bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary Study of the Treatment Strategy for Retaining Traumatic Foreign Bodies Involving the Carotid Artery
Authors: Zhang Chuxi , Wu Jinyang , Zhang Wenbin , Yuan Hao , Yang Chengshuai , Zhang Yong , Zhang Shilei
Published: September 2022

Purpose:

Craniomaxillofacial trauma is usually accompanied by indwelling foreign bodies, and some of those are close to the carotid artery, which increases the risks and difficulties of surgical treatment. The introduction of interventional radiology combined with image-guided surgical navigation may be a good solution for precise surgery to remove foreign bodies.

Patients and Methods:

Four patients were included in the study. All patients underwent digital subtraction angiography and enhanced computed tomography before surgery. The patients were divided into 3 categories (A, B, and C) according to the presence of carotid artery damage and its positional relationship with the foreign body, and 3 corresponding treatment strategies were developed. Treatments were completed using interventional radiology and surgical navigation systems.

Results:

All foreign bodies were completely removed, except for 1 remaining in the jugular foramen in a patient. The prognosis of all patients was good, and no systemic complications occurred.

Conclusion:

The combined interventional radiology and surgical navigation method proposed in this study is an effective method to improve the accuracy and safety of foreign body removal surgery.
Preoperative Fibrinogen Level and Bleeding in Liver Transplantation for End-stage Liver Disease: A Cohort Study
Authors: Carrier François Martin , Deshêtres Annie , Ferreira Guerra Steve , Rioux-Massé Benjamin , Zaouter Cédrick , Lee Nick , Amzallag Éva , Joosten Alexandre , Massicotte Luc , Chassé Michaël
Published: September 2022

Background.

Liver transplantation is a high-risk surgery associated with important perioperative bleeding and transfusion needs. Uncertainties remain on the association between preoperative fibrinogen level and bleeding in this population.

Methods.

We conducted a cohort study that included all consecutive adult patients undergoing a liver transplantation for end-stage liver disease in 1 center. We analyzed the association between the preoperative fibrinogen level and bleeding-related outcomes. Our primary outcome was intraoperative blood loss, and our secondary outcomes were estimated perioperative blood loss, intraoperative and perioperative red blood cell transfusions, reinterventions for bleeding and 1-y graft and patient survival. We estimated linear regression models and marginal risk models adjusted for all important potential confounders. We used restricted cubic splines to explore potential nonlinear associations and reported dose-response curves.

Results.

We included 613 patients. We observed that a lower fibrinogen level was associated with a higher intraoperative blood loss, a higher estimated perioperative blood loss and a higher risk of intraoperative and perioperative red blood cell transfusions (nonlinear effects). Based on an exploratory analysis of the dose-response curves, these effects were observed below a threshold value of 3 g/L for these outcomes. We did not observe any association between preoperative fibrinogen level and reinterventions, 1-y graft survival or 1-y patient survival.

Conclusions.

This study suggests that a lower fibrinogen level is associated with bleeding in liver transplantation. The present results may help improving the selection of patients for further studies on preoperative fibrinogen administration in liver transplant recipients with end-stage liver disease.
Separating Signal from Noise in Wastewater Data: An Algorithm to Identify Community-Level COVID-19 Surges
Authors: Keshaviah Aparna , Huff Ian , Hu Xindi C. , Guidry Virginia , Christensen Ariel , Berkowitz Steven , Reckling Stacie , Noble Rachel T. , Clerkin Thomas , Blackwood Denene , McLellan Sandra , Roguet Adélaïde , Mussa Isabel
Published: September 2022

Wastewater monitoring has shown promise in providing an early warning for new COVID-19 outbreaks, but to date, no approach has been validated to reliably distinguish signal from noise in wastewater data and thereby alert officials to when the data show a need for heightened public health response. We analyzed 62 weeks of data from 19 sites participating in the North Carolina Wastewater Monitoring Network to characterize wastewater metrics before and around the Delta and Omicron surges. We found that, on average, wastewater data identified new outbreaks four to five days before case data (reported based on the earlier of the symptom start date or test collection date). At most sites, correlations between wastewater and case data were similar regardless of how wastewater concentrations were normalized, and correlations were slightly stronger with county-level cases than sewershed-level cases, suggesting that officials may not need to geospatially align case data with sewershed boundaries to gain insights into disease transmission. Wastewater trend lines showed clear differences in the Delta versus Omicron surge trajectories, but no single wastewater metric (detectability, percent change, or flow-population normalized viral concentrations) adequately indicated when these surges started. After iteratively examining different combinations of these three metrics, we developed a simple algorithm that identifies unprecedented signals in the wastewater to help clarify changes in communities’ COVID-19 burden. Our novel algorithm accurately identified the start of both the Delta and Omicron surges in 84% of sites, potentially providing public health officials with an automated way to flag community-level COVID-19 surges.
The spatial-temporal effect of air pollution on GP visits and hospital admissions by ethnicity in the United Kingdom: An individual-level analysis
Authors: Al Ahad Mary Abed
Published: September 2022

Background

Air pollution has been associated with increased rates of hospital admissions and general-practitioner (GP) visits. Yet, more research is to be done to reveal the spatial-temporal dimension of this association and whether ethnic minorities experience greater effects from exposure to air pollution compared to the rest of population. This study investigates the spatial-temporal effect of air pollution on GP visits and hospital admissions by ethnicity in the United-Kingdom (UK).

Methods

We used individual-level longitudinal data from the “UK Household Longitudinal Study” including 46,442 adult individuals who provided 140,466 responses across five years (2015-2019). This data was linked to yearly concentrations of NO2, SO2, and particulate-matter (PM10, PM2.5) pollution using the Lower-Super-Output-Area (LSOA) of residence for each individual. We distinguished between spatial (between areas) and temporal (across time within each area) effects of air pollution on GP visits and hospital admissions and we used multilevel mixed-effects ordered logistic models for analysis.

Results

Results showed higher odds of outpatient hospital admissions with increasing concentrations of NO2 (OR=1.009; 95%CI=1.006-1.013), SO2 (OR=1.063; 95%CI=1.030-1.097), PM10 (OR=1.013; 95%CI=1.006-1.021), and PM2.5 (OR=1.022; 95%CI=1.012-1.032) pollutants. Higher odds of GP visits were also observed with increasing concentrations of NO2 (OR=1.011; 95%CI=1.007-1.015) and SO2 (OR=1.123; 95%CI=1.087-1.160) pollutants. Decomposing air pollution into between (spatial: across LSOAs) and within (temporal: across years within each LSOA) effects, showed significant between effects for air pollution on GP visits and hospital admissions, but not within effects. We observed no differences between ethnic minorities and British-white for the association between air pollution and hospital admissions and GP visits.

Conclusion

Using individual-level longitudinal data, our study supports the presence of a spatial-temporal association between air pollution and hospital admissions and GP visits. However, ethnic minorities do not seem to experience greater health-related effects from exposure to air pollution compared to the rest of population.
Comparisons Between GPS-based and Self-reported Life-space Mobility in Older Adults
Authors: Bai Chen , Zapata Ruben , Karnati Yashaswi , Smail Emily , Hajduk Alexandra M. , Gill Thomas M. , Ranka Sanjay , Manini Todd M. , Mardini Mamoun T.
Published: September 2022

Assessments of Life-space Mobility (LSM) evaluate the locations of movement and their frequency over a period of time to understand mobility patterns. Advancements in and miniaturization of GPS sensors in mobile devices like smartwatches could facilitate objective and high-resolution assessment of life-space mobility. The purpose of this study was to compare self-reported measures to GPS-based LSM extracted from 27 participants (44.4% female, aged 65+ years) who wore a smartwatch for 1-2 weeks at two different site locations (Connecticut and Florida). GPS features (e.g., excursion size/span) were compared to self-reported LSM with and without an indicator for needing assistance. Although correlations between self-reported measures and GPS-based LSM were positive, none were statistically significant. The correlations improved slightly when needing assistance was included, but statistical significance was achieved only for excursion size (r=0.40, P=0.04). The poor correlations between GPS-based and self-reported indicators suggest that they capture different dimensions of life-space mobility.
Super resolution ultrasound imaging Using deep learning based micro-bubbles localization
Authors: Long Feixiao , Zhang Weiguang
Published: September 2022

Super resolution ultrasound imaging has shown its potential to detect minor structures of tissues beyond the limit of diffraction and achieve sub-wavelength resolution through localizing and tracking the ultrasound contrast agents, such as micro-bubbles. Normally, one important step of super resolution ultrasound imaging, micro-bubbles localization is implemented through conventional computer vision techniques, such as local maxima detection etc. However, these classical techniques are generally time consuming and need fine-tuning multiple parameters to achieve the optimal results. Hence, in the manuscript, a deep learning based micro-bubbles localization is proposed, trying to replace or simplify the complex operations of classical methods. The efficiency of our proposed models is preliminarily proved through 2022 ultra-SR challenge.
Bitter taste receptor-stimulated nitric oxide innate immune responses are reduced by loss of CFTR function in nasal epithelial cells and macrophages
Authors: Carey Ryan M. , Palmer James N. , Adappa Nithin D. , Lee Robert J.
Published: September 2022

Bitter taste receptors (T2Rs) are G protein-coupled receptors identified on the tongue but expressed all over the body, including in airway cilia and macrophages, where T2Rs serve an immune role. T2R isoforms detect bitter metabolites (quinolones and acyl-homoserine lactones) secreted by gram negative bacteria, includingPseudomonas aeruginosa, a major pathogen in cystic fibrosis (CF). T2R activation by bitter bacterial products triggers calcium-dependent nitric oxide (NO) production. In airway cells, the NO increases mucociliary clearance and has direct antibacterial properties. In macrophages, the same pathway enhances phagocytosis. Because prior studies linked CF with reduced NO, we hypothesized that CF cells may have reduced T2R/NO responses. Using qPCR, immunofluorescence, and live cell imaging of air-liquid interface cultures, we found primary nasal epithelial cells from both CF and non-CF patients exhibited similar T2R expression, localization, and calcium signals. However, CF cells exhibited reduced NO production also observed in immortalized CFBE41o-CF cells and non-CF 16HBE cells CRISPR modified with CF-causing mutations in the CF transmembrane conductance regulator (CFTR). NO was restored by VX-770/VX-809 corrector/potentiator pre-treatment, suggesting reduced NO in CF cells is due to loss of CFTR function. In nasal cells, reduced NO correlated with reduced ciliary and antibacterial responses. In primary human macrophages, inhibition of CFTR reduced NO production and phagocytosis during T2R stimulation. Together, these data suggest an intrinsic deficiency in T2R/NO signaling caused by loss of CFTR function that may contribute to intrinsic susceptibilities of CF patients toP. aeruginosaand other gram-negative bacteria that activate T2Rs.
GRETA: an R package for mapping in silico genetic interaction and essentiality networks
Authors: Takemon Yuka , Marra Marco A.
Published: September 2022

Mapping genetic interaction and essentiality networks in human cell lines have been used to identify vulnerabilities of cells carrying specific genetic alterations and to associate novel functions to genes, respectively. In vitro and in vivo genetic screens to decipher these networks are resource-intensive, limiting the throughput of samples that can be analyzed. In this application note, we provide an R package we call Genetic inteRaction and EssentialiTy mApper (GRETA). GRETA is an accessible tool for in silico genetic interaction screens and essentiality network analyses using publicly available data, requiring only basic R programming knowledge.

Availability and implementation

The R package, GRETA, is licensed under GNU General Public License v3.0 and freely available at https://github.com/ytakemon/GRETA and https://doi.org/10.5281/zenodo.6940757, with documentation and tutorial. A Singularity container is also available at https://cloud.sylabs.io/library/ytakemon/greta/greta.

Contact

mmarra@bcgsc.ca

Supplemental information

Supplemental materials are available at Bioinformatics online.

Issue section

Systems biology
Palbociclib interferes with replication origin firing in a pRb independent manner
Authors: Kim Su-Jung , Maric Chrystelle , Briu Lina-Marie , Fauchereau Fabien , Baldacci Giuseppe , Debatisse Michelle , Koundrioukoff Stéphane , Cadoret Jean-Charles
Published: September 2022

Over the last decade, CDK4/6 inhibitors (palbociclib, ribociclib and abemaciclib) have emerged as promising anticancer drugs. Numerous studies have demonstrated that CDK4/6 inhibitors efficiently block the pRb-E2F pathway and induce cell cycle arrest in pRb-proficient cells. Based on these studies, the inhibitors have been approved by the FDA for treatment of advanced hormonal receptor (HR) positive breast cancers in combination with hormonal therapy. However, some evidence has recently shown unexpected effects of the inhibitors, promoting needs to understand more about the mechanism of inhibitors beyond pRb. Our study demonstrates here how palbociclib impairs the origin firing in the DNA replication process in pRb-deficient cell lines. Strikingly, despite the absence of pRb, cells treated with palbociclib synthesize less DNA without any induced cell cycle arrest. Furthermore, palbociclib treatment disturbs the temporal program of DNA replication and reduces the density of replication forks. Cells treated with palbociclib show a defect in the loading of proteins of the Pre-initiation complex (Pre-IC) on chromatin, indicating a reduced initiation of DNA replication. Our findings highlight hidden effects of palbociclib on the dynamics of DNA replication and on its cytotoxic consequences on cell viability in the absence of pRb. This study provides a potential therapeutic application of palbociclib to target genomic instability towards pRb deficient patients.

Significance Statement

Palbociclib is a promising anticancer drug for pRb-proficient cell, particularly for hormonal receptor positive breast cancer, that induces the cell cycle arrest. But what about pRb deficient cell lines ? Our results show that Palbociclib disturb the DNA replication process inducing a replicative stress, an increase of DNA damages and leading to a significant decrease in cell viability. Palbociclib impairs the DNA synthesis reducing the number of active origins with the decrease of availability of the pre-initiation complexes. We believe that the demonstration of this effect of palbociclib on pRb-deficient cells may be a new therapeutic entry point in combination with other treatments for these types of cancer. Replicative stress can be one of weaknesses of pRb defficient cancer cells.
From southern Africa and beyond: historical biogeography of a monocotyledonous bulbous geophyte
Authors: Howard Cody Coyotee , Nanyeni Leevi , Mollel Neduvoto , Chuba David , Zuntini Alexandre R. , Malakasi Panagiota , Harvey Timothy S. , Cellinese Nico
Published: September 2022

Aim

Within sub-Saharan Africa, plants inhabiting more seasonal and arid landscapes showcase unique distributional patterns that hint at fascinating evolutionary histories. The Ledebouriinae (Scilloideae, Asparagaceae) are widespread throughout such climates in sub-Saharan Africa, and Madagascar, the Middle East, India, and Sri Lanka. Long-distance dispersal has been hypothesized as leading to such a widespread distribution; however, low taxon sampling and taxonomic uncertainties have made uncovering the history of the Ledebouriinae difficult. Here, using the most comprehensive sampling of the lineage to date, we hypothesize that both vicariance and dispersal events impacted the biogeographical history of these bulbous monocots within and outside of Africa.

Location

Sub-Saharan Africa, Madagascar, Asia

Taxon

Ledebouriinae (Scilloideae, Asparagaceae)

Methods

We infer age estimates using penalized likelihood as implemented in treePL. Capitalizing on our broad geographic sampling, we use ‘BioGeoBEARS’ to reconstruct ancestral ranges and investigate the role of vicariance and dispersal.

Results

Our results suggest the Ledebouriinae originated within the past ∼30 myr in southeastern sub-Saharan Africa, with the major subclades arising soon thereafter. Although long-distance dispersal cannot be fully ruled out, our results lead us to hypothesize vicariance was the major process responsible for the current distribution ofLedebouriain Eurasia. We recover two distinctLedebouriagroups that overlap in eastern Africa, but are divided into mostly northern and southern clades with divergent biogeographical histories, and each showing an independent dispersal to Madagascar. A similar north-south split is seen inDrimiopsis. Additionally, we recover a complex biogeographic history in the predominantly sub-Saharan AfricanLedebouriaclade, with a rapid radiation estimated at ∼14 mya.

Main conclusions

We recover evidence to suggest that the expansion of seasonal rainfall and aridity in sub-Saharan Africa, coupled with orogeny, may have fostered the diversification of the Ledebouriinae and many subclades. Miocene-driven aridification may have caused fragmentation of a once widespread distribution that led to their occurrence in Eurasia.
Rethinking the functions of peacock’s display and lek organisation in native populations of Indian PeafowlPavo cristatus
Authors: Paranjpe Dhanashree Ashok , Mahimkar Vedanti Rajiv , Dange Priyanka
Published: September 2022

Males of Indian Peafowl are known for their extravagant courtship display used to attract mates. The displays are seen in absence of potential mates as well. This study investigates various contexts in which display behaviours are shown by Indian peafowl. Upto 70% of displays were observed in absence of potential mates. High frequency of displays in presence of other males and longer display bouts during the month of May when mating rarely happens, indicated that display behaviours might have a role to play in male-male competition or territory defence in addition to the female mate choice. The males establish and maintain their courtship display territories throughout the breeding season. Earlier studies assume that the choice of location does not depend on any resources as the species has a lek mating system. How these display sites are chosen is still a question. In this study, we investigated factors that might be important for the selection of display sites in a free-ranging Indian Peafowl population. It was observed that display sites were more concentrated within a radius of 300 meters of the food provisioning site and/ or a water resource while the number of display sites decreased considerably beyond the 300 m radius of food and water resources. Overall, the selection of display sites is non-random and highlights the importance of resources in the choice of display territories. The spatial organisation of leks in our study indicate that the mating system in Indian peafowl may be resource-based lek.
The effect of grey wolf (Canis lupus) and human disturbance on the activity of big game species in the Bükk Hills, Hungary
Authors: Szabó Zsófia , Gombkötő Péter , Aranyi Sándor Csaba , Patkó László , Gigler Dóra , Barta Zoltán
Published: September 2022

The recent return of wolves to the Hungarian forests escalates conflicts among stakeholders. Hunting management agencies communicate that the presence of wolves may change the behaviour of big game species leading to difficulties for hunting organization and logistics. Here, we take a data driven approach to explore the activity of wolves and big game species. For this purpose we analysed camera trap data, collected in the Bükk National Park, Hungary. To estimate avoidance among wolves, humans and games we calculated a non-parametric activity overlap coefficient (Δ4) and used a machine learning (XGBoost) model. Our results show that game species have higher overlap coefficient with wolf (Δ4 = 0.83-0.89) than with human activity (Δ4 = 0.26-0.52), because predators and games are active in the same periods of the day, mainly night and dawn, and human activity mainly takes place during daytime. We could detect the refugee effects in the case of all game species. Our XGBoost analyses only found a moderate negative effect of wolf on red deer occurrence, while human activity had higher importance value and lowered the occurrence of all three game species investigated. Our results may thus indicate that human disturbance might be more important in shaping game activity than the presence of the grey wolf in Hungary.
Mouse Memory CD8 T cell subsets defined by Tissue Resident Memory (TRM) Integrin Expression Exhibit Distinct Metabolic Profiles
Authors: Sportiello Mike , Poindexter Alexis , Reilly Emma C. , Geber Adam , Emo Kris Lambert , Jones Taylor N. , Topham David J.
Published: September 2022

Tissue-resident memory CD8 T cells (TRM) principally reside in peripheral non-lymphoid tissues such as lung and skin and confer protection against a variety of illnesses ranging from infections to cancers. The functions of different memory CD8 T cell subsets have been linked with distinct metabolic pathways and differ from other CD8 T cell subsets. For example, skin-derived memory T cells undergo fatty acid oxidation and oxidative phosphorylation to a greater degree than circulating memory and naïve cells. Lung TRMcells defined by the cell surface expression of integrins exist as distinct subsets that differ in gene expression and function. We hypothesize that TRMsubsets with different integrin profiles will utilize unique metabolic programs. To test this, differential expression and pathway analysis were conducted on RNAseq datasets from mouse lung TRMyielding significant differences related to metabolism. Next, metabolic models were constructed and the predictions were interrogated using functional metabolite uptake assays. The levels of oxidative phosphorylation, mitochondrial mass, and neutral lipids were measured. Furthermore, to investigate the potential relationships to TRMdevelopment, T-cell differentiation studies were conductedin vitrowith varying concentrations of metabolites. These demonstrated that lipid conditions impact T cell survival, and that glucose concentration impacts the expression of canonical TRMmarker CD49a, with no effect on central memory-like T-cell marker CCR7. In summary, it is demonstrated that mouse resident memory T cells subsets defined by integrin-expression in the lung have unique metabolic profiles and that nutrient abundance can alter differentiation.
Shape-shifting microgel automata controlled by DNA sequence instructions
Authors: Shi Ruohong , Chen Kuan-Lin , Fern Joshua , Deng Siming , Liu Yixin , Scalise Dominic , Huang Qi , Cowan Noah J. , Gracias David H. , Schulman Rebecca
Published: September 2022

Controlling material shapes using information-bearing molecular signals is central to the creation of autonomous, reconfigurable soft devices. While physical and chemical stimuli can direct simple material swelling, bending, or folding, it has been challenging to direct multi-step shape-change programs crucial for complex, robotic tasks. Here, we demonstrate gel automata— sub-millimeter, photopatterned, highly swellable DNA gels—whose parts grow or shrink in response to easily designed DNA activator sequences, allowing for precisely controlled device articulation. We design and fabricate gel automata that reversibly transform between different letter shapes, and use neural networks to design automata that transform into every even or every odd numeral via designed reconfiguration programs. This sequential and repetitive metamorphosis of materials via chemical reorganization could dramatically advance our ability to manipulate micro-particles, cells, and tissues.

One-Sentence Summary

Photopatterned microgels follow sequences of DNA instructions to transform between complex, meaningful shapes such as letters and numerals.
Proton exchange in the nitrate vacuolar transporter AtCLCa is required for growth and nitrogen use efficiency
Authors: Hodin Julie , Lind Christof , Marmagne Anne , Espagne Christelle , Bianchi Michele Wolfe , De Angeli Alexis , Abou-Choucha Fadi , Bourge Mickaël , Chardon Fabien , Thomine Sebastien , Filleur Sophie
Published: September 2022

Nitrate is a major nutrient and osmoticum for plants. To deal with its fluctuating availability in soils, plants store it into vacuoles. AtCLCa, a 2NO3-/1H+exchanger localized on the vacuole ensures this storage process. It belongs to the CLC family that includes exchangers and channels. A mutation in a glutamate residue conserved across CLC exchangers is likely responsible for the conversion of exchangers to channels. Here, we show that aclcamutant of this residue, E203, behaves as an anion channel in its native membrane. To investigate its physiological importance, we introduced theAtCLCaE203Apoint mutation in aclcaKO mutant. We first showed that theseAtCLCaE203Amutants display a growth deficit linked to water homeostasis disruption. Additionally,AtCLCaE203Aexpression is not able to complement theclcadefect in nitrate accumulation and favors higher N-assimilation at the vegetative stage. Further analyses at post-flowering stages indicated that AtCLCaE203Aresults in an increase of N uptake allocation to seeds, leading to a higher nitrogen use efficiency compared to wild-type. Altogether, these results point out the critical function of the AtCLCa exchanger on the vacuole for plant metabolism and development.
The Phosphate Deprivation Response is Mediated by an Interaction between Brassinosteroid Signaling and Zinc in Tomato
Authors: Demirer Gozde S. , Gibson Donald J. , Yue Xiaoyan , Pan Kelly , Elishav Eshel , Khandal Hitaishi , Horev Guy , Tarkowská Danuše , Cantó-Pastor Alex , Kong Shuyao , Maloof Julin , Savaldi-Goldstein Sigal , Brady Siobhan M.
Published: September 2022

Phosphate is a necessary macronutrient for basic biological processes, plant growth, and agriculture. Plants modulate their root system architecture and cellular processes to adapt to phosphate deprivation albeit with a growth penalty. Excess application of phosphate fertilizer, on the other hand, leads to eutrophication and has a negative environmental impact. Moreover, phosphate mined from rock reserves is a finite and non-recyclable resource and its levels are nearing complete depletion. Here, we show that Solanum pennellii, a wild relative of tomato, is partially insensitive to phosphate deprivation. Furthermore, it mounts a constitutive response under phosphate sufficiency. We demonstrate that activated brassinosteroid signaling through a tomato BZR1 ortholog gives rise to the same constitutive phosphate deficiency response, which is dependent on zinc over-accumulation. Collectively, these results reveal an additional strategy by which plants can adapt to phosphate starvation.
MULTISCALE ANALYSIS AND VALIDATION OF EFFECTIVE DRUG COMBINATIONS TARGETING DRIVER KRAS MUTATIONS IN NON-SMALL CELL LUNG CANCER
Authors: Bruggemann Liana , Falls Zackary , Mangione William , Schwartz Stanley A , Battaglia Sebastiano , Aalinkeel Ravikumar , Mahajan Supriya D. , Samudrala Ram
Published: September 2022

1.

Pharmacogenomics is a rapidly growing field with the goal of providing personalized care to every patient. Previously, we developed the Computational Analysis of Novel Drug Opportunities (CANDO) platform for multiscale therapeutic discovery to screen optimal compounds for any indication/disease by performing analytics on their interactions with large protein libraries. We implemented a comprehensive precision medicine drug discovery pipeline within the CANDO platform to determine which drugs are most likely to be effective against mutant phenotypes of non-small cell lung cancer (NSCLC) based on the supposition that drugs with similar interaction profiles (or signatures) will have similar behavior and therefore show synergistic effects. CANDO predicted that osimertinib, an EGFR inhibitor, is most likely to synergize with four KRAS inhibitors.Validation studies with cellular toxicity assays confirmed that osimertinib in combination with ARS-1620, a KRAS G12C inhibitor, and BAY-293, a pan-KRAS inhibitor, showed a synergistic effect on decreasing cellular proliferation by acting on mutant KRAS. Gene expression studies revealed that MAPK suppression is a key correlate of decreased cellular proliferation following treatment with KRAS inhibitor BAY-293, but not treatment with ARS-1620 or osimertinib. Our precision medicine pipeline may be used to identify compounds capable of synergizing with inhibitors of KRAS G12C, and to assess their likelihood of becoming drugs by understanding their behavior at the proteomic/interactomic scales.
Collaborative partnership model to transform bioinformatics core into a highly effective research partner and multiply the impact
Authors: Karuturi R. Krishna Murthy , Kunde-Ramamoorthy Govindarajan , TeHennepe Gregg , George Joshy , Philip Vivek
Published: September 2022

Many bioinformatics cores face a multitude of challenges. We recognized that the primary source of these challenges was the service-centric approach. So, we initiated the transformation of our bioinformatics core, Computational Sciences (CS), at the Jackson Laboratory (Jax) to be a science-centric collaborative research partner for our faculty and project stakeholders. We call our model as collaborative partnership model. With the effective replacement of the service model with the collaborative partnership model, CS now acts as both an effective collaborator and a co-driver of scientific research and innovation at Jax. In this paper, we describe the principles and practices we adopted to realize this transformation and present the resulting growth in the impact of CS in the research enterprise at Jax.
Glucose PTS Modulates Pyruvate Metabolism, Bacterial Fitness, and Microbial Ecology in Oral Streptococci
Authors: Zeng Lin , Walker Alejandro R. , Burne Robert A. , Taylor Zachary A.
Published: September 2022

Spontaneous mutants with defects in the primary glucose phosphotransferase (PTS) permease (manLMNO) of Streptococcus sanguinis SK36 showed enhanced fitness at low pH. Transcriptomics and metabolomics with a manL deletion mutant (SK36/manL) revealed redirection of pyruvate to production of acetate and formate, rather than lactate. The observations were consistent with measurements of decreased lactic acid accumulation and increased excretion of pyruvate and H2O2. Genes showing increased expression in SK36/manL included those encoding carbohydrate transporters, extracellular glycosidases, intracellular polysaccharide (IPS) metabolism, arginine deiminase, and pathways for metabolism of acetoin, ethanolamine, ascorbate and formate; along with genes required for membrane biosynthesis and adhesion. Streptococcus mutans UA159 persisted much better in biofilm co-cultures with SK36/manL than with SK36, an effect that was further enhanced by culturing the biofilms anaerobically but dampened by adding arginine to the medium. We posited that the enhanced persistence of S. mutans with SK36/manL was in part due to excess excretion of pyruvate by the latter, as addition of pyruvate to S. mutans-S. sanguinis co-cultures increased the proportions of UA159 in the biofilms. Reduction of the buffer capacity or increasing the concentration of glucose benefited UA159 when co-cultured with SK36, but not with SK36/manL; likely due to the altered metabolism and enhanced acid tolerance of the mutant. When manL was deleted in S. mutans or Streptococcus gordonii, the mutants presented altered fitness characteristics. Our study demonstrated that PTS-dependent modulation of central metabolism can profoundly affect streptococcal fitness and metabolic interactions, revealing another dimension in commensal-pathogen relationships influencing dental caries development.

Importance

Dental caries is underpinned by a dysbiotic microbiome and increased acid production. As beneficial bacteria that can antagonize oral pathobionts, oral streptococci such as S. sanguinis and S. gordonii can ferment many carbohydrates, despite their relative sensitivity to low pH. We characterized the molecular basis for why mutants of glucose transporter ManLMNO of S. sanguinis showed enhanced production of hydrogen peroxide and ammonia, and improved persistence under acidic conditions. Significant metabolic shift involving more than 300 genes required for carbohydrate transport, energy production, and envelope biogenesis was observed. Significantly, manL mutants engineered in three different oral streptococci displayed altered capacities for acid production and interspecies antagonism, highlighting the potential for targeting the glucose-PTS to modulate the pathogenicity of oral biofilms.
Rare Maternally Inherited Coding Variants on Chromosome X Carry Predominantly Male Risk in Autism, Tourette Syndrome, and Attention-deficit/Hyperactivity Disorder
Authors: Wang Sheng , Wang Belinda , Drury Vanessa , Drake Sam , Sun Nawei , Alkhairo Hasan , Arbelaez Juan , Duhn Clif ,   Tourette International Collaborative Genetics (TIC Genetics), Bal Vanessa H. , Langley Kate , Martin Joanna , Xing Jinchuan , Heiman Gary A. , Tischfield Jay A. , Fernandez Thomas V. , Owen Michael J. , O’Donovan Michael C. , Thapar Anita , State Matthew W. , Willsey A. Jeremy
Published: September 2022

Autism spectrum disorders (ASD), Tourette syndrome (TS), and attention-deficit/hyperactivity disorder (ADHD) display strong male sex bias, due to a combination of genetic and biological factors, as well as selective ascertainment. While the hemizygous nature of chromosome X (Chr X) in males has long been postulated as a key point of “male vulnerability”, rare genetic variation on this chromosome has not been systematically characterized in large-scale whole exome sequencing studies of “idiopathic” ASD, TS, and ADHD. Here, we take advantage of informative recombinations in simplex ASD families to pinpoint risk-enriched regions on Chr X, within which rare maternally-inherited damaging variants carry substantial risk in males with ASD. We then apply a modified transmission disequilibrium test to 13,052 ASD probands and identify a novel high confidence ASD risk gene at exome-wide significance (MAGEC3). Finally, we observe that rare damaging variants within these risk regions carry similar effect sizes in TS and ADHD, further clarifying genetic mechanisms underlying male vulnerability in multiple neurodevelopmental disorders that can be exploited for systematic gene discovery.
Integrating comparative modeling and accelerated simulations reveals conformational and energetic basis of actomyosin force generation
Authors: Ma Wen , You Shengjun , Regnier Michael , McCammon J. Andrew
Published: September 2022

Muscle contraction is performed by arrays of contractile proteins in the sarcomere. Serious heart diseases, such as cardiomyopathy, can often be results of mutations in myosin and actin. Direct characterization of how small changes in the myosin-actin complex impact its force production remains challenging. Molecular dynamics (MD) simulations, although capable of studying protein structurefunction relationships, are limited owing to the slow timescale of the myosin cycle as well as a lack of various intermediate structures for the actomyosin complex. Here, employing comparative modeling and enhanced sampling MD simulations, we show how the human cardiac myosin generates force during the mechanochemical cycle. Initial conformational ensembles for different myosin-actin states are learned from multiple structural templates with Rosetta. This enables us to efficiently sample the energy landscape of the system using Gaussian accelerated MD. Key myosin loop residues, whose substitutions are related to cardiomyopathy, are identified to form stable or metastable interactions with the actin surface. We find that the actin-binding cleft closure is allosterically coupled to the myosin core transitions and ATP-hydrolysis product release from the active site. Furthermore, a gate between switch I and switch II is suggested to control phosphate release at the pre-powerstroke state. Our approach demonstrates the ability to link sequence and structural information to motor functions.

Significance Statement

Interactions between myosin and actin are essential in producing various cellular forces. Targeting cardiac myosin, several small molecules have been developed to treat cardiomyopathy. A clear mechanistic picture for the allosteric control in the actomyosin complex can potentially facilitate drug design by uncovering functionally important intermediate states. Here, integrating Rosetta comparative modeling and accelerated molecular dynamics, we reveal how ATP-hydrolysis product release correlates with powerstroke and myosin tight binding to actin. The predicted metastable states and corresponding energetics complement available experimental data and provide insights into the timing of elementary mechanochemical events. Our method establishes a framework to characterize at an atomistic level how a molecular motor translocates along a filament.
Genome evolution and transcriptome plasticity associated with adaptation to monocot and eudicot plants inColletotrichumfungi
Authors: Baroncelli Riccardo , Cobo-Díaz José F. , Benocci Tiziano , Peng Mao , Battaglia Evy , Haridas Sajeet , Andreopoulos William , LaButti Kurt , Pangilinan Jasmyn , Lipzen Anna , Koriabine Maxim , Bauer Diane , Floch Gaetan Le , Mäkelä Miia R. , Drula Elodie , Henrissat Bernard , Grigoriev Igor V. , Crouch Jo Anne , de Vries Ronald P. , Sukno Serenella A. , Thon Michael R.
Published: September 2022

Colletotrichumfungi infect a wide diversity of monocot and eudicot hosts, causing plant diseases on almost all economically important crops worldwide. In addition to its economic impact,Colletotrichumis a suitable model for the study of gene family evolution on a fine scale to uncover events in the genome that are associated with the evolution of biological characters important for host interactions. Here we present the genome sequences of 30Colletotrichumspecies, 18 of them newly sequenced, covering the taxonomic diversity within the genus. A time-calibrated tree revealed that theColletotrichumancestor diverged in the late Cretaceous around 70 million years ago (mya) in parallel with the diversification of flowering plants. We provide evidence of independent host jumps from eudicots to monocots during the evolution of this pathogen, coinciding with a progressive shrinking of the degradative arsenal and expansions in lineage specific genes. Comparative transcriptomics of four reference species with different evolutionary histories and adapted to different hosts revealed similarity in gene content but differences in the modulation of their transcription profiles. Only a few orthologs show similar expression profiles on different plant cell walls. Combining genome sequences and expression profiles we identified a set of core genes, such as specific transcription factors, involved in plant cell wall degradation inColletotrichum.Together, these results indicate that the ancestralColletotrichumwere associated with eudicot plants and certain branches progressively adapted to different monocot hosts, reshaping part of the degradative and transcriptional arsenal.
Data driven model discovery and interpretation for CAR T-cell killing using sparse identification and latent variables
Authors: Brummer Alexander B. , Xella Agata , Woodall Ryan , Adhikarla Vikram , Cho Heyrim , Gutova Margarita , Brown Christine E. , Rockne Russell C.
Published: September 2022

In the development of cell-based cancer therapies, quantitative mathematical models of cellular interactions are instrumental in understanding treatment efficacy. Efforts to validate and interpret mathematical models of cancer cell growth and death hinge first on proposing a precise mathematical model, then analyzing experimental data in the context of the chosen model. In this work, we present the first application of the sparse identification of non-linear dynamics (SINDy) algorithm to a real biological system in order discover cell-cell interaction dynamics inin vitroexperimental data, using chimeric antigen receptor (CAR) T-cells and patient-derived glioblastoma cells. By combining the techniques of latent variable analysis and SINDy, we infer key aspects of the interaction dynamics of CAR T-cell populations and cancer. Importantly, we show how the model terms can be interpreted biologically in relation to different CAR T-cell functional responses, single or double CAR T-cell-cancer cell binding models, and density-dependent growth dynamics in either of the CAR T-cell or cancer cell populations. We show how this data-driven model-discovery based approach provides unique insight into CAR T-cell dynamics when compared to an established model-first approach. These results demonstrate the potential for SINDy to improve the implementation and efficacy of CAR T-cell therapy in the clinic through an improved understanding of CAR T-cell dynamics.
When Mechanical Stress Matters: Generation of Polyploid Giant Cancer Cells in Tumor-like Microcapsules
Authors: Bühler Adrian , Krüger René , Monavari Mahshid , Fuentes-Chandía Miguel , Palmisano Ralf , Schödel Johannes , Boccaccini Aldo R. , Boßerhoff Anja K. , Kappelmann-Fenzl Melanie , Letort Gaelle , Leal-Egaña Aldo
Published: September 2022

In this work, we studied the generation and rising of polyploid cancer cells as a product of mechanical stress. To this purpose, MCF7 breast cancer cells were cultured on 2D (i.e. flasks, or flat hydrogels), and in 3D milieus (i.e. Spheroids, or immobilized within alginate-gelatin microbeads, named in this work as tumor-like microcapsules), and further analyzed by biophysical and genetic methods (i.e. single-cell Traction Force Microscopy and RNA-seq respectively).

Our results show that MCF7 cells preconditioned onto 2D surfaces exhibit a low number of polynucleated cells, while their culture in 3D environments triggered their progressive generation with time. Genetic studies enabled us to determine that polyploid cells found in tumor-like microcapsules are likely originated by cell-cell fusion and disrupted cytokinesis, showing most of the genetic markers for Polyploid Giant Cancer Cell, while cells cultured as spheroids seem to be likely generated by other mechanisms, such as cell cannibalisms, entosis, or emperipolesis.

Our outcomes strongly suggest that both mechanical stress and confinement are required to stimulate cell polyploidy, which can be easily addressed by the immobilization of breast cancer cells in tumor-like microcapsules.
One Health Approach for the sampling of different bat species living in a sympatric colony
Authors: Perera Thejanee , Siriwardana Sahan , Muzeniek Therese , Becker-Ziaja Beate , Bas Dilara , Bayram Fatimanur , Öruc Mizgin , Perera Inoka , Weerasena Jagathpriya , Handunnetti Shiroma , Schwarz Franziska , Premawansa Gayani , Premawansa Sunil , Yapa Wipula , Nitsche Andreas , Kohl Claudia
Published: September 2022

Bats are important contributors to the global ecosystems; at the same time, they are known to be a natural reservoir host for a number of human pathogenic viruses. These and many other unique features make them an interdisciplinary research object in the context of One Health, comprising zoology, ecology, virology, microbiology, molecular biology, immunology and public health issues. Performing field studies for bat research often aims to cover several of these topics and requires the combination of specific expertise in different fields. We carried out three individual field studies in Wavul Galge cave (Koslanda, Sri Lanka), where several bat species roost sympatrically. The main goals were to study the bat colony for ecological aspects and to sample bats for virological and molecular biological analyses. In the course of the field studies, we optimized the sampling procedure regarding safety aspects, a preferably low impact on the captured bats and an improved output of high-quality samples for further analysis. Different sampling methods and procedures were compared in order to establish a suitable strategy for frequent sampling and monitoring of these bats. In the present case study, we report on this process of optimizing our field work and provide suggestions for bat sampling methods that cause comparably less stress for the captured animals. We also report on constraints and obstacles encountered during the practical implementation and possible measures to overcome these.

With these practical experiences, we hope to give support to other interdisciplinary research teams preparing for bat field work. Furthermore, we emphasize the need for the respectful treatment of the animals and minimized disturbance of their natural habitat when carrying out sustainable bat research.