maximal wall thickness increasing from 10.2 mm to 13.3 mm). In this G+/P- cohort, significant echocardiographic changes from baseline to last visit were negligible. Over half (56%) had <1 mm change of maximal wall thickness. No adverse cardiac outcomes occurred.

Conclusion

The initial evaluation was high-yield, with HCM being diagnosed in 47% of G+ individuals, more frequently in older males. Over a median 8-year follow-up, 6% of G+/P- individuals developed mild HCM, with no adverse cardiac outcomes. These data support initial screening in all first degree relatives, but (very) low-frequency cardiologic evaluations for G+/P- individuals thereafter.
The Fly Disco: Hardware and software for optogenetics and fine-grained fly behavior analysis
Authors: Robie Alice A. , Taylor Adam L. , Schretter Catherine E. , Kabra Mayank , Branson Kristin
Published: November 2024

In the fruit fly,Drosophila melanogaster, connectome data and genetic tools provide a unique opportunity to study complex behaviors including navigation, mating, aggression, and grooming in an organism with a tractable nervous system of 140,000 neurons. Here we present the Fly Disco, a flexible system for high quality video collection, optogenetic manipulation, and fine-grained behavioral analysis of freely walking and socializing fruit fly groups. The data collection hardware and software automates the collection of videos synced to programmable optogenetic stimuli. Key pipeline features include behavioral analysis based on trajectories of 21 keypoints and optogenetic-specific summary statistics and data visualization. We created themultiflydataset for pose estimation that includes 9701 examples enriched in complex behaviors. All hardware designs, software, and themultiflydataset are freely available.
The Condensin II Complex Regulates the Expression of Essential Gene Expression Programs During Erythropoiesis
Authors: Abid Deanna , Murphy Kristin , Murphy Zachary , Rahman Nabil , Getman Michael , Steiner Laurie
Published: November 2024

Erythropoiesis is characterized by dramatic changes in gene expression in the context of a cell that is rapidly proliferating while simultaneously condensing its nucleus in anticipation of enucleation. The mechanisms that maintain high level expression of erythroid genes and promote nuclear condensation remain poorly understood. Condensin II is a ring-like complex that promotes mitotic chromatin condensation and has roles in regulating interphase chromatin architecture and gene expression. We interrogated the role of Condensin II in erythropoiesis using an erythroid-specific deletion of the Condensin II subunit, Ncaph2. Ncaph2 loss resulted in severe embryonic anemia with lethality at embryonic day 13.5. Ncaph2 mutant erythroid cells had dysregulated maturation and disrupted cell cycle progression, but surprisingly Ncaph2 was dispensable for nuclear condensation. Genomic studies revealed that Ncaph2 occupied the promoter of key erythroid and cell cycle genes that were downregulated following Ncaph2 loss. Together, our results demonstrate an essential role for Ncaph2 in the gene expression programs that regulate cell cycle progression and erythroid differentiation, and identify a key role for the Condensin II complex in the regulation of a lineage-specific differentiation program.

Summary Statement

The Condensin II complex regulates cell cycle progression and erythroid differentiation, but is dispensable for nuclear condensation during terminal erythroid maturation.
NovumRNA: accurate prediction of non-canonical tumor antigens from RNA sequencing data
Authors: Ausserhofer Markus , Rieder Dietmar , Facciolla Manuel , Lamberti Giorgia , Lisandrelli Rebecca , Pellegatta Serena , Trajanoski Zlatko , Finotello Francesca
Published: November 2024

Non-canonical tumor-specific antigens (ncTSAs) can expand the pool of targets for cancer immunotherapy, but require robust and comprehensive computational pipelines for their prediction. Here, we present NovumRNA, a fully-automated Nextflow pipeline for predicting different classes of ncTSAs from patients’ RNA sequencing data. We extensively validated NovumRNA using publicly-available and newly-generated datasets, demonstrating the robustness of its analytical modules and predictions. NovumRNA analysis of colorectal cancer organoid data revealed comparable ncTSA potential for microsatellite stable and unstable tumors and candidate therapeutic targets for patients with low tumor mutational burden. Finally, our investigation of glioblastoma cell lines demonstrated increased ncTSAs burden upon indisulam treatment, and detection by NovumRNA of therapy-induced ncTSAs, which we could validate experimentally. These findings underscore the potential of NovumRNA for identifying synergistic drugs and novel therapeutic targets for immunotherapy, which could ultimately extend its benefit to a broader patient population.
Protein-RNA condensation kinetics via filamentous nanoclusters
Authors: Peralta-Martinez Ramon , Visentin Araceli , Salgueiro Mariano , Borkosky Silvina , Ajalla Aleixo Mariana Araujo , Portugal Rodrigo Villares , Sanchez Ignacio Enrique , Prat-Gay Gonzalo
Published: November 2024

Protein-RNA phase separation is at the center of membraneless biomolecular condensates governing cell physiology and pathology. Using an archetypical viral protein-RNA condensation model, we determined the sequence of events that starts with sub-second formation of a protomer with two RNAs per protein dimer. Association of additional RNA molecules to weaker secondary binding sites in this protomer kickstarts crystallization-like assembly of a molecular condensate. Primary nucleation is faster than the sum of secondary nucleation and growth, which is a multistep process. Protein-RNA nuclei grow over hundreds of seconds into filaments and subsequently into nanoclusters with circa 600 nm diameter. Cryoelectron microscopy reveals an internal structure formed by incoming layers of protein-RNA filaments made of ribonucleoprotein oligomers, reminiscent of genome packing of a nucleocapsid. These nanoclusters progress to liquid condensate droplets that undergo further partial coalescence to yield typical hydrogel-like protein-RNA coacervates that may represent the scaffold of large viral factory condensates in infected cells. Our integrated experimental kinetic investigation exposes rate limiting steps and structures along a key biological multistep pathway present across life kingdoms.
CCR2-driven monocyte recruitment is protective against radiotherapy-induced intestinal toxicity
Authors: Pun Nabina , Cytlak Urszula M , Lee Dave , Domingues Rita G , Cheadle Eleanor J , Forster Duncan , Williams Kaye J , Graham Gerry , Hepworth Matthew R , Travis Mark A , Illidge Timothy M , Dyer Douglas Philip
Published: November 2024

Radiotherapy (RT) is essential in treating abdominal and pelvic cancers but often damages the healthy tissues, particularly the intestines, leading to radiation-induced toxicities with limited treatment options. While the immune system is known to regulate tissue damage, immune mechanisms involved in RT-induced intestinal toxicity are not fully understood. CT-guided localised intestinal irradiation, single-cell RNA sequencing (scRNA-seq) and flow cytometry revealed RT-induced chemokine-dependent recruitment of immune cells. Deletion of C-C chemokine receptor (Ccr)1, Ccr2, Ccr3 and Ccr5, blocked recruitment and worsened radiation induced toxicities. Furthermore, CCR2-deficient mice showed exacerbated weight loss and intestinal permeability, while the transfer of Ly6C+ monocytes alleviated symptoms. Mechanistically, IL-17 cytokine production by group 3 innate lymphoid cells (ILC3s), a critical factor in maintaining intestinal barrier integrity, was reduced in irradiated CCR2-/-, however the transfer of Ly6C+ monocytes resulted in increased IL-17 levels. These findings demonstrate the critical importance of CCR2-mediated monocyte recruitment in mitigating RT-induced toxicities.
Passing the quadrat: inferring biodiversity change over time and across investigators
Authors: Elahi Robin , Micheli Fiorenza , Watanabe James
Published: November 2024

Long-term ecological monitoring inevitably requires a ‘passing of the quadrat’ from one investigator to another. Here we present the challenge and opportunity of inferring biodiversity change over time and across investigators using a rocky intertidal case study. The intertidal transect was surveyed initially by Willis Hewatt in 1931-1933, then resurveyed in detail by Rafe Sagarin, Sarah Gilman, and their mentors in 1993. In total, the transect has been resurveyed 17 times over the past three decades, with annual surveys nested within five distinct investigator eras. We addressed two goals with our dataset. First, we asked whether temporal change in several biodiversity metrics (species richness, Hill-Shannon and Hill-Simpson diversity, spatial beta diversity) was sensitive to investigator era. Second, we identified recent ecological ‘winners’ and ‘losers’, relative to the historical baseline, and asked whether such designations can change over time (1993-2023). We show that investigators contributed to variable trends in species richness over time, and we hypothesize that sampling effort contributed to this effect. In contrast, we highlight declines in the biodiversity of common species (Hill-Shannon) and dominant species (Hill-Simpson) over time, in the absence of investigator effects. These declines were associated with the rise of a few numerically dominant species and a trend of increasing spatial similarity. Relative to the historical baseline, ecological winners included certain barnacles, anemones, and turban snails, while losers included mussels, urchins, limpets and a host of more cryptic taxa. However, we show that such designations can be complicated by non-linear population trajectories and discuss mechanisms related to climate change versus potential artifacts related to investigator effort. We finish with recommendations and emphasize the value of marine stations in providing a venue for sustained periodic ecological monitoring at small spatial scales, long duration, and fine taxonomic resolution.
Estimating the effective reproduction number from wastewater (Rt): A methods comparison
Authors: Hill Dustin T. , Zhu Yifan , Dunham Christopher , Moran Joe , Zhou Yiquan , Collins Mary B. , Kmush Brittany L. , Larsen David A.
Published: November 2024

Background

The effective reproduction number (Rt) is a dynamic indicator of current disease spread risk. Wastewater measurements of viral concentrations are known to correlate with clinical measures of diseases and have been incorporated into methods for estimating the Rt.

Methods

We review wastewater-based methods to estimate the Rtfor SARS-CoV-2 based on similarity to the reference case-based Rt, ease of use, and computational requirements. Using wastewater data collected between August 1, 2022 and February 20, 2024 from 200 wastewater treatment plants across New York State, we fit eight wastewater Rtmodels identified from the literature. Each model is compared to the Rtestimated from case data for New York at the sewershed (wastewater treatment plant catchment area), county, and state levels.

Results

We find a high degree of similarity across all eight methods despite differences in model parameters and approach. Further, two methods based on the common measures of percent change and linear fit reproduced the Rtfrom case data very well and a GLM accurately predicted case data. Model output varied between spatial scales with some models more closely estimating sewershed Rtvalues than county Rtvalues. Similarity to clinical models was also highly correlated with the proportion of the population served by sewer in the surveilled communities (r = 0.77).

Conclusions

While not all methods that estimate Rtfrom wastewater produce the same results, they all provide a way to incorporate wastewater concentration data into epidemic modeling. Our results show that straightforward measures like the percent change can produce similar results of more complex models. Based on the results, researchers and public health officials can select the method that is best for their situation.

Key messages

Wastewater data has been used to estimate the Rtin different ways but the relative strengths and weaknesses of each method were unknown.

Rtestimation results from wastewater data are influenced by sewershed population size and geographic aggregation making selection of the best method dependent on the study location and available data.

Estimating the Rtfrom wastewater is desirable because wastewater data are anonymous, comprehensive, and efficient for measuring disease burden.
Development of a Multifunctional Extracorporeal Life Support (ECLS) System for Lung and Kidney Support: The Pneuma-K ECLS System
Authors: Kwon Jian , Weiss Daniel J. , Lee Patrick C. , Lee Jake K.
Published: November 2024

Multi-organ failure (MOF), particularly in the coexistence of acute kidney injury (AKI) and acute lung injury (ALI), presents a significant challenge in intensive care units (ICU) and is associated with exceedingly high mortality rates. Respiratory and renal failures are frequently managed by extracorporeal membrane oxygenation (ECMO) and continuous renal replacement therapy (CRRT), respectively. However, employing these therapies using separate devices requires specialized facilities, adds to complexity, and increases the risks of clotting due to the extensive artificial surface areas involved. Therefore, an integrated device capable of providing simultaneous respiratory and renal support is essential. This paper introduces the Pneuma-K ECLS system, which incorporates a multifunctional detoxifying filter (MDF) capable of performing gas exchange and renal replacement in a single cartridge. Ex-vivo blood tests confirmed the ability of the MDF to oxygenate blood, remove carbon dioxide, and eliminate uremic toxins. In addition, animal experiments demonstrated the considerable clinical potential of this novel integrated extracorporeal life support approach. Integrating respiratory and renal support into a singular device could mitigate risks, conserve resources, and enhance the survival rates of critically ill patients suffering from concurrent lung and kidney failure.
Impact of different synonymous codon substitution strategies on SARS-CoV-2 nucleocapsid protein expression inEscherichia coli
Authors: Bello Adebayo J. , Omotuyi Ayomide O. , Oladapo Olajumoke B. , Adekunle Adegbayi A. , Udechime Kingsley U. , Akinwande Abdulzamad B. , Odewale Adeyemi F. , Davis Eban , Adamson Olawale , Folarin Onikepe , Okpuzor Joy , Minari Joseph B.
Published: November 2024

SARS-CoV-2 is an enveloped, positive-strand RNA virus. The virus nucleocapsid (N) protein is stable, conserved, highly immunogenic, and less prone to mutation during infection, making it a key antigen inin vitrodiagnosis, vaccine development, immunological and structural studies. synonymous codon substitution, a gene engineering method in synthetic biology is the approach to improve the codon composition of a recombinant gene based on various criteria without altering the amino acid sequence. We analyzed the influence of different synonymous codon substitution strategies on SARS-CoV-2 N-protein expression inE. coli. Using JCat and Genewiz codon optimization tools, and a codon harmonization (CH) tool, we predicted and compared how different parameters such as GC content, Codon Adaptation Index, codon quality and number of rare codons present in these sequences affect the N-protein expression. Our prediction also shows that Minimum Free Energy (MFE) and RNA structure of N-term and C-tail of the N-protein coding sequence influence protein folding. We also demonstrated that the SR-rich region of the N-protein may contribute to slowing down the elongation rate during translation. In general, Genewiz optimization shows better result from our analysis. This work presents a fundamental analysis of how different optimization tools affect SARS-CoV-2 N-protein expression and folding and suggests a basic approach to choosing the best strategy for optimal expression and folding of the protein for further studies.

Key points

Codon substitution affects SARS-CoV-2 nucleocapsid protein expression.

Parameters of different synonymous substitution tools impact variation the SARS-CoV-2 protein expression.

RNA structures of the nucleocapsid N-term and C-tail impact the RNA stability, protein expression and folding.

The SR-rich region of the nucleocapsid protein may slow down elongation rate during translation.

The synonymous codon substitution predicts variation in elongation rhythm pattern.
Single-cell atlas of the human immune system reveals sex-specific dynamics of immunosenescence
Authors: Sopena-Rios Maria , Ripoll-Cladellas Aida , Omidi Fatemeh , Ballouz Sara , Hernandez Jose Alquicira- , Oelen Roy , Franke Lude , van der Wijst Monique G.P. , Powell Joseph E. , Melé Marta
Published: November 2024

Immunosenescence, the gradual deterioration of the immune system with age, leads to an increased susceptibility to a range of diseases associated with immune dysfunction. Notably, sex is an important variable underlying how immune aging unfolds, as, for instance, autoimmunity develops with aging differently between males and females. Even though some clinical and molecular differences have been identified between male and female immunosenescence, it is not known to what extent sex affects the dynamic composition of immune cells over time. Here, we analyze a large single-cell RNA-sequencing dataset of peripheral blood mononuclear cells from a sex-balanced cohort of 982 human donors providing novel transcriptional and cellular insights into immune aging at an unprecedented resolution. We uncover that aging induces cell type-dependent and sex-specific transcriptional shifts that translate into a differential abundance of distinct immune cell subpopulations. These shifts predominantly involve translation-related genes, indicating a strong link between transcriptional and translational throughput with cell function and consequent immune cell composition. This sexual dimorphism overlaps known autoimmune disease-related genetic variants and results in the differential enrichment of functionally distinct immune populations. Specifically, we uncover that a cytotoxic CD8+ T effector memory subpopulation with an NK-like phenotype accumulates with age only in females and identify a distinct B cell subpopulation that expands with age exclusively in males. These cell subpopulations represent novel sex-specific hallmarks of immune aging. Our findings underscore the hidden complexity of immune aging and demonstrate the value of high-resolution, single-cell analyses in large population cohorts. This research paves the way for future sex-specific interventions targeting immunosenescence to ultimately promote a personalized approach to foster healthy aging.
Metaproteomic profiling of the secretome of a granule-formingCa. Accumulibacter enrichment
Authors: van Olst Berdien , Eerden Simon A. , Eštok Nella A. , Roy Samarpita , Abbas Ben , Lin Yuemei , van Loosdrecht Mark C.M. , Pabst Martin
Published: November 2024

Extracellular proteins are supposed to play crucial roles in the formation and structure of biofilms and aggregates. However, often little is known about these proteins, in particular for microbial communities. Here, we use two advanced metaproteomic approaches to study the extracellular proteome in a granularCandidatusAccumulibacter enrichment as a proxy for microbial communities that form solid microbial granules, such as used in biological wastewater treatment. Limited proteolysis of whole granules and metaproteome isolation from the culture’s supernatant successfully identified over 50% of the protein biomass to be secreted. Moreover, structural and sequence-based classification identified 387 proteins, corresponding to over 50% of the secreted biomass, with characteristics that could aid the formation of aggregates, including filamentous, beta-barrel containing, and cell surface proteins. However, while most filamentous proteins originated fromCa. Accumulibacter, among others cell surface proteins did not. This suggests that not only a range of different proteins, but also multiple organisms contribute to granular biofilm formation. Therefore, the obtained extracellular metaproteome data from the granularCa. Accumulibacter enrichment provides a resource for exploring proteins that potentially support the formation and stability of granular biofilms, whereas the demonstrated approaches can be applied to explore biofilms of microbial communities in general.

SIGNIFICANCE

Biofilm-forming microbial communities are widespread and pose both challenges and opportunities in various settings in life. Structure-providing, extracellular proteins likely play a crucial role in the formation of the biofilm matrix, but these proteins are challenging to characterise due to the dynamic and complex nature of these communities. We used two advanced metaproteomic approaches to enrich for the extracellular proteins in a granule-formingCandidatusAccumulibacter enrichment culture as a proxy for granule-forming communities present in wastewater treatment plants. The extracellular proteins were additionally classified using structure and sequence-based annotation tools, which identified multiple different protein categories that potentially aid in granule formation, but also may provide structure to the biofilm matrix. Interestingly, although the granules were highly enriched forCa. Accumulibacter, several structure-providing protein categories originated from other organisms. The obtained metaproteomic data contribute to the understanding of proteins and processes that are potentially involved in granule formation. This could further help to optimise processes involving granular biofilms and identify candidates for the recovery of novel biopolymers for biotechnological applications.
Speech-in-noise perception across the lifespan: A comparative study in Mongolian gerbils and humans
Authors: Jüchter Carolin , Chi Chieh-Ju , Beutelmann Rainer , Klump Georg Martin
Published: November 2024

Many elderly listeners have difficulties with speech-in-noise perception, even if auditory thresholds in quiet are normal. The mechanisms underlying this compromised speech perception with age are still not understood. For identifying the physiological causes of these age-related speech perception difficulties, an appropriate animal model is needed enabling the use of invasive methods. In a comparative behavioral study, we used young-adult and quiet-aged Mongolian gerbils as well as young and elderly human subjects to investigate the age-related changes in speech-in-noise perception evaluating whether gerbils are an appropriate animal model for the age-related decline in speech-in-noise processing of human listeners.

Gerbils and human subjects had to report a deviant consonant-vowel-consonant combination (CVC) or vowel-consonant-vowel combination (VCV) in a sequence of CVC or VCV standards, respectively. The logatomes were spoken by different speakers and masked by a steady-state speech-shaped noise. Response latencies were measured to generate perceptual maps employing multidimensional scaling, visualizing the subjects’ internal representation of the sounds. By analyzing response latencies for different types of vowels and consonants, we investigated whether aging had similar effects on speech-in-noise perception in gerbils compared to humans. For evaluating peripheral auditory function, auditory brainstem responses and audiograms were measured in gerbils and human subjects, respectively.

We found that the overall phoneme discriminability in gerbils was independent of age, whereas consonant discriminability was declined in humans with age. Response latencies were generally longer in aged than in young gerbils and humans, respectively. Response latency patterns for the discrimination of different vowel or consonant types were different between species, but both gerbils and humans made use of the same articulatory features for phoneme discrimination. The species-specific response latency patterns were mostly unaffected by age across vowel types, while there were differential aging effects on the species-specific response latency patterns of different consonant types.
Bacterial warfare is associated with virulence and antimicrobial resistance
Authors: Sharp Connor , Foster Kevin
Published: November 2024

Bacteria have evolved a diverse array of mechanisms to inhibit and kill competitors, commonly known as bacterial weapons. However, why some bacteria carry weapons while others do not remains poorly understood. Here we explore this question using the bacteriocins ofE. colias a model system, which are both well studied and have large well-annotated genomic resources. While bacteriocins are found widely acrossE. colistrains, we find that carriage is particularly associated with pathogenic extra-intestinal (ExPEC) strains, including many clinically-important pandemic strains. These pathogenic strains commonly carry large plasmids that encode the bacteriocins but also virulence factors, including siderophores, and antimicrobial resistance mechanisms. Across allE. colistrains, we find many orphan immunity proteins, which protect against bacteriocins and suggest that bacterial warfare is important in nature. We also present evidence that bacteriocin toxins readily move between strains via plasmid transfer and even between plasmids via transposons. Finally, we show that severalE. colibacteriocins are widely shared with the pathogenSalmonella enterica, further cementing the link to virulence. Our work suggests that the bacteriocins ofE. coliare important antibacterial weapons for dangerous antimicrobial-resistant strains.
AI-Augmented Physics-Based Docking for Antibody-Antigen Complex Prediction
Authors: Gaudreault Francis , Sulea Traian , Corbeil Christopher R.
Published: November 2024

Predicting the structure of antibody-antigen complexes is a challenging task with significant implications for the design of better antibody therapeutics. However, the levels of success have remained dauntingly low, particularly when high standards for model quality are required, a necessity for efficient antibody design. Artificial intelligence (AI) has significantly impacted the landscape of structure prediction for antibodies, both alone and in complex with their antigens. We utilized AI-guided antibody modeling tools to generate ensembles displaying diversity in the complementarity-determining region (CDR) and integrated those into our previously published AlphaFold2-rescored docking pipeline, a strategy called AI-augmented physics-based docking. We highlight that the quality of the ensemble is crucial for docking performance, that including too many models can be detrimental and that prioritization of models is essential for achieving good performance. In this study, we also compare docking performance with AlphaFold, the new benchmark in the field. We distinguish between two types of success tailored to specific downstream applications: 1) criteria sufficient for epitope mapping, where gross quality is adequate and can complement experimental techniques, and 2) criteria for producing higher-quality models suitable for engineering purposes. Our results robustly demonstrate the advantages of AI-augmented docking over AlphaFold2, further accentuated when higher standards in quality are imposed. Docking performance is noticeably lower than the one of AlphaFold3 in both epitope mapping and antibody design. While we observe a strong dependence on CDR-H3 length for physics-based tools on their ability to successfully predict, this helps define an applicability range where physics-based docking can be competitive to AlphaFold3.
Use of Hypochlorous Acid in Infections: Bibliometric Analysis of Scientific Literature
Authors: Ateş Fatih M.
Published: November 2024

Background

Historically, chemicals such as alcohols, aldehydes, chlorinated compounds and hypochlorous acid have been used to eliminate or inactivate infectious agents. Since bibliometrics is a powerful tool for uncovering scientific literature, we decided to conduct a bibliometric analysis of the literature on the use of hypochlorous acid in infections. Emerging trends and common patterns in research were explored, collaborations and networks were monitored and future directions were predicted.

Methods

The Scopus database was searched for documents published between 1982 and 2024 using the keywords “hypochlorous acid”, “infection” and “use”. Data analysis was performed using R-Studio 2024.09.0 Build 375 software with a machine learning bibliometric method based on the bibliometrix R package. The most relevant authors were measured by the number and fractional number of documents written. Author productivity was analyzed with Lotka’s law. Bradford’s law was applied to identify the core of journals focusing on the topic under consideration. The field of mainstream themes included isolated topics (niche themes), new topics (emerging themes), hot topics (engine themes) and core topics (core themes).

Results

A total of 574 documents were found, the vast majority of which were original articles (74%). The annual growth rate was 5.08%. Overall, 424 journals published more than one document. Most of the corresponding authors work in the United States. Neutrophils, animals and hydrogen peroxide are emerging themes, while hypochlorous acid, human, article represent the basic themes.

Conclusions/Applications for Practice

The interests of infection specialists have diversified over time and metabolism, reactive oxygen metabolites, anti-infective agents have been added.
Topoisomerase IIb binding underlies frequently mutated elements in cancer genomes
Authors: Uusküla-Reimand Liis , Lee Christian A. , Oh Robin H. , Klein Zoe P. , Adler Nina , Alvi Sana Akhtar , Langille Ellen , Pasini Elisa , Cheng Kevin C. L. , Abd-Rabbo Diala , Hou Huayun , Tsai Ricky , Bhat Mamatha , Schramek Daniel , Wilson Michael D. , Reimand Jüri
Published: November 2024

Type-II topoisomerases resolve topological stress in DNA through controlled double-strand breaks. While TOP2A is a chemotherapy target in proliferating cells, the ubiquitously expressed TOP2B is a potential off-target. Here we explore roles of TOP2B in mutagenesis by generating DNA-binding maps of TOP2B, CTCF, and RAD21 in human cancer samples and analysing these maps for driver mutations and mutational processes in 6500 whole cancer genomes. TOP2B-CTCF-RAD21 and TOP2B-RAD21 sites are enriched in somatic mutations and structural variants (SVs), especially at evolutionary conserved sites displaying high transcription and long-range chromatin interactions. TOP2B binding underlies SVs and hotspot mutations in cancer-driving genes such asTP53,MYC,FOXA1, andVHL, and many cis-regulatory elements. We show that the TOP2B-bound mutational hotspot atRMRPdrives tumor initiation and growthin vivo. These data highlight TOP2B as a protector of the genome from topological challenges whose aberrant activity promotes driver and passenger mutations in cancer genomes.
Multi-dimensional social relationships shape social attention in monkeys
Authors: Liu Sainan , Huang Jiepin , Chen Suhao , Platt Michael , Yang Yan
Published: November 2024

Social relationships guide individual behavior and ultimately shape the fabric of society. Primates exhibit particularly complex, differentiated, and multidimensional social relationships, which form interwoven social networks, reflecting both individual social tendencies and specific dyadic interactions. How the patterns of behavior that underlie these social relationships emerge from moment-to-moment patterns of social information processing remains unclear. Here, we assess social relationships among a group of four monkeys, focusing on aggression, grooming, and proximity. We show that individual differences in social attention vary with individual differences in patterns of general social tendencies and patterns of individual engagement with specific partners. Oxytocin administration altered social attention and its relationship to both social tendencies and dyadic relationships, particularly grooming and aggression. Our findings link the dynamics of visual information sampling to the dynamics of primate social networks.
Engineered HMGB1 construct with tandem HMG B domains promotes tissue regeneration without potential for deleterious inflammation or thrombosis
Authors: Viñals Guitart Álvaro , Lee Carl , Espírito Santo de Fonseca Ana , Ruan Jia-Ling , Redfield Christina , Yue Wyatt , Burgess-Brown Nicola , Fedorov Oleg , Nanchahal Jagdeep
Published: November 2024

High Mobility Group Box 1 protein in its fully-reduced state (FR-HMGB1) binds to CXC Ligand 12 (CXCL12) and signals through CXC Receptor 4 (CXCR4) to transition stem and progenitor cells from the quiescent G0state to GAlert. On exposure to tissue activating factors, cells in GAlertreadily enter G1to effect tissue repair. However, conversion of FR-HMGB1 to the disulfide form may result in deleterious inflammation through signaling via Toll-Like Receptors 2 (TLR-2) and 4 (TLR-4), and the Receptor for Advanced Glycation End products (RAGE). Using peptide arrays, biolayer interferometry and nuclear magnetic resonance, we mapped the residues and motifs of HMGB1 that interact with CXCL12, TLR-2, TLR-4, and RAGE. Identification of repeating sequences across the Box A and Box B domains that interact with CXCL12 enabled us to design a construct comprising two HMG B Boxes in tandem (dBB12L), which promotes tissue repair as effectively as wild type FR-HMGB1 but is unable to signal through TLR-2, TLR-4 or RAGE.
Uttroside B, a US-FDA-Designated Orphan Drug Against Hepatocellular Carcinoma (HCC), Impedes Non-alcoholic Steatohepatitis (NASH) and NASH -Induced HCC
Authors: Rayginia Tennyson P , Keerthana Chenicheri K. , Aiswarya Sreekumar U. , Shifana Sadiq C. , Jannet S , Varma Sanjay Suresh , Maria Joy P , Swetha Mundanattu , Retnakumary Archana Payickattu , Nath Lekshmi R. , Kalimuthu Kalishwaralal , Jaikumar Vishnu Sunil , Sundaram Sankar , Anto Nikhil Ponnoor , Isakov Noah , Harikumar Kuzhuvelil B. , Lankalapalli Ravi S. , Anto Ruby John
Published: November 2024

Introduction

Non-alcoholic steatohepatitis (NASH) is characterized by excessive accumulation of fat, accompanied by inflammation and liver injury. NASH can lead to chronic conditions like fibrosis and cirrhosis, and has an elevated risk of progressing to hepatocellular carcinoma (HCC). Currently there are no FDA-approved drugs for the treatment of NASH.

Objectives

Our discovery of Uttroside B (Utt-B), a phytosaponin isolated fromSolanum nigrumLinn., which exhibits remarkable anti-HCC potential, has gained global recognition and is currently a US-FDA-designated ‘orphan drug’ against HCC. The present study highlights Utt-B as an anti-NASH molecule, by utilizing a High-Fat-Diet murine model, and as an inhibitor to the progression of NASH to HCC, using a streptozotocin-induced steatohepatitis-derived HCC animal model, thereby warranting its further validation as a propitious candidate drug molecule against NASH and NASH-induced HCC.

Methods

High fat diet-induced NASH and streptozotocin-induced steatohepatitis-derived HCC were developed in C57BL/6 mice. Utt-B was administered intraperitoneally. q-PCR, immunoblotting and staining techniques such as Haematoxylin and eosin, Oil Red O, Sirius Red and Masson’s Trichrome, were performed to assess the therapeutic potency of Utt-B against NASH. Nanostring n-Counter analysis was conducted to verify the anti-fibrotic potential of Utt-B in NASH-induced HCC mouse model.

Results

Utt-B ameliorates the pathological features such as, steatosis, hepatocyte ballooning and inflammation associated with NASH. Utt-B up-regulates the expression of autophagy markers ATG7, Beclin-1 and LC-III and down-regulates the expression of α-SMA, the indicator protein for the activation of hepatic stellate cells. Utt-B hinders the development of fibrosis and halts the progression of NASH to HCC in NASH-induced HCC mouse model.

Conclusion

Our investigation reveals that Utt-B effectively alleviates NASH and abrogates its progression to HCC. As no treatment options are currently available against NASH, our findings are very relevant and strengthen the prospect of developing Utt-B as a potent drug for the treatment of NASH and NASH-induced HCC.

Graphical Abstract
Using a sequential sampling algorithm to apply the niche-neutral model to species occurrence patterns
Authors: Kristensen Nadiah P. , Keita Sin Yong Chee , Lim Hyee Shynn , Rheindt Frank E. , Chisholm Ryan A.
Published: November 2024

Aim

Species occurrence patterns are typically analysed using data-randomisation approaches, which reveal when observed patterns deviate from random expectation, but give little insight why. Mechanistic models, such as neutral models, have been proposed as an alternative null model, but they are computationally expensive. Here, we use an efficient method to simulate such models and to explore likely mechanisms governing the occurrence patterns of birds on islands.

Location

Riau archipelago, Indonesia.

Taxon

Birds.

Methods

We used species richness and island area data to fit a niche–neutral model, where species obey neutral dynamics within non-overlapping discrete niches. We used a sequential sampling algorithm that can efficiently generate randomised presence– absence matrices under the niche-neutral model and used mismatches to identify which mechanisms were potentially important to occurrence patterns.

Results

Birds were more segregated and less nested than expected from both data randomisation and the niche–neutral model. The niche–neutral model reproduced the mean relationship between island size and species richness, but it could not produce sufficient variability to account for the richness data. The model was brought into closer agreement with the data by allowing niche diversity to vary across islands (increased segregation) and allowing the per-capita immigration rate to vary across islands (decreased nestedness).

Main conclusion

While the species-area relationship could be explained by a model with constant per-capita immigration rates and number of niches across islands, interisland heterogeneity was needed to explain higher-order metrics of nestedness and cooccurrence patterns. The sequential sampling algorithm allowed us to explore different scenarios efficiently, and our approach may be useful for identifying the mechanisms structuring occurrence patterns in other systems.
The paternally derived genome opposes seed dormancy induction by the mother plant in Arabidopsis
Authors: Barros-Galvão Thiago , Chen Xiaochao , Penfield Steven
Published: November 2024

Seed dormancy in Arabidopsis is known to be mediated by the interaction of maternal and zygotic genomes during seed maturation. While studies have revealed the extensive influence of maternal processes on dormancy and germination, less is known about the influence of the father. Here we exploit differences in ploidy to explore the role of the paternal genome on progeny seed dormancy. We show that paternal genome acts to reduce seed dormancy regardless of maternal genome dose, resulting in lower dormancy in tetraploid Arabidopsis versus genetically identical diploids. We show that this paternal effect requires synthesis of RNA Polymerase IV-dependent RNAs in the male gametophyte which oppose the dormancy-inducing effects of maternal siRNAs on seed coat and endosperm development. We conclude that the paternal genome has evolved to subvert the dormancy-inducing role of the mother plant in progeny seeds.
Epstein-Barr Virus Latent Membrane Protein 1 Subverts IMPDH pathways to drive B-cell oncometabolism
Authors: Burton Eric M. , Liang Jin Hua , Mitra Bidisha , Asara John M. , Gewurz Benjamin E.
Published: November 2024

Epstein-Barr virus (EBV) is associated with multiple types of cancers, many of which express the key viral oncoprotein Latent Membrane Protein 1 (LMP1). LMP1 is the only EBV-encoded protein whose expression is sufficient to transform both epithelial and B-cells. Although metabolism reprogramming is a cancer hallmark, much remains to be learned about how LMP1 alters lymphocyte oncometabolism. To gain insights into key B-cell metabolic pathways subverted by LMP1, we performed systematic metabolomic analyses on B cells with conditional LMP1 expression. This approach highlighted that LMP highly inducesde novopurine biosynthesis, with xanthosine-5-P (XMP) as one of the most highly LMP1-upregulated metabolites. Consequently, IMPDH inhibition by mycophenolic acid (MPA) triggered apoptosis of LMP1-expressing EBV-transformed lymphoblastoid cell lines (LCL), a key model for EBV-driven immunoblastic lymphomas. Whereas MPA instead caused growth arrest of Burkitt lymphoma cells with the EBV latency I program, conditional LMP1 expression triggered their apoptosis. Although both IMPDH isozymes are expressed in LCLs, only IMPDH2 was critical for LCL survival, whereas both contributed to proliferation of Burkitt cells with the EBV latency I program. Both LMP1 C-terminal cytoplasmic tail domains critical for primary human B-cell transformation were important for XMP production, and each contributed to LMP1-driven Burkitt cell sensitivity to MPA. MPA also de-repressed EBV lytic antigens including LMP1 in latency I Burkitt cells, highlighting crosstalk between the purine biosynthesis pathway and the EBV epigenome. These results suggest novel oncometabolism-based therapeutic approaches to LMP1-driven lymphomas.

IMPORTANCE

Altered metabolism is a hallmark of cancer, yet much remains to be learned about how EBV rewires host cell metabolism to support multiple malignancies. While the oncogene LMP1 is the only EBV-encoded gene that is sufficient to transform murine B-cells and rodent fibroblasts, knowledge has remained incomplete about how LMP1 alters host cell oncometabolism to aberrantly drive infected B-cell growth and survival. Likewise, it has remained unknown whether LMP1 expression creates metabolic vulnerabilities that can be targeted by small molecule approaches to trigger EBV-transformed B-cell programmed cell death. We therefore used metabolomic profiling to define how LMP1 signaling remodels the B-cell metabolome. We found that LMP1 upregulated purine nucleotide biosynthesis, likely to meet increased demand. Consequently, LMP1 expression sensitized Burkitt B-cells to growth arrest upon inosine monophosphate dehydrogenase blockade. Thus, while LMP1 itself may not be a therapeutic target, its signaling induces dependence on downstream druggable host cell nucleotide metabolism enzymes, suggesting rational therapeutic approaches.
Functional divergence of TBP homologs through distinct DNA binding dynamics
Authors: Cui Jieying H. , Kwan James Z.J. , Faghihi Armin , Nguyen Thomas F. , Teves Sheila S.
Published: November 2024

The TATA box-binding protein (TBP) is an evolutionarily conserved basal transcription factor common in the pre-initiation complex of all three eukaryotic RNA polymerases (RNA Pols). Despite their high conservation, homologous TBPs exhibit species- and tissue-specific functions that may contribute to the increasingly complex gene expression regulation across evolutionary time. To determine the molecular mechanisms of species- and tissue-specificity for homologous TBPs, we examined the ability of yeast TBP and murine TBP paralogs to replace the endogenous TBP in mouse embryonic stem cells. We show that, despite the high conservation in the DNA binding domain among the homologs, they cannot fully rescue the lethality of TBP depletion in mESCs, largely due to their inability to support RNA Pol III transcription. Furthermore, we show that the homologs differentially support stress-induced transcription reprogramming, with the divergent N-terminal domain playing a role in modulating changes in transcriptional response. Lastly, we show that the homologs have vastly different DNA binding dynamics, suggesting a potential mechanism for the distinct functional behavior observed among the homologs. Taken together, these data show a remarkable balance between flexibility and essentiality for the different functions of homologous TBP in eukaryotic transcription.