Miracle-dz/UniFAR-FTUs huggingface dataset:
Environmental heterogeneity generates intra-population variation in life-history traits in an annual plant.

Environmental variation affects a plant's life cycle by influencing the timing of germination and flowering, and the duration of the growing season. Yet we know little about how environmental heterogeneity generates variation in germination schedules and the consequences for growth and fecundity through genetic and plastic responses. We use an annual population of Mimulus guttatus where, in nature, seeds germinate in both fall and spring. We investigate whether there is a genetic basis to the timing of germination, the effect of germination timing on fecundity, and if growth and flowering respond plastically to compensate for different season lengths. Using sibling families grown in simulated seasonal conditions, we find families do not differ in their propensity to germinate between seasons. However, germination season affects subsequent growth and flowering time, with significant GxE. Most GxE is due to unequal variance between seasons, because the spring cohort harbors little genetic variance. Despite their different season lengths, the cohorts do not differ in flower number (fecundity). Heterogeneous environments with unpredictable risks may maintain promiscuous germination, which then affects flowering time. Thus, if selection at particular life stages changes with climate change, there may be consequences for the entire life cycle. This article is protected by copyright. All rights reserved.
A Computational Model of Oxytocin Modulation of Olfactory Recognition Memory

Abstract Social recognition in mammals depends on complex interactions between sensory and other brain areas as well as modulatory inputs by specific neuropeptides such as oxytocin (OXT). Social recognition memory specifically has been shown to depend among others on olfactory processing, and can be probed using methods similar to those used when probing non-social odor memory. We here use a computational model of two interconnected olfactory networks in the mouse, the olfactory bulb (OB) and anterior olfactory nucleus, to propose a mechanism for olfactory short-term recognition memory and its modulation in social situations. Based on previous experiments, we propose one early locus for memory to be the OB. During social encounters in mice, pyramidal cells in the anterior olfactory nucleus, themselves driven by olfactory input, are rendered more excitable by OXT release, resulting in stronger feedback to OB local interneurons. This additional input to the OB creates stronger dynamics and improves signal-to-noise ratio of odor responses in the OB proper. As a consequence, mouse social olfactory memories are more strongly encoded and their duration is modulated.
Alternating EM algorithm for a bilinear model in isoform quantification from RNA-seq data

Abstract Motivation Estimation of isoform-level gene expression from RNA-seq data depends on simplifying assumptions, such as uniform read distribution, that are easily violated in real data. Such violations typically lead to biased estimates. Most existing methods provide bias correction step(s), which is based on biological considerations—such as GC content—and applied in single samples separately. The main problem is that not all biases are known. Results We have developed a novel method called XAEM based on a more flexible and robust statistical model. Existing methods are essentially based on a linear model Xβ, where the design matrix X is known and is computed based on the simplifying assumptions. In contrast XAEM considers Xβ as a bilinear model with both X and β unknown. Joint estimation of X and β is made possible by a simultaneous analysis of multi-sample RNA-seq data. Compared to existing methods, XAEM automatically performs empirical correction of potentially unknown biases. We use an alternating expectation-maximization (AEM) algorithm, alternating between estimation of X and β. For speed XAEM utilizes quasi-mapping for read alignment, thus leading to a fast algorithm. Overall XAEM performs favorably compared to recent advanced methods. For simulated datasets, XAEM obtains higher accuracy for multiple-isoform genes. In a differential-expression analysis of a real single-cell RNA-seq dataset, XAEM achieves substantially better rediscovery rates in independent validation sets. Availability and implementation The method and pipeline are implemented as a tool and freely available for use at http://fafner.meb. ki.se/biostatwiki/xaem/. Supplementary information Supplementary data are available at Bioinformatics online.
The Informational Substrate of Chemical Evolution: Implications for Abiogenesis

A key aspect of biological evolution is the capacity of living systems to process information, coded in deoxyribonucleic acid (DNA), and used to direct how the cell works. The overall picture that emerges today from fields such as developmental, synthetic, and systems biology indicates that information processing in cells occurs through a hierarchy of genes regulating the activity of other genes through complex metabolic networks. There is an implicit semiotic character in this way of dealing with information, based on functional molecules that act as signs to achieve self-regulation of the whole network. In contrast to cells, chemical systems are not thought of being able to process information, yet they must have preceded biological organisms, and evolved into them. Hence, there must have been prebiotic molecular assemblies that could somehow process information, in order to regulate their own constituent reactions and supramolecular organization processes. The purpose of this essay is then to reflect about the distinctive features of information in living and non-living matter, and on how the capacity of biological organisms for information processing was possibly rooted in a particular type of chemical systems (here referred to as autonomous chemical systems), which could self-sustain and reproduce through organizational closure of their molecular building blocks.
Coffin–Lowry syndrome in Chinese

Coffin–Lowry syndrome (CLS) is a well‐described syndrome characterized by intellectual disability, growth retardation, recognizable dysmorphic features, and skeletal changes. It is an X‐linked syndrome where males are more severely affected and females have high variability in clinical presentations. This case series reports nine molecularly confirmed Chinese CLS patients from six unrelated families (three with familial variants and three with de novo variants). There is a wide genotypic spectrum with five novel variants in RPS6KA3 gene. Clinical phenotype and facial features of these Chinese CLS patients are comparable to what has been described in other ethnicities.
High-mannose intercellular adhesion molecule-1 (ICAM-1) enhances CD16+ monocyte adhesion to the endothelium.

Human monocytes have been classified into three distinct groups - classical (anti-inflammatory; CD14+/CD16-), non-classical (patrolling; CD14+/CD16++), and intermediate (pro-inflammatory; CD14++/CD16+). Adhesion of non-classical / intermediate monocytes with the endothelium is important for innate immunity, and also vascular inflammatory disease. However, there is an incomplete understanding of the mechanisms that regulate CD16+ vs. CD16- monocyte adhesion to the inflamed endothelium. Here, we tested the hypothesis that a high mannose (HM) N-glycoform of intercellular adhesion molecule-1 (ICAM-1) on the endothelium mediates the selective recruitment of CD16+ monocytes. Using TNFα treatment of human umbilical vein endothelial cells (HUVECs), and using proximity ligation assay (PLA) for detecting proximity of specific N-glycans and ICAM-1, we show that TNFa induces HM-ICAM-1 formation on the endothelial surface in a time-dependent manner. Next, we measured CD16- or CD16+ monocyte rolling and adhesion to TNFα treated HUVECs in which HM- or hybrid ICAM-1 N-glycoforms were generated using the a-mannosidase class I and II inhibitors, Kifunensine and Swainsonine, respectively. Expression of HM-ICAM-1 selectively enhanced CD16+ monocyte adhesion under flow with no effect on CD16- monocytes noted. CD16+ monocyte adhesion was abrogated by blocking either HM-epitopes or ICAM-1. A critical role for HM-ICAM-1 in mediating CD16+ monocyte rolling and adhesion was confirmed using Cos-1 cells engineered to express HM- or complex ICAM-1 N-glycoforms. These data suggest that HM-ICAM-1 selectively recruits non-classical/intermediate CD16+ monocytes to the activated endothelium.
Perspective on current and emerging drugs in the treatment of acute and chronic toxoplasmosis

ABSTRACT No new drugs for treatment of toxoplasmosis have been approved in over 60 years, despite the burden of toxoplasmosis on human society. The small selection of effective drugs is limited by important side effects, often limiting patient use. This perspective highlights promising late-stage drug candidates in the treatment of toxoplasmosis. Presently, drugs target the tachyzoite form of the parasite Toxoplasma gondii responsible for the acute infection but do not eradicate the tissue cyst form underlying chronic infection. Pyrimethamine – the first-line and only approved drug for treatment of toxoplasmosis in the United States – inhibits parasite DNA synthesis by inhibiting dihydrofolate reductase (DHFR). Two novel DHFR inhibitors with improved potency and selectivity for parasite DHFR over human DHFR are in clinical-stage development. One of the most advanced and promising therapeutic targets, demonstrating potential to treat both acute and chronic toxoplasmosis, is the calcium-dependent protein kinase 1 (CDPK1) which plays an essential role in the intracellular replicative cycle of the parasite, and has no direct mammalian homolog. Two CDPK1 inhibitor programs have identified potent and selective lead series, demonstrating acceptable systemic and CNS exposure, and in vivo efficacy in animal models of acute and chronic infection. Physicians need a better arsenal of parasiticidal drugs for the treatment of toxoplasmosis, particularly those active against tissue cysts.
Spectral Quantification of Nonlinear Elasticity Using Acoustoelasticity and Shear-Wave Dispersion

Tissue biomechanical properties are known to be sensitive to pathological changes. Accordingly, various techniques have been developed to estimate tissue mechanical properties. Shear-wave elastography (SWE) measures shear-wave speed (SWS) in tissues, which can be related to shear modulus. Although viscosity or stress–strain nonlinearity may act as confounder of SWE, their explicit characterization may also provide additional information about tissue composition as a contrast modality. Viscosity can be related to frequency dispersion of SWS, which can be characterized using multi-frequency measurements, herein called spectral SWE (SSWE). Additionally, nonlinear shear modulus can be quantified and parameterized based on SWS changes with respect to applied stress, a phenomenon called acoustoelasticity (AE). In this work, we characterize the nonlinear parameters of tissue as a function of excitation frequency by utilizing both AE and SSWE together. For this, we apply incremental amounts of quasi-static stress on a medium, while imaging and quantifying SWS dispersion via SSWE. Results from phantom and ex vivo porcine liver experiments demonstrate the feasibility of measuring frequency-dependent nonlinear parameters using the proposed method. SWS propagation in porcine liver tissue was observed to change from 1.8 m/s at 100 Hz to 3.3 m/s at 700 Hz, while increasing by approximately 25% from a strain of 0% to 12% across these frequencies.
Regulation of the Germinal Center Reaction and Somatic Hypermutation Dynamics by Homologous Recombination

Key Points HR supports germinal center B cell survival and Ab affinity maturation. HR is active at the hypermutating Ig locus and influences the SHM mutation pattern. The magnitude of A:T mutagenesis during SHM of the Ig V region increases over time. Visual Abstract During somatic hypermutation (SHM) of Ig genes in germinal center B cells, lesions introduced by activation-induced cytidine deaminase are processed by multiple error-prone repair pathways. Although error-free repair by homologous recombination (HR) is crucial to prevent excessive DNA strand breakage at activation-induced cytidine deaminase off-target genes, its role at the hypermutating Ig locus in the germinal center is unexplored. Using B cell–specific inactivation of the critical HR factor Brca2, we detected decreased proliferation, survival, and thereby class switching of ex vivo–activated B cells. Intriguingly, an HR defect allowed for a germinal center reaction and affinity maturation in vivo, albeit at reduced amounts. Analysis of SHM revealed that a certain fraction of DNA lesions at C:G bp was indeed repaired in an error-free manner via Brca2 instead of being processed by error-prone translesion polymerases. By applying a novel pseudo-time in silico analysis of mutational processes, we found that the activity of A:T mutagenesis during SHM increased during a germinal center reaction, but this was in part defective in Brca2-deficient mice. These mutation pattern changes in Brca2-deficient B cells were mostly specific for the Ig V region, suggesting a local or time-dependent need for recombination repair to survive high rates of SHM and especially A:T mutagenesis.
Intersubject and Intrasubject Variability of Potential Plasma and Urine Metabolite and Protein Biomarkers in Healthy Human Volunteers

A limited understanding of intersubject and intrasubject variability hampers effective biomarker translation from in vitro/in vivo studies to clinical trials and clinical decision support. Specifically, variability of biomolecule concentration can play an important role in interpretation, power analysis, and sampling time designation. In the present study, a wide range of 749 plasma metabolites, 62 urine biogenic amines, and 1,263 plasma proteins were analyzed in 10 healthy male volunteers measured repeatedly during 12 hours under tightly controlled conditions. Three variability components in relative concentration data are determined using linear mixed models: between (intersubject), time (intrasubject), and noise (intrasubject). Biomolecules such as 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furanpropanoate, platelet‐derived growth factor C, and cathepsin D with low noise potentially detect changing conditions within a person. If also the between component is low, biomolecules can easier differentiate conditions between persons, for example cathepsin D, CD27 antigen, and prolylglycine. Variability over time does not necessarily inhibit translatability, but requires choosing sampling times carefully.
Sex Differences in Adrenal Bmal1 Deletion-Induced Augmentation of Glucocorticoid Responses to Stress and ACTH in Mice.

The circadian glucocorticoid (GC) rhythm is dependent on a molecular clock in the suprachiasmatic nucleus (SCN) and an adrenal clock that is synchronized by the SCN. To determine whether the adrenal clock modulates GC responses to stress, experiments used female and male Cyp11A1Cre/+:: Bmal1Fl/Fl KO (SCC-KO) mice, in which the core clock gene, Bmal1, is deleted in all steroidogenic tissues including the adrenal cortex. Following restraint stress, female and male SCC-KO mice demonstrate augmented plasma corticosterone, but not plasma ACTH. In contrast, following submaximal scruff stress, plasma corticosterone was elevated only in female SCC-KO mice. Adrenal sensitivity to ACTH was measured in vitro using acutely dispersed adrenocortical cells. Maximal corticosterone responses to ACTH were elevated in cells from female KO mice without affecting the EC50 response. Neither the maximum nor the EC50 response to ACTH was affected in male cells, indicating that female SCC-KO show a stronger adrenal phenotype. Parallel experiments were done using female Cyp11B2 (Aldosterone Synthase)Cre/+:: Bmal1Fl/Fl mice, adrenal cortex-specific Bmal1 null (Ad-KO) mice. Plasma corticosterone was increased in Ad-KO mice following restraint or scruff stress, and in vitro responses to ACTH were elevated in adrenal cells from Ad-KO mice, replicating data from female SCC-KO mice. Gene analysis showed increased expression of adrenal genes in female SCC-KO mice involved in cell cycle control, cell adhesion-extracellular matrix interaction and ligand receptor activity that could promote steroid production. These observations underscore a role for adrenal Bmal1 as an attenuator of steroid secretion that is most prominent in female mice.
Beyond power amplification: latch-mediated spring actuation is an emerging framework for the study of diverse elastic systems

ABSTRACT Rapid biological movements, such as the extraordinary strikes of mantis shrimp and accelerations of jumping insects, have captivated generations of scientists and engineers. These organisms store energy in elastic structures (e.g. springs) and then rapidly release it using latches, such that movement is driven by the rapid conversion of stored elastic to kinetic energy using springs, with the dynamics of this conversion mediated by latches. Initially drawn to these systems by an interest in the muscle power limits of small jumping insects, biologists established the idea of power amplification, which refers both to a measurement technique and to a conceptual framework defined by the mechanical power output of a system exceeding muscle limits. However, the field of fast elastically driven movements has expanded to encompass diverse biological and synthetic systems that do not have muscles – such as the surface tension catapults of fungal spores and launches of plant seeds. Furthermore, while latches have been recognized as an essential part of many elastic systems, their role in mediating the storage and release of elastic energy from the spring is only now being elucidated. Here, we critically examine the metrics and concepts of power amplification and encourage a framework centered on latch-mediated spring actuation (LaMSA). We emphasize approaches and metrics of LaMSA systems that will forge a pathway toward a principled, interdisciplinary field. Summary: A framework centered on the dynamic interactions of springs and latches enables clear, comparable measurements and productive interdisciplinary pathways for biological analysis and engineering design.
Oral Silica Nanoparticles Lack of Neurotoxic Effects in a Parkinson’s Disease Model: A Possible Nanocarrier?

Silica nanoparticles (SiO<sub>2</sub>-NP) are an option as drug carriers due to their biodegradability, biocompatibility, and capacity to bind themselves to other compounds. However, until now, the effect of these particles on the brain when neurodegeneration occurs is unknown. Hence, this work focused on the <italic>in vivo</italic> evaluation of the neurotoxic effects of SiO<sub>2</sub>-NP when oxidative and inflammation are present during the development of Parkinson’s disease. To determine whether SiO<sub>2</sub>-NP may act as a non-neurotoxic carrier we evaluated if the intragastric administration (ig) of SiO<sub>2</sub>-NP of 150 nm (25, 50 and 100 mg/kg administered for five consecutive days) increased neuronal damage induced with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. SiO<sub>2</sub>-NP administration did not further decrease cell viability assessed by MTT reduction, nor increased lipid peroxidation measured by TBARS or TNF<inline-formula> <tex-math notation="LaTeX">$\alpha $ </tex-math></inline-formula> levels in the striatum and the substantia nigra in the MPTP model. Furthermore, we observed no additional reduction in striatal dopamine levels. The present results suggest that SiO<sub>2</sub>-NP of 150 nm are suitable nanocarrier for Parkinson’s disease drugs without generating any additional damage.
Improving methodology in heart rate variability analysis for the premature infants: Impact of the time length

Background Heart rate variability (HRV) has been emerging in neonatal medicine. It may help for the early diagnosis of pathology and estimation of autonomous maturation. There is a lack of standardization and automation in the selection of the sequences to analyze and some features have not been explored in this specific population. The main objective of this study was to analyze the impact of the time length of the sequences on the estimation of linear and non-linear HRV features, including horizontal visibility graphs (HVG). Methods HRV features were repeatedly measured with linear and non-linear methods on 2-, 5-, 10-minute sequences selected from the longest 15-min sequence and recorded on a weekly basis in 39 infants less than 31 weeks at birth. The associations between HRV measurements were analyzed through principal component analysis and k-means clustering. The effects of the time lengths on HRV measurements and post-menstrual age (PMA) were analyzed by linear mixed effect model for repeated measures. Results The domains of analysis were concordant for their descriptive parameters of short (rMSSD, SD1 and HF) and long-term (SD, SD2 and LF) variability. α1 was correlated with the LF/HF and SD2/SD1. DC and AC were correlated with short-term variability estimates and significantly increased with GA and PMA. Shortening the windows of analysis increased the random measurement error for all the features and increased the bias for all but short term features and HVGs. Conclusion The linear and non-linear measurements of HRV are correlated each other. Shortening the windows of analysis increased the random error for all the features and increased the bias for all but short term features and HVGs. Short-term HRV can be an index for evaluating the maturation in whatever sequence length.
Albumin Coating Prevents Cardiac Effect of the Magnetic Nanoparticles

We have showed that surface layer can determine cardiac effects of the magnetic nanoparticles (MNPs). Considering the high binding capacity of albumin and low side-effects, the aim of this study was to evaluate the influence of albumin coating on the cardiovascular effects of two manganese ferrite-based MNPs: citrate-coated and bare MNPs. Isolated rat hearts were perfused with citrate-coated magnetic nanoparticles (CiMNPs), citrate albumin-coated magnetic nanoparticles (CiAlbMNPs), bare magnetic nanoparticles (BaMNPs), and albumin-coated magnetic nanoparticles (AlbMNPs). CiMNPs induce a transient decrease in the left ventricular end-systolic pressure, +dP/dt and −dP/dt. These effects were not worsened by albumin coating. BaMNPs significantly increased the left ventricular end-diastolic pressure and perfusion pressure and decreased the +dP/dt and −dP/dt. These effects were completely absent in hearts perfused with AlbMNPs. None of the MNPs changed heart rate or arterial blood pressure in conscious rats. Magnetic signals in isolated hearts perfused with BaMNPs were significantly higher than AlbMNPs perfused hearts. However, the magnetic signal in heart tissue was similar when the MNPs were infused in conscious rats. These data indicate that albumin-coated can reduce cardiovascular effects of MNPs. These findings suggest a protective effect of albumin surface in MNPs, favoring its future therapeutic applications.