bluuebunny/crossref_metadata_2025 huggingface dataset:
Leveraging multiple data types for improved compound-kinase bioactivity prediction
Authors: Theisen Ryan , Wang Tianduanyi , Ravikumar Balaguru , Rahman Rayees , Cichońska Anna
Published: March 2024

Machine learning methods offer time- and cost-effective means for identifying novel chemical matter as well as guiding experimental efforts to map enormous compound-kinase interaction spaces. However, considerable challenges for compound-kinase interaction modeling arise from the heterogeneity of available bioactivity readouts, including single-dose compound profiling results, such as percentage inhibition, and multi-dose-response results, such as IC50. Standard activity prediction approaches utilize only dose-response data in the model training, disregarding a substantial portion of available information contained in single-dose measurements. Here, we propose a novel machine learning methodology for compound-kinase activity prediction that leverages both single-dose and dose-response data. Our two-stage model first learns a mapping between single-dose and dose-response bioactivity readouts, and then generates proxy dose-response activity labels for compounds that have only been tested in single-dose assays. The predictions from the first-stage model are then integrated with experimentally measured dose-response activities to model compound-kinase binding based on chemical structures and kinase features. We demonstrate that our two-stage approach yields accurate activity predictions and significantly improves model performance compared to training solely on dose-response labels, particularly in the most practical and challenging scenarios of predicting activities for new compounds and new compound scaffolds. This superior performance is consistent across five evaluated machine learning methods, including traditional models such as random forest and kernel learning, as well as deep learning-based approaches. Using the best performing model, we carried out extensive experimental profiling on a total of 347 selected compound-kinase pairs, achieving a high hit rate of 40% and a negative predictive value of 78%. We show that these rates can be improved further by incorporating model uncertainty estimates into the compound selection process. By integrating multiple activity data types, we demonstrate that our approach holds promise for facilitating the development of training activity datasets in a more efficient and cost-effective way.
Variation and interaction of distinct subgenomes contribute to growth diversity in intergeneric hybrid fish
Authors: Ren Li , Luo Mengxue , Cui Jialin , Gao Xin , Zhang Hong , Wu Ping , Wei Zehong , Tai Yakui , Li Mengdan , Luo Kaikun , Liu Shaojun
Published: March 2024

Intergeneric hybridization greatly reshapes regulatory interactions among allelic and non-allelic genes. However, their effects on growth diversity remain poorly understood in animals. In this study, we conducted whole-genome sequencing and mRNA-seq analyses in diverse hybrid varieties resulting from the intergeneric hybridization of goldfish (Carassius auratusred var.) and common carp (Cyprinus carpio). These hybrid individuals were characterized by distinct mitochondrial genomes and copy number variations. Through a weighted gene correlation network analysis, we identified 3693 genes as candidate growth-regulated genes. Among them, the expression of 3672 genes in subgenome R (originating from goldfish) displayed negative correlations with growth rate, whereas 20 genes in subgenome C (originating from common carp) exhibited positive correlations. Notably, we observed intriguing patterns in the expression ofslc2a12in subgenome C, showing opposite correlations with body weight that changed with water temperatures, suggesting differential interactions between feeding activity and weight gain in response to seasonal changes for hybrid animals. In 40.31% of alleles, we observed dominanttrans-regulatory effects in the regulatory interaction between distinct alleles from subgenomes R and C. Integrating analyses of allelic-specific expression and DNA methylation data revealed that the influence of DNA methylation on both subgenomes shapes the relative contribution of allelic expression to the growth rate. These findings provide novel insights into the interaction of distinct subgenomes that underlie heterosis in growth traits and contribute to a better understanding of multiple-allele traits in animals.
Hyperinsulinemia counteracts inflammation by suppressing IFNγ and inducing senescence in CD4+T cells of patients with rheumatoid arthritis
Authors: Erlandsson Malin C , Weman Lauri , Malmhäll-Bah Eric , Chandrasekaran Venkataragavan , Tuameh Mahomud , Andersson Karin ME , Silfverswärd Sofia Töyrä , Nilsson Lisa M , Sandström Tatiana Zverkova , Pullerits Rille , Dehlin Mats , Sokka-Isler Tuulikki , Bokarewa Maria I
Published: March 2024

Background

Clinical evidence connects hyperinsulinemia with obesity, and development of type 2 diabetes (T2D). However, its role in autoimmune conditions was questioned. We investigated consequences of hyperinsulinemia for development of T2D and CD4 T cell function in rheumatoid arthritis (RA).

Methods

Incident T2D was prospectively studied in two independent RA cohorts and in gout patients matched to RA by age and gender, for 10 years. Effect of hyperinsulinemia and JAK-STAT signaling inhibition (JAKi) in CD4 T cells was studied by integrating transcriptional sequencing with direct effect of insulin, and JAKi on cell proliferation, DNA enrichment, and cytokine production.

Results

T2D was 3.2-2.5 times less prevalent in RA compared to gout, particularly in females. Hyperinsulinemia predicted the development of T2D, regardless of metabolic parameters and insulin resistance. Additionally, hyperinsulinemia correlated with the senescence-associated high serum levels of IL6, IL8, and VEGF.

Hyperinsulinemia, along with ex-vivo exposure of CD4 cells to insulin, inhibited cell cycle progression and induced DNA enrichment through the suppression of the PI3K-Src kinases and cell cycle promoting genes. It also reduced IFNγ production. JAKi-treated CD4+cells regained insulin sensitivity, which activated glucose metabolism and facilitated senescence. This insulin-dependent mechanism promoted the accumulation of naïve CD4 cells in JAKi-treated patients.

Conclusions

This study shows that insulin has important immunosuppressive ability controlling the adaptive immunity by suppressing IFNγ production and inducing senescence in the effector CD4 T cells. Inhibition of JAK-STAT signaling enhances insulin sensitivity and rejuvenates CD4 cell population in RA patients.
Cardioprotective effects of antiretroviral treatment in adolescents with perinatal HIV infection are heterogeneous depending on age at treatment initiation
Authors: Magodoro Itai M , Guerrero-Chalela Carlos E , Claggett Brian , Jermy Stephen , Samuels Petronella , Myer Landon , Zar Heather , Jao Jennifer , Ntsekhe Mpiko , Siedner Mark J , Ntusi Ntobeko AB
Published: March 2024

The cardioprotective effects of antiretroviral treatment (ART) in adolescents with perinatal HIV infection (APHIV) may depend on age at ART initiation. We used cardiovascular magnetic resonance (CMR) to characterize and compare residual cardiac changes in apparently healthy APHIV with early and delayed ART initiation compared to sex- and age-similar HIV uninfected peers. We defined early and delayed ART as, respectively, treatment initiated at <5 years and ≥5 years of age. Cardiac function, mechanical deformation, geometry and tissue composition were assessed. APHIV had distinct albeit subclinical cardiac phenotypes depending on timing of ART initiation. For example, changes in early ART suggested comparatively worse diastology with preserved systolic function while delayed ART was associated with comparatively increased diffuse fibrosis and LV dilatation with reduced systolic function. The long-term clinical significance of these changes remains to be determined.
Multicenter Randomized Controlled Trial of Exercise in Aortic Dissection Survivors: Rationale, Design, and Initial Hemodynamic Data
Authors: Toy Yasmin A. , House Kayla N. , Boyer Leslie M. , McNamara Jennifer L. , Hofmann-Bowman Marion A. , Eagle Kim A. , Lim Michelle S. , Braverman Alan C. , Prakash Siddharth K.
Published: March 2024

There are currently no evidence-based guidelines for exercise after thoracic aortic dissection (TAD), leading to highly variable recommendations that frequently lead patients to restrict their physical activities. This multicenter randomized controlled trial was intended to evaluate the safety and efficacy of a moderate intensity guided exercise program for TAD survivors. Participants were eligible for the trial if they had a Type A or Type B dissection at least 90 days before enrollment and could attend two in-person study visits. The guided exercise circuit consisted of six aerobic, isotonic, or isometric exercises that participants continued at home with virtual follow up sessions. The primary endpoint is the change in the composite anxiety and depression PROMIS-29 T-score at 12 months. Secondary endpoints include changes in grip strength, weight, 24-hr ambulatory blood pressure, and arterial biomechanical properties measured by central arterial waveform analysis. Preliminary analysis of the first 81 enrolled participants demonstrated that the guided exercise circuit was completed safely and was not associated with severe exertional hypertension, injury, or adverse cardiovascular events. At enrollment, most participants had adverse central waveform or ABPM characteristics that are associated with increased cardiovascular mortality, such as increased arterial stiffness, nocturnal hypertension, elevated pulse pressure, or blunted nocturnal dipping. Follow up of enrolled participants with longitudinal hemodynamic data to evaluate the impact of the exercise program will conclude in October 2024.
A Reassessment of Sodium Correction Rates and Hospital Length of Stay Accounting for Admission Diagnosis
Authors: Gottlieb Eric Raphael , Celi Leo Anthony
Published: March 2024

Background

Slow correction of severe hyponatremia has been historically recommended due to the risk of rare but catastrophic neurologic events with rapid correction. A recent study challenging this paradigm reported that rapid correction is associated with shorter hospital length of stay, but that study did not control for admission diagnosis. The objective of this study was to determine whether rapid correction is associated with shorter length of stay when controlling for admission diagnosis.

Methods

This retrospective cohort study is based on the fourth edition of the Medical Information Mart for Intensive Care, MIMIC-IV, a deidentified, publicly available clinical research database which includes admissions from 2008-2019. Patients were identified who presented to the hospital with initial sodium <120 mEq/L and were categorized according to total sodium correction achieved in the first day (<6 mEq/L; 6-10 mEq/L; >10 mEq/L). Linear regression was used to assess for an association between correction rate and hospital length of stay, and to determine if this association was significant when controlling for admission diagnosis classifications based on diagnosis related groups (DRGs).

Results

There were 419 patients with severe hyponatremia (<120 mEq/L) included in this study, of whom 374 survived to discharge. Median [IQR] hospital length of stay was 6 [4, 11] days. In a univariable linear regression, there was a trend towards a significant association between the highest rate of correction (>10 mEq/L) and shorter length of stay, as compared with a moderate rate of correction (coef. -2.764, 95% CI [-5.791, 0.263], p=0.073), but the association was not significant when controlling for admission diagnosis group (coef. -1.561, 95% CI [-4.398, 1.276], p=0.280). There was a significant association in the survivor subset (coef. -3.455, 95% CI [-6.668, -0.242], p=0.035), but it was also not significant when controlling for admission diagnosis group (coef. -2.200, 95% CI [-5.144, 0.743], p=0.142).

Conclusions

Rapid correction is not associated with shorter length of stay when controlling for admission diagnosis, suggesting that the disease state confounds this association. Findings from prior and future studies reporting this association should not drive clinical decision making if the confounding effect of hospital admission diagnosis and competing risk of death are not fully accounted for.
Automated Detection of Keratorefractive Laser Surgeries on Optical Coherence Tomography using Deep Learning
Authors: Assaf Jad F. , Yazbeck Hady , Reinstein Dan Z. , Archer Timothy , Assaf Roland , de Ortueta Diego , Arbelaez Juan , Arbelaez Maria Clara , Awwad Shady T.
Published: March 2024

PURPOSE

To report a deep learning neural network on anterior segment optical coherence tomography (AS-OCT) for automated detection of different keratorefractive laser surgeries— including Laser In-Situ Keratomileusis with femtosecond microkeratome (Femto-LASIK), LASIK with mechanical microkeratome, photorefractive keratectomy (PRK), keratorefractive lenticule extraction (KLEx), and non-operated eyes—while also distinguishing the targeted ametropias, such as myopic and hyperopic treatments, within these procedures.

DESIGN

Cross-sectional retrospective study.

METHODS

A total of 14,948 eye scans from 2,278 eyes of 1,166 subjects were used to develop a deep learning neural network algorithm with an 80/10/10 patient distribution for training, validation, and testing phases, respectively. The algorithm was evaluated for its accuracy, F1-scores, area under precision-recall curve (AUPRC), and area under receiver operating characteristic curve (AUROC).

RESULTS

On the test dataset, the neural network was able to detect the different surgical classes with an accuracy of 96%, a weighted-average F1-score of 96% and a macro-average F1-score of 96%. The neural network was further able to detect hyperopic and myopic subclasses within each surgical class, with an accuracy of 90%, weighted-average F1 score of 90%, and macro-average F1-score of 83%.

CONCLUSIONS

Determining a patient’s keratorefractive laser history is vital for customizing treatments, performing precise intraocular lens (IOL) calculations, and enhancing ectasia risk assessments, especially when electronic health records are incomplete or unavailable. Neural networks can be used to accurately classify keratorefractive laser history from AS-OCT scans, a step in transforming the AS-OCT from a diagnostic to a screening tool in the refractive clinic.
Dynamics of T cell responses to COVID-19 vaccines and breakthrough infection in people living with HIV receiving antiretroviral therapy
Authors: Datwani Sneha , Kalikawe Rebecca , Waterworth Rachel , Mwimanzi Francis M. , Liang Richard , Sang Yurou , Lapointe Hope R. , Cheung Peter K. , Omondi F. Harrison , Duncan Maggie C. , Barad Evan , Speckmaier Sarah , Moran-Garcia Nadia , DeMarco Mari L. , Hedgcock Malcolm , Costiniuk Cecilia T. , Hull Mark , Harris Marianne , Romney Marc G. , Montaner Julio S.G. , Brumme Zabrina L. , Brockman Mark A.
Published: March 2024

Introduction

People living with HIV (PLWH) can exhibit impaired immune responses to vaccines. Accumulating evidence indicates that PLWH, particularly those receiving antiretroviral therapy, mount strong antibody responses to COVID-19 vaccination, but fewer studies have examined cellular immune responses to vaccination. We measured SARS-CoV-2 spike-specific CD4+ and CD8+ T cell responses generated by two and three doses of COVID-19 vaccine in PLWH receiving antiretroviral therapy, compared to control participants without HIV. We also quantified T cell responses after post-vaccine breakthrough infection, and receipt of fourth vaccine doses, in a subset of PLWH.

Methods

We quantified CD4+ and CD8+ T cells reactive to overlapping peptides spanning the ancestral SARS-CoV-2 spike protein in 50 PLWH and 87 controls without HIV, using an activation induced marker (AIM) assay. All participants remained SARS-CoV-2 naïve until at least one month after their third vaccine dose. SARS-CoV-2 infection was determined by seroconversion to nucleocapsid (N) antigen, which occurred in 21 PLWH and 38 controls post-third dose. Multivariable regression analyses were used to investigate relationships between sociodemographic, health and vaccine-related variables and vaccine-induced T cell responses, as well as breakthrough infection risk.

Results

A third vaccine dose boosted spike-specific CD4+ and CD8+ T cell frequencies significantly above those measured after the second dose (all p<0.0001). Median T cell frequencies did not differ between PLWH and controls after the second dose (p>0.1), but CD8+ T cell responses were modestly lower in PLWH after the third dose (p=0.02), an observation that remained significant after adjustment for sociodemographic, health and vaccine-related variables (p=0.045). In PLWH who experienced breakthrough infection, median T cell frequencies increased even higher than those observed after three vaccine doses (p<0.03), and CD8+ T cell responses in this group remained higher even after a fourth vaccine dose (p=0.03). In multivariable analysis, the only factor associated with increased breakthrough infection risk was younger age, consistent with the rapid increases in SARS-CoV-2 seropositivity among younger adults in Canada after the initial appearance of the Omicron variant.

Conclusion

PLWH receiving antiretroviral therapy mount strong T cell responses to COVID-19 vaccines that can be enhanced by booster doses or breakthrough infection.
Unveiling the Microbial Realm with VEBA 2.0: A modular bioinformatics suite for end-to-end genome-resolved prokaryotic, (micro)eukaryotic, and viral multi-omics from either short- or long-read sequencing
Authors: Espinoza Josh L. , Phillips Allan , Prentice Melanie B. , Tan Gene S. , Kamath Pauline L. , Lloyd Karen G. , Dupont Chris L.
Published: March 2024

The microbiome is a complex community of microorganisms, encompassing prokaryotic (bacterial and archaeal), eukaryotic, and viral entities. This microbial ensemble plays a pivotal role in influencing the health and productivity of diverse ecosystems while shaping the web of life. However, many software suites developed to study microbiomes analyze only the prokaryotic community and provide limited to no support for viruses and microeukaryotes. Previously, we introduced the Viral Eukaryotic Bacterial Archaeal (VEBA) open-source software suite to address this critical gap in microbiome research by extending genome-resolved analysis beyond prokaryotes to encompass the understudied realms of eukaryotes and viruses. Here we present VEBA 2.0 with key updates including a comprehensive clustered microeukaryotic protein database, rapid genome/protein-level clustering, bioprospecting, non-coding/organelle gene modeling, genome-resolved taxonomic/pathway profiling, long-read support, and containerization. We demonstrate VEBA's versatile application through the analysis of diverse case studies including marine water, Siberian permafrost, and white-tailed deer lung tissues with the latter showcasing how to identify integrated viruses. VEBA represents a crucial advancement in microbiome research, offering a powerful and accessible platform that bridges the gap between genomics and biotechnological solutions.
Strain heterogeneity in a non-pathogenic fungus highlights factors contributing to virulence
Authors: Rinker David C. , Sauters Thomas J. C. , Steffen Karin , Gumilang Adiyantara , Raja Huzefa A. , Rangel-Grimaldo Manuel , Pinzan Camila Figueiredo , de Castro Patrícia Alves , dos Reis Thaila Fernanda , Delbaje Endrews , Houbraken Jos , Goldman Gustavo H. , Oberlies Nicholas H. , Rokas Antonis
Published: March 2024

Fungal pathogens exhibit extensive strain heterogeneity, including variation in virulence. Whether closely related non-pathogenic species also exhibit strain heterogeneity remains unknown. Here, we comprehensively characterized the pathogenic potentials (i.e., the ability to cause morbidity and mortality) of 16 diverse strains ofAspergillus fischeri, a non-pathogenic close relative of the major pathogenAspergillus fumigatus.In vitroimmune response assays andin vivovirulence assays using a mouse model of pulmonary aspergillosis showed thatA. fischeristrains varied widely in their pathogenic potential. Furthermore, pangenome analyses suggest thatA. fischerigenomic and phenotypic diversity is even greater. Genomic, transcriptomic, and metabolomic profiling identified several pathways and secondary metabolites associated with variation in virulence. Notably, strain virulence was associated with the simultaneous presence of the secondary metabolites hexadehydroastechrome and gliotoxin. We submit that examining the pathogenic potentials of non-pathogenic close relatives is key for understanding the origins of fungal pathogenicity.
A reference database of reptile images
Authors: Uetz Peter , Patel Maya , Gbadamosi Zainab , Nguyen Jeremy , Shoope Stacey
Published: March 2024

While there are millions of reptile images available online, they are not well organized and not easily findable, accessible, interoperable, or reproducible (FAIR). More importantly, they are not standardized and thus hardly comparable. Here we present a reference database of more than 14,000 standardized images of 1,045 reptile species (969 lizard and 76 snake species), that are based on preserved specimens in 20 different collections, including 533 type species of genera and type specimens of 72 species. All images were taken with standardized views, including dorsal and ventral body shots as well as dorsal, ventral, and lateral views of the heads and other body parts. Although only 11 out of the 20 collections are cross-referenced in Vertnet, some others are indexed in GBIF, and this fraction will certainly grow in the near future. The utility of this and similar image collections will further grow with additional material and further cross-referencing, e.g., to DNA sequence databases or citizen science projects. The images are searchable and freely available onMorphobank.org(Project 5121) and on Figshare.com.
Hypsochromic shift of phyC complements the inhibition of hypocotyl elongation under moderate red/far-red light
Authors: Yoshihara Shizue , Okajima Koji , Tokutomi Satoru
Published: March 2024

Phytochrome (phy) is a plant photoreceptor that regulates various photomorphogenesis, and occurs in two forms, a red light (R)-absorbing form (Pr) and a far-red light (FR)-absorbing form (Pfr). Absorption spectral analyses of the photosensory module (PSM) showed that phyC in the Pr ofArabidopsis thaliana,Solanum lycopersicumandZea maysexhibited the absorption maxima shift toward shorter wavelengths (hypsochromic shift) compared with those of phyA and phyB. Substitution of the chromophore-binding domain complemented the hypsochromic shift in the spectra of phyC in the Pr. The effect of the hypsochromic shift on the inhibition of hypocotyl elongation was studied under R/FR ratio from 0.5-10. PhyB was revealed to play a major role in inhibition, and phyC showed a complementary role under R/FR <2.0. This may result from the activation peak of the phyC PSM, which was hypsochromically shifted compared with that of the phyB PSM from the Pr to Pfr. The leaf-filtered light measurement suggested that phyC enables plants to receive more R and contributes to survival in the field. Under low R/FR conditions, the activation efficiency of phyC was greater than that of phyB, suggesting that the hypsochromic shift of phyC is necessary for the robust growth of angiosperms.

Highlight

Angiosperm phyC with hypsochromically shifted activation inhibit hypocotyl elongation under relatively low red/far-red light conditions, in which phyB is not fully functional.
AllTheBacteria - all bacterial genomes assembled, available and searchable
Authors: Hunt Martin , Lima Leandro , Anderson Daniel , Hawkey Jane , Shen Wei , Lees John , Iqbal Zamin
Published: March 2024

The bacterial sequence data publicly available at the global DNA archives is a vast source of information on the evolution of bacteria and their mobile elements. However, most of it is either unassembled or inconsistently assembled and QC-ed. This makes it unsuitable for large-scale analyses, and inaccessible for most researchers to use. In 2021 Blackwell et al therefore released a uniformly assembled set of 661,405 genomes, consisting of all publicly available whole genome sequenced bacterial isolate data as of November 2018, along with various search indexes. In this study we extend that dataset up to August 2024, more than tripling the number of genomes. We also expand the scope, as we begin a global collaborative project to generate annotations for different species as desired by different research communities.

In this study we describe the project as of release 2024-08, comprising 2,440,377 assemblies (including the 661k dataset). All 2.4 million have been uniformly reprocessed for quality criteria and to give taxonomic abundance estimates with respect to the GTDB phylogeny. We also provide antimicrobial resistance (AMR) gene and mutation annotation via AMRFinderPlus. Using an evolution-informed compression approach, the full set of genomes is just 130Gb in batched xz archives. We also provide multiple search indexes and a method for alignment to the full dataset. Finally, we outline plans for future annotations to be provided in further releases.
Risk assessment predicts most of the salmonellosis risk in raw chicken parts is concentrated in those few products with high-levels of high-virulent serotypes ofSalmonella
Authors: Kim Minho , Barnett-Neefs Cecil , Chavez Ruben A. , Kealey Erin , Wiedmann Martin , Stasiewicz Matthew J.
Published: March 2024

Salmonellaprevalence has reduced in U.S. raw poultry products since adopting prevalence-basedSalmonellaperformance standards, but human illnesses did not reduce proportionally. We used Quantitative Microbial Risk Assessment to evaluate public health risks of raw chicken parts contaminated with different levels of allSalmonellaand specific high- and low-virulent serotypes. LognormalSalmonellalevel distributions were fitted using data from 2012 USDA-FSIS Baseline Survey and 2023 USDA-FSIS HACCP verification sampling data. Three different dose-response (DR) models were used: Single DR for all serotypes, reduced virulence for Kentucky, multiple serotype- specific DR models. All scenarios found risk concentrated in the few products with highSalmonellalevels. Using a single DR model with Baseline data (μ=-3.19, σ=1.29), 68% and 37% of illnesses were attributed to the 0.7% and 0.06% of products > 1 and 10 CFU/gSalmonella, respectively. More recent HACCP data (μ=-4.85, σ=2.44) showed that 99.9% and 99.6% of illnesses were attributed to the 2.3% and 0.8% of products > 1 and 10 CFU/gSalmonella, respectively. Scenarios with serotype-specific DR models showed more concentrated risk at higher levels. Baseline data showed 91.5% and 63.7% and HACCP data showed >99.9% and 99.9% of illnesses were attributed to products > 1 and 10 CFU/gSalmonella, respectively. Regarding serotypes, 0.003% and 0.3% of illnesses were attributed to the 0.2% and 0.7% of products with > 1 CFU/g of Kentucky, respectively, while 69% and 78.7% of illnesses were attributed to the 0.3% and 1.2% of products > 1 CFU/g containing either Enteritidis, Infantis, or Typhimurium using Baseline or HACCP input data, respectively. These results suggest public health risk in chicken parts is concentrated in the few finished products with high-levels and specifically high- levels of high-virulent serotypes. Low-virulent serotypes, such as Kentucky, are predicted to contribute to extremely few human cases.
Cell type-specific dynamics of prefrontal gamma synchrony during flexible behavior
Authors: Phensy Aarron J. , Hagopian Lara L. , Sohal Vikaas S.
Published: March 2024

The prefrontal cortex (PFC) is required for many cognitive processes that are disrupted in conditions such as schizophrenia. The PFC is composed of neuronal networks which are organized by both local microcircuitry and inter-regional projections, within which precisely tuned neuronal activity generates appropriate cognitive responses. Parvalbumin-positive interneurons (PVI) play an integral role by synchronizing select networks to oscillations in the gamma frequency range (∼30-100 Hz). Synchronized gamma oscillations seem to facilitate information transfer between neurons and across regions. In particular, our lab has previously shown that PVI-generated gamma oscillations in the left and right prefrontal cortices become synchronized during cognitive tasks and this synchronization is necessary for animals to learn rule shifts. Here, we examine how this synchrony propagates through prefrontal circuits using novel genetically encoded voltage indicators (GEVIs) to examine gamma oscillations in specific populations of deep layer projection neurons targeting either the mediodorsal thalamus (PFC-MD) or dorsal striatum (PFC-DS). We first designed a novel analysis which found that PVI exhibit inter-hemispheric gamma synchrony immediately (within seconds) following trial outcomes, during a specific subset of trials associated with the adoption of a new behavioral strategy. PFC-MD neurons did not exhibit gamma synchrony during these outcome periods, but did synchronize during the pre-decision period of the next trial. Furthermore, pre-decision gamma synchrony in PFC-MD neurons was dependent on PVI and did not occur in PFC-DS neurons. Together, our findings suggest that gamma synchrony is transmitted from PVI to PFC-MD neurons during rule shifts in a task-phase and cell type-specific manner to facilitate the updating of behavioral strategies.
Precision-based causal inference modulates audiovisual temporal recalibration
Authors: Li Luhe , Hong Fangfang , Badde Stephanie , Landy Michael S.
Published: March 2024

Cross-modal temporal recalibration guarantees stable temporal perception across ever-changing environments. Yet, the mechanisms of cross-modal temporal recalibration remain unknown. Here, we conducted an experiment to measure how participants’ temporal perception was affected by exposure to audiovisual stimuli with consistent temporal delays. Consistent with previous findings, recalibration effects plateaued with increasing audiovisual asynchrony and varied by which modality led during the exposure phase. We compared six observer models that differed in how they update the audiovisual temporal bias during the exposure phase and whether they assume modality-specific or modality-independent precision of arrival latency. The causal-inference observer shifts the audiovisual temporal bias to compensate for perceived asynchrony, which is inferred by considering two causal scenarios: when the audiovisual stimuli have a common cause or separate causes. The asynchrony-contingent observer updates the bias to achieve simultaneity of auditory and visual measurements, modulating the update rate by the likelihood of the audiovisual stimuli originating from a simultaneous event. In the asynchrony-correction model, the observer first assesses whether the sensory measurement is asynchronous; if so, she adjusts the bias proportionally to the magnitude of the measured asynchrony. Each model was paired with either modality-specific or modality-independent precision of arrival latency. A Bayesian model comparison revealed that both the causal-inference process and modality-specific precision in arrival latency are required to capture the nonlinearity and asymmetry observed in audiovisual temporal recalibration. Our findings support the hypothesis that audiovisual temporal recalibration relies on the same causal-inference processes that govern cross-modal perception.
Altered circadian rhythm, sleep, andrhodopsin 7-dependent shade preference during diapause inDrosophila melanogaster
Authors: Meyerhof Geoff T. , Easwaran Sreesankar , Bontempo Angela E. , Montell Craig , Montell Denise J.
Published: March 2024

To survive adverse environments, many animals enter a dormant state such as hibernation, dauer, or diapause. VariousDrosophilaspecies undergo adult reproductive diapause in response to cool temperatures and/or short day-length. While it is known that flies are less active during diapause, an in-depth understanding of diapause effects on circadian rhythms and sleep is lacking. Here we show that, in diapause-inducing conditions,Drosophila melanogasterexhibit altered circadian activity profiles, including a severely reduced morning activity peak and an advanced evening activity peak. Consequently, the flies have a single activity peak at a time similar to when non-diapausing flies have a siesta. Temperatures ≤15 °C, rather than short day-length, primarily drive the behavior. At cool temperatures, flies also rapidly enter a deep sleep state that lacks the sleep cycles of flies at higher temperatures and requires particularly high levels of stimulation for arousal. Furthermore, we show that at 18–25 °C, flies prefer to siesta in the shade, a preference that is virtually eliminated at 10 °C. Resting in the shade is driven by an aversion to blue light, sensed by rhodopsin 7 (Rh7) outside of the eyes. Flies at 10 °C show neuronal markers of elevated sleep pressure, including increased expression of Bruchpilot and elevated Ca2+in the R5 ellipsoid body neurons. Therefore sleep pressure might overcome blue light aversion. Thus at temperatures known to cause reproductive arrest, preserve germline stem cells, and extend lifespan,Drosophila melanogasterare prone to deep sleep and exhibit dramatically altered – yet rhythmic – daily activity patterns.

Significance statement

Climate change is impacting many animals, including insects. In diverse organisms, adverse environments trigger dormancy programs such as hibernation and diapause. Fruit flies undergo diapause to survive winter. Here we develop new methods and show that the same cool temperatures that delay fruit fly reproduction and extend lifespan, also promote deep sleep. Cool flies rapidly fall asleep and are difficult to arouse. Once awake, they immediately fall back to sleep. Whereas in warm environments, midday blue light drives flies to siesta in the shade, in cool temperatures the need to sleep overwhelms light-aversion, reducing shade preference. Animals that adjust their behavior directly to temperature, rather than day length, may be more resilient to a changing climate.
Improved functions for non-linear sequence comparison using SEEKR
Authors: Li Shuang , Eberhard Quinn , Ni Luke , Calabrese J. Mauro
Published: March 2024

SEquence Evaluation throughk-mer Representation (SEEKR) is a method of sequence comparison that utilizes sequence substrings calledk-mers to quantify non-linear similarity between nucleic acid species. We describe the development of new functions within SEEKR that enable end-users to estimate p-values that ascribe statistical significance to SEEKR-derived similarities as well as visualize different aspects ofk-mer similarity. We apply the new functions to identify chromatin-enriched long noncoding RNAs (lncRNAs) that harborXIST-like sequence fragments and show that several of these fragments are bound byXIST-associated proteins. We also highlight the best practice of using RNA-Seq data to evaluate support for lncRNA annotations prior to their in-depth study in cell types of interest.
High-throughput Screening of Compounds against Autoluminescent NonreplicatingMycobacterium tuberculosisunder Diverse Conditions
Authors: Tian Xirong , Ma Wanli , Yusuf Buhari , Li Chunyu , Hameed H.M. Adnan , Wang Xinyue , Zhong Nanshan , Hu Jinxing , Zhang Tianyu
Published: March 2024

The screening of new anti-mycobacterial chemicals is primarily focused on inhibiting the active growing bacteria. However, a major challenge in tuberculosis control is the ability ofMycobacterium tuberculosisto enter a nonreplicating state for extended periods, rendering it resistant to many clinical drugs and complicating eradication efforts. Existing low-oxygen-recovery assays designed for screening compounds targeting nonreplicatingM. tuberculosishave limitations, including the colony-forming unit counting for non-luminousM. tuberculosisand the instability of the free plasmid carryingluxABgenes in luminescentM. tuberculosis, along with exogenous substrate requirements for light producing. Moreover, these assays fail to accurately replicate the growth conditions of nonreplicatingM. tuberculosis in vitro, thus resulting in less convincing results. To address these challenges, we have developed an autoluminescence-based, cholesterol-enriched culture evaluation model to assess 17 anti-tuberculosis drugs of different classes against nonreplicatingM. tuberculosis. Our findings indicate that the relative light unit, measured in real-time, serves as a reliable surrogate marker for colony-forming unit, which typically becomes available one month later. This suggests the utility of our model for the rapid determination of drug susceptibility dynamically. The autoluminescentM. tuberculosis, harbouringluxCDABEgene cluster within its genome, can emit blue-green light stably and autonomously without requiring an external substrate supplement. The minimal inhibitory concentrations of all the drugs tested under anaerobic conditions are significantly different from that detected in aerobic environment. Our model allows for rapid, precise, and efficient assessment of drug activity under anaerobic conditions, thereby enabling a more comprehensive evaluation of anti-mycobacterial efficacy. Overall, our model represents a significant advancement in anti-tuberculosis drug discovery and pharmaceutical development.
Extremely acidic proteomes and metabolic flexibility in bacteria and highly diversified archaea thriving in geothermal chaotropic brines
Authors: Gutierrez-Preciado Ana , Dede Bledina , Baker Brittany , Eme Laura , Moreira David , Lopez-Garcia Purificacion
Published: March 2024

Few described archaeal, and fewer bacterial, lineages thrive at salt-saturating conditions, such as solar saltern crystallizers (salinity above 30%-w/v). They accumulate molar K+ cytoplasmic concentrations to maintain osmotic balance ("salt-in" strategy), and have proteins adaptively enriched in negatively charged, acidic amino acids. Here, we analyzed metagenomes and metagenome-assembled genomes (MAGs) from geothermally influenced hypersaline ecosystems with increasing chaotropicity in the Danakil Depression. Normalized abundances of universal single-copy genes confirmed that haloarchaea and Nanohaloarchaeota encompass 99% of microbial communities in the near life-limiting conditions of the Western-Canyon Lakes (WCLs). Danakil metagenome- and MAG-inferred proteomes, compared to those of freshwater, seawater and solar saltern ponds up to saturation (6-14-32% salinity), showed that WCL archaea encode the most acidic proteomes ever observed (median protein isoelectric points ≤4.4). We identified previously undescribed Halobacteria families as well as an Aenigmatarchaeota family and a bacterial phylum independently adapted to extreme halophily. Despite phylum-level diversity decreasing with increasing salinity-chaotropicity, and unlike in solar salterns, adapted archaea exceedingly diversified in Danakil ecosystems, challenging the notion of decreasing diversity under extreme conditions. Metabolic flexibility to utilize multiple energy and carbon resources generated by local hydrothermalism along feast-and-famine strategies seemingly shape microbial diversity in these ecosystems near life limits.
The functional anatomy of nociception: effective connectivity in chronic pain and placebo responders
Authors: Nara Sanjeev , Baliki Marwan N. , Friston Karl J. , Ray Dipanjan
Published: March 2024

There is growing recognition of cortical involvement in nociception. The present study is motivated by predictive coding formulations of pain perception that stress the importance of top-down and bottom-up information flow in the brain. It compares forward and backward effective connectivity - estimated from resting-state fMRI - between chronic osteoarthritic patients and healthy control subjects. Additionally, it assesses differences in effective connectivity between placebo responders and non-responders and asks whether these differences can be used to predict pain perception and placebo response. To assess hierarchical processing in nociception, we defined two primary cortical regions: primary somatosensory cortex (SSC) and posterior insula (PI) (primary interoceptive cortex) and lateral frontal pole (FP1), a terminal relay station of the pain processing pathways. The directed (effective) connectivity within and between these regions were estimated using spectral dynamic causal modeling (DCM). 56 osteoarthritis patients and 18 healthy controls were included in the analysis. Within the patient group, effective connectivity was compared between placebo responders and non-responders.

In osteoarthritic patients, contra control group, forward connectivity from SSC to FP1 and from PI to FP1 was enhanced in the left hemisphere. Backward connections from FP1 to SSC were more inhibitory. Intrinsic (i.e., inhibitory recurrent or self-connectivity) of left FP1 increased. In placebo responders compared to non-responders, forward connections from bilateral SSC to PI, left SSC to FP1, left PI to left FP1 were more inhibitory. In addition, self-connections of bilateral PI and top-down connections from right FP1 to right SSC were disinhibited; whereas self-connections of right FP1 became increasingly inhibitory. We confirmed the robustness of these results in a leave-one-out cross-validation analysis of (out-of-sample) effect sizes. Overall, effective extrinsic and intrinsic effective connectivity among higher and lower cortical regions involved in pain processing emerges as a promising and quantifiable candidate marker of nociception and placebo response. The significance of these findings for clinical practice and neuroscience are discussed in relation to predictive processing accounts of placebo effects and chronic pain.
Pf bacteriophages hinder sputum antibiotic diffusion via electrostatic binding
Authors: Chen Qingquan , Cai Pam , Chang Tony Hong Wei , Burgener Elizabeth , Kratochvil Michael J. , Gupta Aditi , Hargil Aviv , Secor Patrick R. , Nielsen Josefine Eilsø , Barron Annelise E. , Milla Carlos , Heilshorn Sarah C. , Spakowitz Andy , Bollyky Paul L.
Published: March 2024

Despite great progress in the field, chronicPseudomonas aeruginosa(Pa) infections remain a major cause of morbidity and mortality in patients with cystic fibrosis, necessitating treatment with inhaled antibiotics. Pf phage is a filamentous bacteriophage produced byPathat has been reported to act as a structural element inPabiofilms. Pf presence has been associated with resistance to antibiotics and poor outcomes in cystic fibrosis, though the underlying mechanisms are unclear. Here, we have investigated how Pf phages and sputum biopolymers impede antibiotic diffusion using human sputum samples and fluorescent recovery after photobleaching. We demonstrate that tobramycin interacts with Pf phages and sputum polymers through electrostatic interactions. We also developed a set of mathematical models to analyze the complex observations. Our analysis suggests that Pf phages in sputum reduce the diffusion of charged antibiotics due to a greater binding constant associated with organized liquid crystalline structures formed between Pf phages and sputum polymers. This study provides insights into antibiotic tolerance mechanisms in chronicPainfections and may offer potential strategies for novel therapeutic approaches.

Teaser

Pf phages and sputum polymers reduce antibiotic diffusion via electrostatic interactions and liquid crystal formation.
Reconfigurable multi-component nanostructures built from DNA origami voxels
Authors: Luu Minh Tri , Berengut Jonathan F. , Daljit Singh Jasleen Kaur , Coffi Dit Glieze Kanako , Turner Matthew , Skipper Karuna , Meppat Sreelakshmi , Fowler Hannah , Close William , Doye Jonathan P.K. , Abbas Ali , Wickham Shelley F.J.
Published: March 2024

In cells, proteins rapidly self-assemble into sophisticated nanomachines. Bio-inspired self-assembly approaches, such as DNA origami, have achieved complex 3D nanostructures and devices. However, current synthetic systems are limited by lack of structural diversity, low yields in hierarchical assembly, and challenges in reconfiguration. Here, we develop a modular system of DNA origami ‘voxels’ with programmable 3D connections. We demonstrate multifunctional pools of up to 12 unique voxels that can assemble into many shapes, prototyping 50 structures. Multi-step assembly pathways with sequential reduction in conformational freedom were then explored to increase yield. Voxels were first assembled into flexible chains and then folded into rigid structures, increasing yield 100-fold. Furthermore, programmable switching of local connections between flexible and rigid states achieved rapid and reversible reconfiguration of global structures. We envision that foldable chains of DNA origami voxels can be integrated with scalable assembly methods to achieve new levels of complexity in reconfigurable nanomaterials.
Silica seed particles improve the efficiency and throughput of nanoparticle acoustic trapping
Authors: Havers Megan , Baasch Thierry , Lenshof Andreas , Evander Mikael , Laurell Thomas
Published: March 2024

Silica has rarely been used as a seed particle material in acoustic trapping of nanoparticles. Here we use fluorescent nanoparticles, which are frequently used as a model system, to demonstrate that throughput and nanoparticle trapping efficiency can be improved by using silica seed particles as opposed to traditionally used polystyrene seed particles. The 10 times larger dipole scattering coefficient of silica seed particles compared with polystyrene seed particles in water leads to a higher retention force against fluid flow and thus enables higher throughput. Seed particles retained at an actuation voltage of approximately 10 V p.p. can withstand flow rates up to 2100 ± 200 µl/min for silica and 200 ± 50 µl/min for polystyrene. Furthermore, silica is found to be 40%–2000% more efficient (number of trapped nanoparticles as measured by fluorescent intensity) than polystyrene seed particles in trapping 270-nm polystyrene nanoparticles from suspensions of 1010–1011 particles/ml. Moreover, after enriching nanoparticles into a silica seed particle cluster, the washing flow rate can be increased from 30 µl/min to 200 µl/min (the flow rate at which polystyrene clusters are unstable), halving the total sample processing time without losing the silica seed particle cluster or compromising the nanoparticle trapping efficiency. Thus, material properties (particularly density) of the seed particles are critical to both nanoparticle trapping efficiency and throughput.

Published by the American Physical Society
2024
Incommensurate charge density wave order in
U2Ti
Authors: Stevens Callum R. , Hermann Andreas , Huxley Andrew , Wermeille Didier
Published: March 2024

Density functional theory predicted that the ground state of U2Ti should undergo a Peierls-like doubling of its unit cell along the c axis on cooling from high temperature [G. Kaur , ]. We report x-ray diffraction, heat capacity, and resistivity measurements showing that with decreasing temperature the transition from the parent hexagonal structure occurs in two steps, via an incommensurate state below TICDW=71(1) K which then undergoes a lock-in transition to the predicted commensurate Peierls-like state at TCCDW=46(3) K. The signatures of the upper transition in thermodynamic and transport measurements are weak, meaning that similar incommensurate charge density waves (ICDWs) preceding CDWs might occur more widely in other systems but elude detection. The collinear nature of both the ICDW and Peierls-like states we report is much simpler than more complex incommensurate states seen in α−U, which may in time provide greater insight into the mechanism for ICDW formation.

Published by the American Physical Society
2024