Miracle-dz/UniFAR-FTUs huggingface dataset:
Ecological and evolutionary consequences of viral plasticity

Viruses can infect any organism. Because viruses use the host machinery to replicate, their performance depends on the host physiological state. For bacteriophages, this host-viral performance link has been characterized empirically and with intracellular theories. Such theories are too detailed to be included in models that study host-phage interactions in the long term, which hinders our understanding of systems that range from pathogens infecting gut bacteria to marine phage shaping present and future oceans. Here, we combined data and models to study the short- and long-term consequences that host physiology has on bacteriophage performance. We compiled data showing the dependence of lytic-phage traits on host growth rate (viral phenotypic “plasticity”) to deduce simple expressions representing such plasticity. We included these expressions in a standard host-phage model, to understand how viral plasticity can break the expected evolutionary trade-off between infection time and viral offspring number. Furthermore, viral plasticity influences dramatically dynamic scenarios (e.g. sudden nutrient pulses or host starvation). We show that the effect of plasticity on offspring number, not generation time, drives the phage ecological and evolutionary dynamics. Standard models do not account for this plasticity, which handicaps their predictability in realistic environments. Our results highlight the importance of viral plasticity to unravel host-phage interactions, and the need of laboratory and field experiments to characterize viral plastic responses across systems.
Temporal Binding and Segmentation in Visual Search: A Computational Neuroscience Analysis

Human visual search operates not only over space but also over time, as old items remain in the visual field and new items appear. Preview search (where one set of distractors appears before the onset of a second set) has been used as a paradigm to study search over time and space [Watson, D. G. , & Humphreys, G. W. Visual marking: Prioritizing selection for new objects by top–down attentional inhibition of old objects. Psychological Review, 104, 90–122, 1997], with participants showing efficient search when old distractors can be ignored and new targets prioritized. The benefits of preview search are lost, however, if a temporal gap is introduced between a first presentation of the old items and the re-presentation of all the items in the search display [Kunar, M. A. , Humphreys, G. W. , & Smith, K. J. History matters: The preview benefit in search is not onset capture. Psychological Science, 14, 181–185, 2003a], consistent with the old items being bound by temporal onset to the new stimuli. This effect of temporal binding can be eliminated if the old items reappear briefly before the new items, indicating also a role for the memory of the old items. Here we simulate these effects of temporal coding in search using the spiking search over time and space model [Mavritsaki, E. , Heinke, D. , Allen, H. , Deco, G. , & Humphreys, G. W. Bridging the gap between physiology and behavior: Evidence from the sSoTS model of human visual attention. Psychological Review, 118, 3–41, 2011]. We show that a form of temporal binding by new onsets has to be introduced to the model to simulate the effects of a temporal gap, but that effects of the memory of the old item can stem from continued neural suppression across a temporal gap. We also show that the model can capture the effects of brain lesion on preview search under the different temporal conditions. The study provides a proof-of-principle analysis that neural suppression and temporal binding can be sufficient to account for human search over time and space.
Targeted DNA Methylation Profiling of Human Cardiac Tissue Reveals Novel Epigenetic Traits and Gene Deregulation Across Different Heart Failure Patient Subtypes

Background: Limited knowledge exists of the extent of epigenetic alterations, such as DNA methylation, in heart failure (HF). We conducted targeted DNA methylation sequencing to identify DNA methylation alterations in coding and noncoding RNA (ncRNA) across different etiological subtypes of HF. Methods and Results: A targeted bisulfite sequence capture sequencing platform was applied to DNA extracted from cardiac interventricular septal tissue of 30 male HF patients encompassing causes including hypertrophic obstructive cardiomyopathy, ischemic cardiomyopathy, dilated cardiomyopathy, and 9 control patients with nonfailing hearts. We detected 62 678 differentially methylated regions in the studied HF cohort. By comparing each HF subgroup to the nonfailing control group, we identified 195 unique differentially methylated regions: 5 in hypertrophic obstructive cardiomyopathy, 151 in dilated cardiomyopathy, and 55 in ischemic cardiomyopathy. These translated to 4 genes/1 ncRNA in hypertrophic obstructive cardiomyopathy, 131 genes/17 ncRNA in dilated cardiomyopathy, and 51 genes/5 ncRNA in ischemic cardiomyopathy. Subsequent gene/ncRNA expression analysis was assessed using quantitative reverse transcription polymerase chain reaction and revealed 6 genes: 4 hypermethylated (HEY2, MSR1, MYOM3, and COX17), 2 hypomethylated (CTGF and MMP2); and 2 microRNA: 1 hypermethylated (miR-24-1), 1 hypomethylated (miR-155) with significantly upregulated or downregulated expression levels consistent with the direction of methylation in the particular HF subgroup. Conclusions: For the first time DNA methylation alterations and associated gene expression changes were identified in etiologically variant pathological HF tissue. The methylation-sensitive and disease-associated genes/ncRNA identified from this study represent a unique cohort of loci that demonstrate a plausible potential as a novel diagnostic and therapeutic target in HF and warrant further investigation.
Application of an Iterative Fragment Selection (IFS) Method to Estimate Entropies of Fusion and Melting Points of Organic Chemicals

The main objective of this study is to develop and evaluate novel Quantitative Structure‐Property Relationships (QSPRs) for predicting entropy of fusion (ΔSM) and melting point (TM) of organic chemicals from chemical structure. The QSPRs are developed using the Iterative Fragment Selection (IFS) method that requires only 2D structural information from the user (SMILES codes) for property prediction. The QSPRs also provide information on the applicability domain for each calculation and uncertainty estimates for the predictions. The root mean square error (RMSE) for the external validation sets are 11.8 J mol−1 K−1 and 46.9 K for the ΔSM and TM QSPRs, respectively. The performance of the new QSPRs is comparable to other predictive methods but has advantages with respect to availability and ease of use as well as the guidance on applicability domain for each prediction. Limitations of the new QSPRs are discussed. The QSPRs are coded as a user‐friendly, freely available tool.
Multiomics analysis reveals a distinct mechanism of oleaginousness in the emerging model alga Chromochloris zofingiensis.

Chromochloris zofingiensis, featured due to its capability to simultaneously synthesize triacylglycerol (TAG) and astaxanthin, is emerging as a leading candidate alga for production uses. To better understand the oleaginous mechanism of this alga, we conducted a multiomics analysis by systematically integrating time-resolved transcriptomes, lipidomes and metabolomes in response to nitrogen deprivation. The data analysis unraveled the distinct mechanism of TAG accumulation, which involved coordinated stimulation of multiple biological processes including supply of energy and reductants, carbon reallocation from protein and starch, and 'pushing' and 'pulling' carbon to TAG synthesis. Unlike the model alga Chlamydomonas, de novo fatty acid synthesis in C. zofingiensis was promoted, together with enhanced turnover of both glycolipids and phospholipids, supporting the drastic need of acyls for TAG assembly. Moreover, genomewide analysis identified many key functional enzymes and transcription factors that had engineering potential for TAG modulation. Two genes encoding glycerol-3-phosphate acyltransferase (GPAT), the first committed enzyme for TAG assembly, were found in the C. zofingiensis genome; in vivo functional characterization revealed that extrachloroplastic GPAT instead of chloroplastic GPAT played a central role in TAG synthesis. These findings illuminate distinct oleaginousness mechanisms in C. zofingiensis and pave the way towards rational manipulation of this alga to becone an emerging model for trait improvements.
Loss of ferritin‐positive microglia relates to increased iron, RNA oxidation, and dystrophic microglia in the brains of aged male marmosets

Microglia are cells that protect brain tissue from invading agents and toxic substances, first by releasing pro‐inflammatory cytokines, and thereafter by clearing tissue by phagocytosis. Microglia express ferritin, a protein with ferroxidase activity capable of storing iron, a metal that accumulates in brain during aging. Increasing evidence suggests that ferritin plays an important role in inflammation. However, it is not known if ferritin/iron content can be related to the activation state of microglia. To this end, we aimed to delineate the role of ferritin in microglia activation in a non‐human primate model. We analyzed brains of male marmosets and observed an increased density of ferritin+ microglia with an activated phenotype in hippocampus and cortex of old marmosets (mean age 11.25 ± 0.70 years) compared to younger subjects. This was accompanied by an increased number of dystrophic microglia in old marmosets. However, in aged subjects (mean age 16.83 ± 2.59 years) the number of ferritin+ microglia was decreased compared to old ones. Meanwhile, the content of iron in brain tissue and cells with oxidized RNA increased during aging in all hippocampal and cortical regions analyzed. Abundant amoeboid microglia were commonly observed surrounding neurons with oxidized RNA. Notably, amoeboid microglia were arginase1+ and IL‐10+, indicative of a M2 phenotype. Some of those M2 cells also presented RNA oxidation and a dystrophic phenotype. Therefore, our data suggest that ferritin confers protection to microglia in adult and old marmosets, while in aged subjects the decline in ferritin and the increased amount of iron in brain tissue may be related to the increased number of cells with oxidized RNA, perhaps precluding the onset of neurodegeneration.
Antiglycative Activity and RAGE Expression in Rett Syndrome

Rett syndrome (RTT) is a human neurodevelopmental disorder, whose pathogenesis has been linked to both oxidative stress and subclinical inflammatory status (OxInflammation). Methylglyoxal (MG), a glycolytic by-product with cytotoxic and pro-oxidant power, is the major precursor in vivo of advanced glycation end products (AGEs), which are known to exert their detrimental effect via receptor- (e.g., RAGE) or non-receptor-mediated mechanisms in several neurological diseases. On this basis, we aimed to compare fibroblasts from healthy subjects (CTR) with fibroblasts from RTT patients (N = 6 per group), by evaluating gene/protein expression patterns, and enzymatic activities of glyoxalases (GLOs), along with the levels of MG-dependent damage in both basal and MG-challenged conditions. Our results revealed that RTT is linked to an alteration of the GLOs system (specifically, increased GLO2 activity), that ensures unchanged MG-dependent damage levels. However, RTT cells underwent more pronounced cell death upon exogenous MG-treatment, as compared to CTR, and displayed lower RAGE levels than CTR, with no alterations following MG-treatment, thus suggesting that an adaptive response to dicarbonyl stress may occur. In conclusion, besides OxInflammation, RTT is associated with reshaping of the major defense systems against dicarbonyl stress, along with an altered cellular stress response towards pro-glycating insults.
Psychiatric readmissions in a community-based sample of patients with mental disorders.

OBJECTIVE This study examined whether receipt of outpatient psychiatric services after hospital discharge was associated with reduced risk of readmission. METHODS Treatment records from patients admitted to San Diego County psychiatric hospitals over a one-year period were obtained from the San Diego County Behavioral Health Services electronic health record system. A discrete-time proportional hazards model was used to examine the association of receipt of outpatient psychiatric services with readmission within 30 days of discharge from the index hospitalization. RESULTS Of the 4,663 patients, 16% were readmitted within 30 days. In an adjusted model, receipt of outpatient therapy after discharge was associated with a greater likelihood of being readmitted (hazard ratio=1.36, 95% confidence interval=1.14-1.67), whereas receipt of case management or medication management was not associated with readmission. CONCLUSIONS The differential risk of readmission by service type suggests a need for studies that explore reasons for an increased risk of readmission with certain types of services.
Responsiveness to PD-1 Blockade in End-Stage Colon Cancer with Gene Locus 9p24.1 Copy-Number Gain

Most patients with metastasis of large bowel cancer do not benefit from immune therapy. This case study shows that a rare gene mutation, termed 9p24.1 copy-number gain, in this otherwise incurable tumor provoked a response to immune therapy. Most patients whose large bowel cancer has spread to other organs do not respond to immune therapy. We detected a rare gene mutation, termed 9p24.1 copy-number gain (CNG), in an otherwise incurable colorectal cancer that provoked an immune therapy response. We identified this gene mutation by gene-panel sequencing of DNA from a liver metastasis biopsy from a patient who had disease refractory to standard therapies. Following immune checkpoint blockade (ICB) with pembrolizumab (anti–PD-1), the patient experienced conversion of the tumor phenotype from one with epithelial features to that of an inflamed microenvironment, detected by high-resolution RNA sequencing. Circulating tumor DNA disappeared over the first weeks of therapy. As assessed by standard radiographic measurement, the patient had a partial response that was durable. This patient's response may support the use of histology-agnostic ICB in solid tumors that carry the rare 9p24.1 CNG.
A systematic review of plant-conjugated masked mycotoxins: Occurrence, toxicology, and metabolism

Abstract Masked mycotoxins are biologically modified phase II metabolites formed by plant defense mechanisms through glucosylation catalyzed by uridine diphosphate -glucosyltransferases. Most of the current reports focus on the occurrence of masked mycotoxins in Europe, America, Africa, and cover other geographic regions, e.g. China and Japan. High proportions of masked mycotoxins co-occurring with their parent forms in various cereal-based food and feedstuff could clearly increase total exposures and pose additional health risks to humans and animals. In contrast to the parent mycotoxins, the data on the toxicity of masked mycotoxins are still scarce, however, the poor existing information showed that masked mycotoxins generally exhibit significant in vitro and in vivo toxicities lower than those of their parent forms, especially for deoxynivalenol-3-glucoside, which is the only thoroughly investigated masked mycotoxin. Although the lower toxicity level of masked mycotoxins, these are probably hydrolyzed into their free forms by intestinal microorganisms in the digestive tract of mammals and thus contribute to unpredicted toxicity. The metabolic characteristics of reported masked mycotoxins are species-specific. The most relevant animal model of human sensitivity, the pig, is most sensitive to masked mycotoxins. This review focuses on updates in the current knowledge on country-specific natural-occurrence data in global surveys, as well as in vitro and in vivo toxicology and metabolic investigations of masked mycotoxins.
Synthesis, anticholinesterase activity and molecular modeling studies of novel carvacrol-substituted amide derivatives

Abstract In the present study, 23 novel carvacrol derivatives involving the amide moiety as a linker between the alkyl chains and/or the heterocycle nucleus were synthesized and tested in vitro as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. 2-(5-Isopropyl-2-methylphenoxy)-N-(quinolin-8-yl)acetamide (5v) revealed the highest inhibition properties against AChE and BuChE with the IC50 values of 1.93 and 0.05 µM, respectively. The blood–brain barrier (BBB) permeability of the potent inhibitor (5v) was also assessed by the widely used parallel artificial membrane permeability assay (PAMPA-BBB). The results showed that 5v is capable of crossing the BBB. Pharmacokinetic and toxicity profiles of the studied molecule predictions were investigated by MetaCore/MetaDrug comprehensive systems biology analysis suite. Bioactive conformations of the synthesized molecules, their predicted binding energies as well as structural and dynamical profiles of molecules at the binding pockets of AChE and BuChE targets were also investigated using different docking algorithms and molecular dynamics (MD) simulations. Communicated by Ramaswamy H. Sarma
Survey of the Current Use of Dexmedetomidine and Management of Withdrawal Symptoms in Critically Ill Children.

OBJECTIVES Dexmedetomidine use for sedation in the pediatric intensive care units (PICUs) has increased since its initial US Food and Drug Administration (FDA) approval in adults. However, there is limited evidence to direct providers regarding current usage, dosing, and monitoring for withdrawal symptoms in pediatric patients. This study sought to determine the utilization of dexmedetomidine and management of dexmedetomidine withdrawal symptoms among PICU physicians. METHODS A questionnaire survey was distributed to all members of the American Academy of Pediatrics Section on Critical Care. It assessed the practice site demographics, indication, dosing, and duration of dexmedetomidine infusion, unit protocol, and strategies for management of dexmedetomidine withdrawal. RESULTS A total of 147 surveys (21.1%) were returned and analyzed. The reported uses for dexmedetomidine were as a primary sedative (59.9%), adjunctive agent for sedation (82.3%), and adjunctive agent to assist weaning sedation (62.6%) or from mechanical ventilation (70.1%). One hundred twenty-nine respondents (87.8%) had concerns over dexmedetomidine withdrawal, with 59 respondents becoming concerned after 120 hours of infusion (45.7%). Most respondents reported managing dexmedetomidine withdrawal symptoms via a regimented wean and initiation of clonidine (81%). Units with >1000 admissions per year were more likely to have a protocol related to dexmedetomidine use (p = 0.021). Units with >1000 admissions per year reported using clonidine for withdrawal at a higher rate, whereas units with ≤1000 admissions per year used a systematic wean of dexmedetomidine (p = 0.014). CONCLUSIONS Dexmedetomidine use in the PICU is varied among pediatric intensive care physicians. Intensivists have withdrawal concerns after dexmedetomidine discontinuation, and the primary management of this withdrawal phenomenon is the initiation of clonidine with a regimented dexmedetomidine wean.
The effects of 8DSS peptide on remineralization in a rat model of enamel caries evaluated by two nondestructive techniques

Nowadays, dental caries is one of the most common oral health problems, affecting most individuals. It has been found that, by remineralizing enamel at an early stage in the formation of enamel caries, teeth can be effectively protected from dental caries. In this work, a peptide with eight repetitive sequences of aspartate-serine-serine (8DSS) is applied as the bio-mineralizer in an in-vivo rat enamel caries model. Nondestructive quantitative light-induced fluorescence-digital (QLF-D) imaging and micro-computed tomography (micro-CT) are used to evaluate the remineralization of enamel carious lesions by measuring the total fluorescence radiance loss of the molar area (ΔQTotal), acquired using QLF-D imaging, and the mineral density and residual molar enamel volume, acquired using micro-CT. Correlations are explored between ΔQTotal and mineral density (strong correlation, r = 0.8000, p < 0.001) and ΔQTotal and residual molar enamel volume (moderate correlation, r = 0.6375, p < 0.001). Our results demonstrate that 8DSS is a promising in-vivo remineralization agent that exhibits comparable effects to NaF (p < 0.05), which has been verified using the classical Keyes method. Moreover, the nondestructive QLF-D and micro-CT methods can be combined to quantify the remineralization of enamel carious lesions three-dimensionally in vivo, making them broadly applicable in quantifying hard tissues.
From clear lakes to murky waters - tracing the functional response of high-latitude lake communities to concurrent 'greening' and 'browning'.

Climate change and the intensification of land use practices are causing widespread eutrophication of subarctic lakes. The implications of this rapid change for lake ecosystem function remain poorly understood. To assess how freshwater communities respond to such profound changes in their habitat and resource availability, we conducted a space-for-time analysis of food-web structure in 30 lakes situated across a temperature-productivity gradient equivalent to the predicted future climate of subarctic Europe (temperature +3°C, precipitation +30% and nutrient +45 μg L-1 total phosphorus). Along this gradient, we observed an increase in the assimilation of pelagic-derived carbon from 25 to 75% throughout primary, secondary and tertiary consumers. This shift was overwhelmingly driven by the consumption of pelagic detritus by benthic primary consumers and was not accompanied by increased pelagic foraging by higher trophic level consumers. Our data also revealed a convergence of the carbon isotope ratios of pelagic and benthic food web endmembers in the warmest, most productive lakes indicating that the incorporation of terrestrial derived carbon into aquatic food webs increases as land use intensifies. These results, reflecting changes along a gradient characteristic of the predicted future environment throughout the subarctic, indicate that climate and land use driven eutrophication and browning are radically altering the function and fuelling of aquatic food webs in this biome.
Bayesian-based noninvasive prenatal diagnosis of single-gene disorders

In the last decade, noninvasive prenatal diagnosis (NIPD) has emerged as an effective procedure for early detection of inherited diseases during pregnancy. This technique is based on using cell-free DNA (cfDNA) and fetal cfDNA (cffDNA) in maternal blood, and hence, has minimal risk for the mother and fetus compared with invasive techniques. NIPD is currently used for identifying chromosomal abnormalities (in some instances) and for single-gene disorders (SGDs) of paternal origin. However, for SGDs of maternal origin, sensitivity poses a challenge that limits the testing to one genetic disorder at a time. Here, we present a Bayesian method for the NIPD of monogenic diseases that is independent of the mode of inheritance and parental origin. Furthermore, we show that accounting for differences in the length distribution of fetal- and maternal-derived cfDNA fragments results in increased accuracy. Our model is the first to predict inherited insertions–deletions (indels). The method described can serve as a general framework for the NIPD of SGDs; this will facilitate easy integration of further improvements. One such improvement that is presented in the current study is a machine learning model that corrects errors based on patterns found in previously processed data. Overall, we show that next-generation sequencing (NGS) can be used for the NIPD of a wide range of monogenic diseases, simultaneously. We believe that our study will lead to the achievement of a comprehensive NIPD for monogenic diseases.