bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the relationship between antipsychotic drug use and prolidase enzyme activity and oxidative stress in schizophrenia patients: a case-control study
Authors: Yazla Ece , Cetin Ihsan , Kayadibi Huseyin
Published: July 2023

Background

The relationship between proline, its association with oxidative stress, and its connection to schizophrenia is a subject that has not been sufficiently investigated.

Objective

The aim of this study is to evaluate the possible effects of atypical and combined (typical and atypical) antipsychotic use on serum prolidase enzyme activity (SPEA) and serum oxidative stress parameters, and to assess the relationship between SPEA and oxidative stress in patients with schizophrenia.

Methods

A total of 57 patients with schizophrenia, of which 34 were using atypical (AAPG) and 23 were using combined (typical and atypical) (CAPG) antipsychotic therapy, and 28 healthy volunteers (control group) were included in this case-control study.

Results

SPEA levels of AAPG and CAPG were significantly lower than that of control group (P = 0.003). The oxidative stress index (OSI) value of AAPG was significantly higher than the other two groups (P = 0.001). SPEA (<1860 U/l) and OSI (≥0.54) could discriminate schizophrenia patients with antipsychotic therapy from control groups (P = 0.001 and P = 0.007, respectively). Lower SPEA levels were associated with antipsychotic use (P = 0.007).

Conclusion

The SPEA values of patients with schizophrenia on antipsychotics were significantly lower compared to controls. OSI values were significantly higher in atypical antipsychotic recipients compared to those on combined antipsychotics and healthy controls.
Target capture sequencing for the first Nigerian genotype I ASFV genome
Authors: Adeola Adeniyi C. , Luka Pam D. , Jiang Xiang-Xiang , Cai Zheng-Fei , Oluwole Olufunke O. , Shi Xian , Oladele Bukola M. , Olorungbounmi Temilola O. , Boladuro Bamidele , Omotosho Oladipo , Okoro Victor M. O. , Dawuda Philip M. , Olaogun Sunday C. , Sanke Oscar J. , Xie Hai-Bing , Bishop Richard P. , Han Jianlin , Li Jianbo , Zhang Ya-Ping , Peng Min-Sheng
Published: July 2023

African swine fever (ASF) is a contagious viral disease that affects domestic pigs and wild boars, causing significant economic losses globally. After the first Nigerian outbreak in 1997, there have been frequent reports of ASF in pig-producing regions in the country. To facilitate control, it is important to understand the genotype and phylogenetic relationship of ASF viruses (ASFVs). Recent genetic analysis of Nigerian ASFV isolates has revealed the presence of both genotypes I and II; this is based on analysis of a few selected genes. Phylogenetic analysis of ASFV whole genomes highlights virus origins and evolution in greater depth. However, there is currently no information on the ASFV genome from Nigerian isolates. Two ASFV-positive samples were detected during a random survey of 150 Nigerian indigenous pig samples collected in 2016. We assembled near-complete genomes of the two ASFV-positive samples using in-solution hybrid capture sequencing. The genome-wide phylogenetic tree assigned these two genomes into p72 genotype I, particularly close to the virulent Benin 97/1 strain. The two ASFVs share 99.94 and 99.92 % genomic sequence identity to Benin97/1. This provides insight into the origin and relationship of ASFV strains from Nigeria and Italy. The study reports for the first time the determination of near-complete genomes of ASFV using in-solution hybrid capture sequencing, which represents an important advance in understanding the global evolutionary landscape of ASFVs.
Predictors of second-line antiretroviral treatment virological failure at Felege hiwot and University of Gondar comprehensive specialized hospitals Amhara region, Northwest Ethiopia: a case-control study
Authors: Wubetu Getahun Ayenew , Ambelie Yeshambel Agumas , Shibabaw Tebkew , Getaneh Gebremariam , Abate Michael Getie
Published: July 2023

Background

Second-line HIV treatment failure has become increasing worldwide, mainly in sub- Sahara Africa including Ethiopia. Even though the problem becomes increasing, inadequate information was available about its magnitude and predictors in the current study area.

Objective

To assess the predictors of second line Anti-Retroviral Treatment virological failure among second line ART users.

Method and materials

Institutional based unmatched case control study design was conducted from first September 2021 to December last 2021 at Felege Hiowt and University of Gondar Comprehensive Specialized Hospitals; Amhara region, Northwest Ethiopia. A total of 216 patients (60 cases and 156 controls) were recruited by Simple random sampling technique with 1:3 cases-to-controls ratio. Patients who had two viral load results>1000 copies/ml within a 3-month interval after taking ART drugs for at least 6 months were cases whereas ≤1,000 copies/ mL were controls. The sample size was calculated by using Epi-Info version 7.2.4. Structured questionnaires were used to gather the required information. SPSS version 26 was used to summarize the findings. In bivariate logistic regression model, Variables with two-tailed P-value ≤ 0.25 at 95% confidence interval were transferred into multivariate binary logistic regression mode and P value at ≤ 0.05 was set as statistically significant.

Results

Out of 216 patients recruited, 212 were participated with a response rate of 98.2%. Among the participants, 117 (55.2%) were males and 187 (88.2%) were urban dwellers. 208 (98.1%) of the respondents had age > 24 years, 73 (34.4%) had elementary level of education, 72(34%) had poor ART adherence and 112(52.8) did not disclose their HIV status. Likewise, most of the patients 147(69.37) didn’t used condom. The Predictors were not disclosing HIV status (AOR=3.4, 95% CI: 1.52 – 7.79), poor adherence level (AOR=5.27, 95% CI: 2.2 - 12.5), not using condom (AOR=4.47, 95% CI: 1.63 – 12.2) and high Viral load (>1000 copes/ml) when switched to second line ART (AOR=3.56, 95% CI: 1.5 - 8).

Conclusion and recommendations

The Predictors of second line Anti-Retroviral Treatment virological failure were non-disclosure, poor adherence, not using condom and high Viral load (>1000 copes/ml) at switched to second line ART. Disclosing their HIV status, using condom and improving their adherence level for patients and counselling about the importance of disclosure and good adherence for health care providers are crucial.
Monitoring single root hairs using a micro-chambered hydroponics system MiCHy reveals a new mode of action of the aminosteroid U73122
Authors: Shikata Hiromasa , Sato Yoshikatsu , Schwechheimer Claus
Published: July 2023

When using chemical probes and inhibitors for cell biological studies, the uniform and rapid access of the chemical to the sample is key for the accuracy of the analysis. Until now, however, this could only be accomplished by using expensive equipment and labor-intensive and often lengthy procedures. Here, we introduce MiCHy, a micro-chambered hydroponics system, as an accessible and versatile method for chemical treatments and demonstrate its use for imaging roots ofArabidopsis thaliana, the major model system for plant cell biological research. Using lipid biosensors in combination with established chemicals, such as the phosphoinositol 4-kinase (PI4K) inhibitor phenylarsine oxide and the phosphoinositide-specific phospholipase C (PI-PLC) inhibitor U73122, we demonstrate the suitability of MiCHy for studying the relationship between growth and lipid dynamics in root hairs. We further reveal novel effects of U73122 on the plasma membrane localization of phosphatidylinositol-4-phosphate 5-kinase 3 (PIP5K3), which is the first evidence demonstrating a role for U73122 besides its role as a PI-PLC inhibitor in plants.
Concurrent profiling of multiscale 3D genome organization and gene expression in single mammalian cells
Authors: Zhou Tianming , Zhang Ruochi , Jia Deyong , Doty Raymond T. , Munday Adam D. , Gao Daniel , Xin Li , Abkowitz Janis L. , Duan Zhijun , Ma Jian
Published: July 2023

The organization of mammalian genomes within the nucleus features a complex, multiscale three-dimensional (3D) architecture. The functional significance of these 3D genome features, however, remains largely elusive due to limited single-cell technologies that can concurrently profile genome organization and transcriptional activities. Here, we report GAGE-seq, a highly scalable, robust single-cell co-assay that simultaneously measures 3D genome structure and transcriptome within the same cell. Employing GAGE-seq on mouse brain cortex and human bone marrow CD34+ cells, we comprehensively characterized the intricate relationships between 3D genome and gene expression. We found that these multiscale 3D genome features collectively inform cell type-specific gene expressions, hence contributing to defining cell identity at the single-cell level. Integration of GAGE-seq data with spatial transcriptomic data revealedin situvariations of the 3D genome in mouse cortex. Moreover, our observations of lineage commitment in normal human hematopoiesis unveiled notable discordant changes between 3D genome organization and gene expression, underscoring a complex, temporal interplay at the single-cell level that is more nuanced than previously appreciated. Together, GAGE-seq provides a powerful, cost-effective approach for interrogating genome structure and gene expression relationships at the single-cell level across diverse biological contexts.
HaploCatcher: An R Package for Prediction of Haplotypes
Authors: Winn Zachary James , Hudson-Arns Emily , Hammers Mikayla , DeWitt Noah , Lyerly Jeanette , Bai Guihua , St. Amand Paul , Nachappa Punya , Haley Scott , Mason Richard Esten
Published: July 2023

Wheat (Triticum aestivumL.) is crucial to global food security, but is often threatened by diseases, pests, and environmental stresses. Wheat stem sawfly (Cephus cinctusNorton) poeses a major threat to food security in the United States, and solid-stem varieties, which carry the stem-solidness locus (Sst1), are the main source of genetic resistance against sawfly. Marker-assisted selection uses molecular markers to identify lines possessing beneficial haplotypes, like that of theSst1locus. In this study, an R package titled "HaploCatcher" was developed to predict specific haplotypes of interest in genome-wide genotyped lines. A training population of 1,056 lines genotyped for theSst1locus, known to confer stem solidness, and genome-wide markers was curated to make predictions of theSst1haplotypes for 292 lines from the Colorado State University wheat breeding program. PredictedSst1haplotypes were compared to marker derived haplotypes. Our results indicated that the training set was substantially predictive, with kappa scores of 0.83 for k-nearest neighbors and 0.88 for random forest models. Forward validation on newly developed breeding lines demonstrated that a random forest model, trained on the total available training data, had comparable accuracy between forward and cross-validation. Estimated group means of lines classified by haplotypes from PCR-derived markers and predictive modeling did not significantly differ. The HaploCatcher package is freely available and may be utilized by breeding programs, using their own training populations, to predict haplotypes for whole genome sequenced early generation material.

CORE IDEAS

Identification, introgression, and frequency increase of large effect loci are important for cultivar development.

TheSst1locus has a significant effect on cutting score in fields exposed to sawfly infestation.

Historical genetic information can be utilized to predict haplotypes for lines which have genome-wide genetic data.

An R package, HaploCatcher, has been developed to facilitate this analysis in other programs.
RAPID ALKALINIZATION FACTOR 22 is a key modulator of the proliferation and hyper-elongation responses of root hairs to microbial volatiles in Arabidopsis
Authors: León Morcillo Rafael Jorge , Leal-López Jesús , López-Serrano Lidia , Baroja-Fernández Edurne , Gámez-Arcas Samuel , Doblas Verónica G. , Férez-Gómez Alberto , Pozueta-Romero Javier
Published: July 2023

RAPID ALKALINIZATION FACTOR (RALF) peptides are important players in regulating cell expansion. In Arabidopsis, volatile compounds (VCs) emitted by the fungal phytopathogenPenicillium aurantiogriseumpromote root hair (RH) proliferation and hyper-elongation through ethylene and enhanced photosynthesis signalling actions. A striking alteration in the proteome of fungal VC-treated roots involves up-regulation of RALF22. To test the possible involvement of RALF22 in the fungal VC-promoted RH changes, we characterized RH density and number responses to fungal VCs inralf22andfer-4plants impaired in RALF22 and its receptor FERONIA, respectively. Unlike WT plants,ralf22andfer-4RHs responded weakly to fungal VCs, strongly indicating that the RALF22-FERONIA module is a key determinant of the RH response to fungal VCs. To investigate the regulatory mechanisms behind this response, we analysed theRALF22transcript levels in roots ofetr1-3andeir1ethylene signalling mutants and those of ethylene-responsive, RH-relatedRSL4, RHD2, PRX1andPRX44transcripts inralf22andfer-4roots. Moreover, we characterized the RH andRALF22transcript level responses to fungal VCs of thecfbp1mutant defective in photosynthetic responsiveness to VCs. Unlike in WT roots, fungal VCs weakly enhancedRALF22expression inetr1-3, eir1andcfbp1roots, andRSL4, RHD2, PRX1andPRX44expression inralf22andfer-4roots. In addition, fungal VCs weakly promoted RH changes incfbp1roots. Collectively, our findings showed that the ethylene and enhanced photosynthesis signalling-mediated RH response to fungal VCs involves RALF22-FERONIA.
3 Directional Inception-ResUNet: deep spatial feature learning for multichannel singing voice separation with distortion
Authors: Wang DaDong , Wang Jie , Sun MingChen
Published: July 2023

Singing voice separation on robots faces the problem of interpreting ambiguous auditory signals. The acoustic signal, which the humanoid robot perceives through its onboard microphones, is a mixture of singing voice, music, and noise, with distortion, attenuation, and reverberation. In this paper, we used the 3 directional Inception-Resnet structure in the U-shaped encoding and decoding network to improve the utilization of the spatial and spectral information of the spectrograms.

Multi-objectives were used to train the model: magnitude consistency loss, phase consistency loss, and magnitude correlation consistency loss. We recorded the singing voice and accompaniment derived from the MIR-1k datasets with NAO robots and synthesized the 10-channel datasets for training the model. The experimental results show that the proposed model trained by multi-objective reaches an average NSDR of 11.55db on the test datasets, which outperforms the comparison model.

Author summary

The mixture in the real singing voice separation is always mixed with noise and distortion. In this paper, the acoustic signals with distortion and noise perceived by the robot are used to study the separation of singing voices in real scenes. This paper described how to synthesize the training datasets, proposed a 3 directional Inception-ResUNet structure for multichannel singing voice separation, and adopted multi-objectives including magnitude correlation consistency loss to train the model. The experimental results showed that the magnitude correlation consistency loss reduces distortions, the proposed model achieves better performance than the compared models.
FLECS Technology for High-Throughput Screening of Hypercontractile Cellular Phenotypes in Fibrosis: A Function-First Approach to Anti-Fibrotic Drug Discovery
Authors: Wang Yao , Cortes Enrico , Huang Ricky , Wan Jeremy , Hinz Boris , Damoiseaux Robert , Pushkarsky Ivan
Published: July 2023

The pivotal role of myofibroblast contractility in the pathophysiology of fibrosis is widely recognized, yet HTS approaches are not available to quantify this critically important function in drug discovery. We develop, validate, and scale-up a HTS platform that quantifies contractile function of primary human lung myofibroblasts upon treatment with pro-fibrotic TGF-β1. With the fully automated assay we screened a library of 40,000 novel small molecules in under 80 h of total assay run-time. We identified 42 hit compounds that inhibited the TGF-β1-induced contractile phenotype of myofibroblasts, and enriched for 19 that specifically target myofibroblasts but not phenotypically related smooth muscle cells. Selected hits were validated in anex vivolung tissue models for their inhibitory effects on fibrotic gene upregulation by TGF-β1. Our results demonstrate that integrating a functional contraction test into the drug screening process is key to identify compounds with targeted and diverse activity as potential anti-fibrotic agents.
Sensory event-related potential morphology predicts age in premature infants
Authors: Zandvoort Coen S. , van der Vaart Marianne , Robinson Shellie , Usman Fatima , Schmidt Mellado Gabriela , Evans Fry Ria , Worley Alan , Adams Eleri , Slater Rebeccah , Baxter Luke , de Vos Maarten , Hartley Caroline
Published: July 2023

Preterm infants undergo substantial neurosensory development in the first weeks after birth. Infants born prematurely are more likely to have long-term adverse neurological outcomes and early detection of abnormal brain development is essential for timely interventions. We investigated whether sensory-evoked cortical potentials could be used to accurately estimate the age of an infant. Such a model could be used to identify infants who deviate from normal neurodevelopment by comparing the brain age to the infant’s postmenstrual age (PMA). Infants aged between 28- and 40-weeks PMA from a training and test sample (consisting of 101 and 65 recording sessions in 82 and 14 infants, respectively) received trains of approximately 10 visual and 10 tactile stimuli (interstimulus interval approximately 10 seconds). PMA could be predicted accurately from the magnitude of the evoked responses (training set mean absolute error (MAE and 95% confidence intervals): 1.41 [1.14; 1.74] weeks,p= 0.0001; test set MAE: 1.55 [1.21; 1.95] weeks,p= 0.0002. Moreover, we show with two examples that brain age, and the deviations between brain age and PMA, may be biologically and clinically meaningful. By firstly demonstrating that brain age is correlated with a measure known to relate to maturity of the nervous system (based on animal and human literature, the magnitude of reflex withdrawal is used) and secondly by linking brain age to long-term neurological outcomes, we show that brain age deviations are related to biologically meaningful individual differences in the rate of functional nervous system maturation rather than noise generated by the model. In summary, we demonstrate that sensory-evoked potentials are predictive of age in premature infants. It takes less than 5 minutes to collect the stimulus electroencephalographic data required for our model, hence, increasing its potential utility in the busy neonatal care unit. This model could be used to detect abnormal development of infant’s response to sensory stimuli in their environment and may be predictive of later life abnormal neurodevelopmental outcome.
Consistent decrease in conifer embolism resistance from the stem apex to base resulting from axial trends in tracheid and pit traits
Authors: Dario Zambonini , Tadeja Savi , Sabine Rosner , Giai Petit
Published: July 2023

Drought-induced embolism formation in conifers is associated with several tracheid and pit traits, which vary in parallel from stem apex to base. We tested whether this axial anatomical variability is associated with a progressive variation in embolism vulnerability along the stem from apex to base.

We assessed the xylem pressure at 50% loss of conductivity (P50), the tracheid hydraulic diameter (Dh) and mean pit membrane area (PMA) on longitudinal stem segments extracted at different distances from the stem apex (DFA) in aPicea abiesand anAbies albatree. In both trees,DhandPMAscaled withDFA0.2.P50varied for more than 3 MPa from the treetop to the stem base, according to a scaling of -P50withDFA-0.2. The largestDh,PMAandP50variation occurred forDFA<1.5 m.PMAandDhscaled isometrically (exponentb=1).

Pit traits vary proportionally with tracheid lumen diameter. Apex-to-base trends in tracheid and pit traits determine a largeDFA-dependentP50variability. Such aDFAeffect onP50did not receive sufficient attention so far, although analysing the relationshipsP50vs.DFAis fundamental for the assessment of embolism vulnerability at the individual level.

Highlights

Conifer embolism vulnerability depends on pit properties, in agreement with published data.

Pit dimensions increase with tracheid lumen diameter, in agreement with published data

Tracheid lumen diameter and pit dimensions increase progressively from the stem apex to base, in agreement with published data.

Xylem vulnerability to embolism formation (P50) varies for > 3 MPa from the stem apex to base, with the largest variation occurring within 1.5 m from the stem apex.

Axial anatomical patterns should be accounted for when analyzing hydraulic properties at individual, intra- and inter-specific scales.
Changes in spatial self-consciousness elicit grid cell-like representation in entorhinal cortex
Authors: Moon Hyuk-June , Albert Louis , Falco Emanuela De , Tasu Corentin , Gauthier Baptiste , Park Hyeong-Dong , Blanke Olaf
Published: July 2023

Grid cells in entorhinal cortex (EC) encode an individual’s location in space and rely on environmental cues and multisensory bodily cues. Body-derived signals are also primary signals for the sense of self as the continuous application of visuo-tactile bodily stimuli elicits illusory drifts in perceived self-location. It is unknown whether illusory changes in self-location are sufficient to elicit grid cell like representation (GCLR) in EC and how this compares to GCLR during conventional virtual navigation. Our results show that illusory changes in perceived self-location (independent of changes in environmental navigation cues and explicit imagined navigation) evoke entorhinal GCLR, correlating in strength with the magnitude of perceived self-location, and characterized by similar grid orientation as during conventional virtual navigation. These data demonstrate that the same grid-like representation is recruited when navigating based on environmental, mainly visual cues, or when experiencing illusory forward drifts in self-location, driven by perceptual multisensory bodily cues.
Microbial community organization designates distinct pulmonary exacerbation types and predicts treatment outcome in cystic fibrosis
Authors: Widder Stefanie , Opron Kristopher , Carmody Lisa A. , Kalikin Linda M. , Caverly Lindsay J. , LiPuma John J.
Published: July 2023

Polymicrobial infection of the airways is a hallmark of obstructive lung diseases such as cystic fibrosis (CF), non-CF bronchiectasis, and chronic obstructive pulmonary disease (COPD). Intermittent pulmonary exacerbations (PEx) in these conditions are associated with lung function decline and higher mortality rates. An understanding of the microbial underpinnings of PEx is challenged by high inter-patient variability in airway microbial community profiles. We analyzed 880 near-daily CF sputum samples and developed non-standard microbiome descriptors to model community reorganization prior and during 18 PEx. We identified two communal microbial regimes with opposing ecology and dynamics. Whereas pathogen-governed dysbiosis showed hierarchical community organization and reduced diversity, anaerobic bloom dysbiosis displayed stochasticity and increased diversity. Microbiome organization modulated the relevance of pathogens and a simulation of antimicrobial treatment predicted better efficacy for hierarchically organized microbiota. This causal link between PEx, microbiome organization, and treatment success advances the development of personalized dysbiosis management in CF and, potentially, other obstructive lung diseases.
Mobile version of the Battery for the Assessment of Auditory Sensorimotor and Timing Abilities (BAASTA): Implementation and adult norms
Authors: Bella Simone Dalla , Foster Nicholas E.V. , Laflamme Hugo , Zagala Agnès , Melissa Kadi , Komeilipoor Naeem , Blais Mélody , Rigoulot Simon , Kotz Sonja A.
Published: July 2023

Timing and rhythm abilities are complex and multidimensional skills that are highly widespread in the general population. This complexity can be partly captured by the Battery for the Assessment of Auditory Sensorimotor and Timing Abilities (BAASTA). The battery, consisting of 4 perceptual and 5 sensorimotor tests (finger tapping), has been used in healthy adults and in clinical populations (e.g., Parkinson’s disease, ADHD, developmental dyslexia, stuttering), and shows sensitivity to individual differences and impairment. However, major limitations for the generalized use of this tool are the lack of reliable and standardized norms and of a version of the battery that can be used outside the lab. To circumvent these caveats we put forward a new version of BAASTA on a tablet device capable of ensuring lab-equivalent measurements of timing and rhythm abilities. We present normative data obtained with this version of BAASTA from over 100 healthy adults between the ages of 18 and 87 years in a test-retest protocol. Moreover, we propose a new composite score to summarize beat-based rhythm capacities, the Beat Tracking Index (BTI), with close to excellent test-retest reliability. BTI derives from two BAASTA tests (beat alignment, paced tapping), and offers a swift and practical way of measuring rhythmic abilities when research imposes strong time constraints. This mobile BAASTA implementation is more inclusive and far-reaching, while opening new possibilities for reliable remote testing of rhythmic abilities by leveraging accessible and cost-efficient technologies.
Length-dependent RNA foci formation and RAN translation are associated with SCA12 disorder
Authors: Kumar Manish , Sahni Shweta , Anand Vivek , Kumar Deepak , Kushwah Neetu , Goel Divya , Kapoor Himanshi , Srivastava Achal K , Faruq Mohammed
Published: July 2023

Spinocerebellar ataxia type-12 (SCA-12) is a neurodegenerative disease caused by tandem CAG repeat expansion in the 5’-UTR/non-coding region ofPPP2R2B. Molecular pathology of SCA12 has not been studied in the context of CAG repeats and no appropriate models exist. We found in human SCA12-iPSC derived neuronal lineage that expanded CAG inPPP2R2Btranscript forms nuclear RNA foci and were found to sequester variety of proteins. Further, the ectopic expression of transcript containing varying length of CAG repeats exhibits non-canonical Repeat Associated Non-AUG (RAN) translation in multiple frames in HEK293T cells, which was further validated in patient-derived neural stem cells using specific antibodies. mRNA sequencing of the SCA12 and control neurons have shown a network of crucial transcription factors affecting neural fate, in addition to alteration of various signaling pathways involved in neurodevelopment. Altogether, this study identifies the molecular signatures of spinocerebellar ataxia type-12 disorder using patient-derived neuronal cell lines.
Physicochemical Targeting of Lipid Nanoparticles to the Lungs Induces Clotting: Mechanisms and Solutions
Authors: Omo-Lamai Serena , Zamora Marco E. , Patel Manthan N. , Wu Jichuan , Nong Jia , Wang Zhicheng , Peshkova Alina , Chase Liam S. , Essien Eno-Obong , Muzykantov Vladimir , Marcos-Contreras Oscar , Myerson Jacob W. , Brenner Jacob S.
Published: July 2023

Lipid nanoparticles (LNPs) have become the dominant drug delivery technology in industry, holding the promise to deliver RNA to up- or down-regulate any protein of interest. LNPs have been targeted to specific cell types or organs by physicochemical targeting, in which LNP’s lipid compositions are adjusted to find mixtures with the desired tropism. In a popular approach, physicochemical targeting is accomplished by formulating with charged lipids. Negatively charged lipids localize LNPs to the spleen, and positively charged lipids to the lungs. Here we found that lung-tropic LNPs employing cationic lipids induce massive thrombosis. We demonstrate that thrombosis is induced in the lungs and other organs, and greatly exacerbated by pre-existing inflammation. This clotting is induced by a variety of formulations with cationic lipids, including LNPs and non-LNP nanoparticles. The mechanism depends on the LNPs binding to fibrinogen and inducing platelet and thrombin activation. Based on these mechanisms, we engineered multiple solutions which enable positively charged LNPs to target the lungs while not inducing thrombosis. Our findings implicate thrombosis as a major barrier that blood erects against LNPs with cationic components and illustrate how physicochemical targeting approaches must be investigated early for risks and re-engineered with a careful understanding of biological mechanisms.
Meta-colored compacted de Bruijn graphs
Authors: Pibiri Giulio Ermanno , Fan Jason , Patro Rob
Published: July 2023

Motivation

The colored compacted de Bruijn graph (c-dBG) has become a fundamental tool used across several areas of genomics and pangenomics. For example, it has been widely adopted by methods that perform read mapping or alignment, abundance estimation, and subsequent downstream analyses. These applications essentially regard the c-dBG as a map fromk-mers to the set of references in which they appear. The c-dBG data structure should retrieve this set — thecolorof thek-mer — efficiently for any givenk-mer, while using little memory. To aid retrieval, the colors are stored explicitly in the data structure and take considerable space for large reference collections, even when compressed. Reducing the space of the colors is therefore of utmost importance for large-scale sequence indexing.

Results

We describe themeta-coloredcompacted de Bruijn graph (Mac-dBG) — a new colored de Bruijn graph data structure where colors are represented holistically, i.e., taking into account their redundancy across the whole collection being indexed, rather than individually as atomic integer lists. This allows the factorization and compression of common sub-patterns across colors. While optimizing the space of our data structure is NP-hard, we propose a simple heuristic algorithm that yields practically good solutions. Results show that the Mac-dBG data structure improves substantially over the best previous space/time trade-off, by providing remarkably better compression effectiveness for the same (or better) query efficiency. This improved space/time trade-off is robust across different datasets and query workloads.

Code availability

AC++17implementation of the Mac-dBG is publicly available on GitHub at:https://github.com/jermp/fulgor.
Developmental trajectories of EEG aperiodic and periodic components: Implications for understanding thalamocortical development during infancy
Authors: Wilkinson Carol L. , Yankowitz Lisa , Chao Jerry Y. , Gutiérrez Rodrigo , Rhoades Jeff L. , Shinnar Shlomo , Purdon Patrick L. , Nelson Charles A.
Published: July 2023

The development of neural circuits has long-lasting effects on brain function, yet our understanding of early circuit development in humans remains limited. Here, periodic EEG power features and aperiodic components were examined from longitudinal EEGs collected from 592 healthy 2–44 month-old infants, revealing age-dependent nonlinear changes suggestive of distinct milestones in early brain maturation. Consistent with the transient developmental progression of thalamocortical circuitry, we observe the presence and then absence of periodic alpha and high beta peaks across the three-year period, as well as the emergence of a low beta peak (12-20Hz) after six months of age. We present preliminary evidence that the emergence of the low beta peak is associated with higher thalamocortical-dependent, anesthesia-induced alpha coherence. Together, these findings suggest that early age-dependent changes in alpha and beta periodic peaks may reflect the state of thalamocortical network development.
Whole genomes of the amazonianCacajaoreveal complex connectivity and fast differentiation driven by high environmental dynamism
Authors: Hermosilla-Albala Núria , Silva Felipe Ennes , Cuadros-Espinoza Sebastián , Fontsere Claudia , Valenzuela-Seba Alejandro , Pawar Harvinder , Gut Marta , Kelley Joanna L. , Ruibal-Puertas Sandra , Alentorn-Moron Pol , Faella Armida , Lizano Esther , Farias Izeni , Hrbek Tomas , Valsecchi Joao , Gut Ivo G. , Rogers Jeffrey , Farh Kyle Kai-How , Kuderna Lukas F. K. , Marques-Bonet Tomas , Boubli Jean P.
Published: July 2023

Despite showing the greatest primate diversity on the planet, genomic studies on Amazonian primates show very little representation in the literature. With 48 geolocalized high coverage whole genomes from wild uakari monkeys, we present the first population-level study on platyrrhines using whole genome data. In a very restricted range of the Amazon rainforest, eight uakari species (Cacajaogenus) have been described and categorized into bald and black uakaris, based on phenotypic and ecological differences. Despite a slight habitat overlap, we show that posterior to their split 0.92 Mya, bald and black uakaris have remained independent, without gene flow. Nowadays, these two groups present distinct genetic diversity and group-specific variation linked to pathogens. We propose differing hydrology patterns and effectiveness of geographic barriers have modulated the intra-group connectivity and structure of uakari populations. Beyond increasing their representation, with this work we explored the effects of the Amazon rainforest’s dynamism on platyrrhine species.
Fine-scale contemporary recombination variation and its fitness consequences in adaptively diverging stickleback fish
Authors: Venu Vrinda , Harjunmaa Enni , Dreau Andreea , Brady Shannon , Absher Devin , Kingsley David , Jones Felicity
Published: July 2023

Despite deep evolutionary conservation, recombination varies greatly across the genome, among individuals, sexes, and populations and can be a major evolutionary force in the wild. Yet this variation in recombination and its impact on adaptively diverging populations is not well understood. To elucidate the nature and potential consequences of recombination rate variation, we characterized fine-scale recombination landscapes by combining pedigrees, functional genomics and field fitness measurements in an adaptively divergent pair of marine and freshwater threespine stickleback populations from River Tyne, Scotland. Through whole-genome sequencing of large nuclear families, we identified the genomic location of almost 50,000 crossovers and built recombination maps for 36 marine, freshwater, and hybrid individuals at 3.8 kilobase resolution. Using these maps, we quantified the factors driving variation in recombination rate: we find strong heterochiasmy between sexes (68% of the variation) but also differences among ecotypes (21.8%). Hybrids show evidence of significant recombination suppression, both in overall map length and in individual loci. We further tested and found reduced recombination rates both within single marine–freshwater adaptive loci and between loci on the same chromosome, suggestive of selection on linked ‗cassettes‘. We tested theory supporting the evolution of linked selection using temporal sampling along a natural hybrid zone, and found that recombinants with shuffled alleles across loci show traits associated with reduced fitness. Our results support predictions that divergence in cis-acting recombination modifiers whose mechanisms are disrupted in hybrids, may have an important role to play in the maintenance of differences among adaptively diverging populations.
Biophysical principles predict fitness of SARS-CoV-2 variants
Authors: Wang Dianzhuo , Huot Marian , Mohanty Vaibhav , Shakhnovich Eugene I.
Published: July 2023

SARS-CoV-2 employs its spike protein’s receptor binding domain (RBD) to enter host cells. The RBD is constantly subjected to immune responses, while requiring efficient binding to host cell receptors for successful infection. However, our understanding of how RBD’s biophysical properties contribute to SARS-CoV-2’s epidemiological fitness remains largely incomplete. Through a comprehensive approach, comprising large-scale sequence analysis of SARS-CoV-2 variants and the discovery of a fitness function based on binding thermodynamics, we unravel the relationship between the biophysical properties of RBD variants and their contribution to viral fitness. We developed a biophysical model that uses statistical mechanics to map the molecular phenotype space, characterized by binding constants of RBD to ACE2, LY-CoV016, LY-CoV555, REGN10987, and S309, onto a epistatic fitness landscape. We validate our findings through experimentally measured and machine learning (ML) estimated binding affinities, coupled with infectivity data derived from population-level sequencing. Our analysis reveals that this model effectively predicts the fitness of novel RBD variants and can account for the epistatic interactions among mutations, including explaining the later reversal of Q493R. Our study sheds light on the impact of specific mutations on viral fitness and delivers a tool for predicting the future epidemiological trajectory of previously unseen or emerging low frequency variants. These insights offer not only greater understanding of viral evolution but also potentially aid in guiding public health decisions in the battle against COVID-19 and future pandemics.

Significance Statement

This research presents a biophysical model that maps the molecular properties of SARS-CoV-2’s receptor binding domain into an epistatic fitness landscape. By linking the binding affinities of the virus to its epidemic fitness, we offer a powerful tool for understanding and predicting the emergence and success of new viral variants. Our model, validated with real-world data and informed by theoretical insights, provides a foundation for interpreting the evolutionary trajectory of past pandemics and predicting those of the future. The adaptability of this biophysical model extends to the key proteins of other viruses as well, signifying its potential in guiding public health interventions, and advancing our understanding of viral evolution.
hadge: a comprehensive pipeline for donor deconvolution in single cell
Authors: Curion Fabiola , Wu Xichen , Heumos Lukas , Gonzales Mariana , Halle Lennard , Grant-Peters Melissa , Rich-Griffin Charlotte , Yeung Hing-Yuen , Dendrou Calliope A. , Schiller Herbert B. , Theis Fabian J.
Published: July 2023

Single cell multiplexing techniques (cell hashing and genetic multiplexing) allow to combine multiple samples, thereby optimizing sample processing and reducing batch effects. Cell hashing conjugates antibody-tags or chemical-oligonucleotides to cell membranes, while genetic multiplexing allows to mix genetically diverse samples and relies on aggregation of RNA reads at known genomic coordinates. We developed hadge (hashingdeconvolution combined withgenotype information), a Nextflow pipeline that combines 12 methods to perform both hashing- and genotype-based deconvolution. We propose a joint deconvolution strategy combining the best performing methods and we demonstrate how this approach leads to recovery of previously discarded cells in a nuclei hashing of fresh-frozen brain tissue.
Activation of the mevalonate pathway in response to anti-cancer treatments drives glioblastoma recurrences through activation of Rac-1
Authors: He Ling , Ioannidis Angeliki , Arambula Evelyn , Hoffman Carter J. , Joshi Purva , Kathiravan Anoushka , Whitelegge Julian , Liau Linda M. , Kornblum Harley I. , Pajonk Frank
Published: July 2023

Glioblastoma is the deadliest adult brain cancer. Under the current standard of care almost all patients succumb to the disease and novel treatments are urgently needed. Dopamine receptor antagonists have been shown to target cancer cell plasticity in GBM and repurposing these FDA-approved drugs in combination with radiation improves the efficacy of radiotherapy in glioma models. In cells surviving this combination treatment the mevalonate pathway is upregulated at the transcriptional and functional level.

Here we report that glioblastoma treatments that converge in the immediate early response to radiation through activation of the MAPK cascade universally upregulate the mevalonate pathway and increase stemness of GBM cells through activation of the Rho-GTPase Rac-1. Activation of the mevalonate pathway and Rac-1 is inhibited by statins, which leads to improved survival in mouse models of glioblastoma when combined with radiation and drugs that target the glioma stem cell pool and plasticity of glioma cells.
ME3BP-7 is a targeted cytotoxic agent that rapidly kills pancreatic cancer cells expressing high levels of monocarboxylate transporter MCT1
Authors: Rincon-Torroella Jordina , Dal Molin Marco , Mog Brian , Han Gyuri , Watson Evangeline , Wyhs Nicolas , Ishiyama Shun , Ahmedna Taha , Minn Il , Azad Nilofer S. , Bettegowda Chetan , Papadopoulos Nickolas , Kinzler Kenneth W. , Zhou Shibin , Vogelstein Bert , Gabrielson Kathleen , Sur Surojit
Published: July 2023

Nearly 30% of Pancreatic ductal adenocarcinoma (PDAC)s exhibit a marked overexpression of Monocarboxylate Transporter 1 (MCT1) offering a unique opportunity for therapy. However, biochemical inhibitors of MCT1 have proven unsuccessful in clinical trials. In this study we present an alternative approach using 3-Bromopyruvate (3BP) to target MCT1 overexpressing PDACs. 3BP is a cytotoxic agent that is known to be transported into cells via MCT1, but its clinical usefulness has been hampered by difficulties in delivering the drug systemically. We describe here a novel microencapsulated formulation of 3BP (ME3BP-7), that is effective against a variety of PDAC cells in vitro and remains stable in serum. Furthermore, systemically administered ME3BP-7 significantly reduces pancreatic cancer growth and metastatic spread in multiple orthotopic models of pancreatic cancer with manageable toxicity. ME3BP-7 is, therefore, a prototype of a promising new drug, in which the targeting moiety and the cytotoxic moiety are both contained within the same single small molecule.

One Sentence Summary

ME3BP-7 is a novel formulation of 3BP that resists serum degradation and rapidly kills pancreatic cancer cells expressing high levels of MCT1 with tolerable toxicity in mice.
Sex-specific actions of estradiol and testosterone on human fibroblast and endothelial cell proliferation, bioenergetics, and vasculogenesis
Authors: Martier Ashley T. , Maurice Yasmin V. , Conrad K. Michael , Mauvais-Jarvis Franck , Mondrinos Mark J.
Published: July 2023

Progress toward the development of sex-specific tissue engineered systems has been hampered by the lack of research efforts to define the effects of sex-specific hormone concentrations on relevant human cell types. Here, we investigated the effects of defined concentrations of estradiol (E2) and dihydrotestosterone (DHT) on primary human dermal and lung fibroblasts (HDF and HLF), and human umbilical vein endothelial cells (HUVEC) from female (XX) and male (XY) donors in both 2D expansion cultures and 3D stromal vascular tissues. Sex-matched E2 and DHT stimulation in 2D expansion cultures significantly increased the proliferation index, mitochondrial membrane potential, and the expression of genes associated with bioenergetics (Na+/K+ ATPase, somatic cytochrome C) and beneficial stress responses (chaperonin) in all cell types tested. Notably, cross sex hormone stimulation, i.e., DHT treatment of XX cells in the absence of E2 and E2 stimulation of XY cells in the absence of DHT, decreased bioenergetic capacity and inhibited cell proliferation. We used a microengineered 3D vasculogenesis assay to assess hormone effects on tissue scale morphogenesis. E2 increased metrics of vascular network complexity compared to vehicle in XX tissues. Conversely, and in line with results from 2D expansion cultures, E2 potently inhibited vasculogenesis compared to vehicle in XY tissues. DHT did not significantly alter vasculogenesis in XX or XY tissues but increased the number of non-participating endothelial cells in both sexes. This study establishes a scientific rationale and adaptable methods for using sex hormone stimulation to develop sex-specific culture systems.
Inducible nitric oxide synthase (iNOS) is necessary for GBP-mediatedT. gondiirestriction in murine macrophages via vacuole nitration and intravacuolar network collapse
Authors: Zhao Xiao-Yu , Lempke Samantha L. , Urbán Arroyo Jan C. , Yin Bocheng , Holness Nadia K. , Smiley Jamison , Ewald Sarah E.
Published: July 2023

Toxoplasma gondiiis an obligate intracellular, protozoan pathogen of rodents and humans.T. gondii’sability to grow within cells and evade cell-autonomous immunity depends on the integrity of the parasitophorous vacuole (PV). Interferon-inducible guanylate binding proteins (GBPs) are central mediators ofT. gondiiclearance, however, the precise mechanism linking GBP recruitment to the PV andT. gondiirestriction is not clear. This knowledge gap is linked to heterogenous GBP-targeting across a population of vacuoles and the lack of tools to selectively purify the intact PV. To identify mediators of parasite clearance associated with GBP2-positive vacuoles, we employed a novel protein discovery tool automated spatially targeted optical micro proteomics (autoSTOMP). This approach identified inducible nitric oxide synthetase (iNOS) enriched at levels similar to the GBPs in infected bone marrow-derived myeloid cells. iNOS expression on myeloid cells was necessary for mice to controlT. gondiigrowth in vivo and survive acute infection.T. gondiiinfection of IFNγ-primed macrophage was sufficient to robustly induce iNOS expression. iNOS restrictedT. gondiiinfection through nitric oxide synthesis rather than arginine depletion, leading to robust and selective nitration of the PV. Optimal parasite restriction by iNOS and vacuole nitration depended on the chromosome 3 GBPs. Notably, GBP2 recruitment and ruffling of the PV membrane occurred in iNOS knockouts, however, these vacuoles contained dividing parasites. iNOS activity was necessary for the collapse of the intravacuolar network of nanotubular membranes which connects parasites to each other and the host cytosol. Based on these data we conclude reactive nitrogen species generated by iNOS cooperate with the chromosome 3 GBPs to target distinct biology of the PV that are necessary for optimal parasite clearance in murine myeloid cells.