Systematic mapping of organism-scale gene-regulatory networks in aging using population asynchrony.

In aging, physiologic networks decline in function at rates that differ between individuals, producing a wide distribution of lifespan. Though 70% of human lifespan variance remains unexplained by heritable factors, little is known about the intrinsic sources of physiologic heterogeneity in aging. To understand how complex physiologic networks generate lifespan variation, new methods are needed. Here, we present Asynch-seq, an approach that uses gene-expression heterogeneity within isogenic populations to study the processes generating lifespan variation. By collecting thousands of single-individual transcriptomes, we capture the Caenorhabditis elegans "pan-transcriptome"-a highly resolved atlas of non-genetic variation. We use our atlas to guide a large-scale perturbation screen that identifies the decoupling of total mRNA content between germline and soma as the largest source of physiologic heterogeneity in aging, driven by pleiotropic genes whose knockdown dramatically reduces lifespan variance. Our work demonstrates how systematic mapping of physiologic heterogeneity can be applied to reduce inter-individual disparities in aging.

Best practices for the execution, analysis, and data storage of plant single-cell/nucleus transcriptomics.

Single-cell and single-nucleus RNA-sequencing technologies capture the expression of plant genes at an unprecedented resolution. Therefore, these technologies are gaining traction in plant molecular and developmental biology for elucidating the transcriptional changes across cell types in a specific tissue or organ, upon treatments, in response to biotic and abiotic stresses, or between genotypes. Despite the rapidly accelerating use of these technologies, collective and standardized experimental and analytical procedures to support the acquisition of high-quality data sets are still missing. In this commentary, we discuss common challenges associated with the use of single-cell transcriptomics in plants and propose general guidelines to improve reproducibility, quality, comparability, and interpretation and to make the data readily available to the community in this fast-developing field of research.

Biologically meaningful regulatory logic enhances the convergence rate in Boolean networks and bushiness of their state transition graph.

Boolean models of gene regulatory networks (GRNs) have gained widespread traction as they can easily recapitulate cellular phenotypes via their attractor states. Their overall dynamics are embodied in a state transition graph (STG). Indeed, two Boolean networks (BNs) with the same network structure and attractors can have drastically different STGs depending on the type of Boolean functions (BFs) employed. Our objective here is to systematically delineate the effects of different classes of BFs on the structural features of the STG of reconstructed Boolean GRNs while keeping network structure and biological attractors fixed, and explore the characteristics of BFs that drive those features. Using $10$ reconstructed Boolean GRNs, we generate ensembles that differ in BFs and compute from their STGs the dynamics' rate of contraction or 'bushiness' and rate of 'convergence', quantified with measures inspired from cellular automata (CA) that are based on the garden-of-Eden (GoE) states. We find that biologically meaningful BFs lead to higher STG 'bushiness' and 'convergence' than random ones. Obtaining such 'global' measures gets computationally expensive with larger network sizes, stressing the need for feasible proxies. So we adapt Wuensche's $Z$-parameter in CA to BFs in BNs and provide four natural variants, which, along with the average sensitivity of BFs computed at the network level, comprise our descriptors of local dynamics and we find some of them to be good proxies for bushiness. Finally, we provide an excellent proxy for the 'convergence' based on computing transient lengths originating at random states rather than GoE states.

Leveraging developmental landscapes for model selection in Boolean gene regulatory networks.

Boolean models are a well-established framework to model developmental gene regulatory networks (DGRNs) for acquisition of cellular identities. During the reconstruction of Boolean DGRNs, even if the network structure is given, there is generally a large number of combinations of Boolean functions that will reproduce the different cell fates (biological attractors). Here we leverage the developmental landscape to enable model selection on such ensembles using the relative stability of the attractors. First we show that previously proposed measures of relative stability are strongly correlated and we stress the usefulness of the one that captures best the cell state transitions via the mean first passage time (MFPT) as it also allows the construction of a cellular lineage tree. A property of great computational importance is the insensitivity of the different stability measures to changes in noise intensities. That allows us to use stochastic approaches to estimate the MFPT and thereby scale up the computations to large networks. Given this methodology, we revisit different Boolean models of Arabidopsis thaliana root development, showing that a most recent one does not respect the biologically expected hierarchy of cell states based on relative stabilities. We therefore developed an iterative greedy algorithm that searches for models which satisfy the expected hierarchy of cell states and found that its application to the root development model yields many models that meet this expectation. Our methodology thus provides new tools that can enable reconstruction of more realistic and accurate Boolean models of DGRNs.

Electromagnetic Forces and Torques: From Dielectrophoresis to Optical Tweezers.

Electromagnetic forces and torques enable many key technologies, including optical tweezers or dielectrophoresis. Interestingly, both techniques rely on the same physical process: the interaction of an oscillating electric field with a particle of matter. This work provides a unified framework to understand this interaction both when considering fields oscillating at low frequencies─dielectrophoresis─and high frequencies─optical tweezers. We draw useful parallels between these two techniques, discuss the different and often unstated assumptions they are based upon, and illustrate key applications in the fields of physical and analytical chemistry, biosensing, and colloidal science.

Planar 16-band metasurface-enhanced spectral filter for integrated image sensing.

We study theoretically and demonstrate experimentally a 16-band narrow band wavelength selective filter in the near-infrared range. The combination of a pair of distributed Bragg reflectors with a sub-wavelength grating metasurface embedded in the intra-cavity provides a narrow response which can be tuned by adjusting the geometry of the sub-wavelength grating metasurface. The key advantage of this approach is its ease of fabrication, where the spectral response is tuned by merely changing the grating period, resulting in a perfectly planar geometry that can be easily integrated with a broad variety of photodetectors, thus enabling attractive applications such as bio-imaging, time-of-flight sensors and LiDAR. The experimental results are supported by numerical simulations and effective medium theory that unveil the mechanisms that lead to the optical response of the device. It is also shown how the polarization dependence of the structure can be used to determine very accurately the polarization of incoming light.

An audit of central venous catheter insertion and management practices in two French university hospitals.

OBJECTIVE: To assess the compliance with French guidelines for the prevention of central venous catheter (CVC)-related infections in two university hospitals. METHODS: An observational audit was conducted in 7 wards using a digital tool. RESULTS: The prerequisite of hand hygiene (HH) were respected by 90% of health-care worker; 86% performed HH prior to equipment preparation and 59% repeated it prior to infusion. Wearing gloves when necessary and rinsing were respected in 46.7% and 75.6% of the observations. CONCLUSION: Findings showed an acceptable level of adherence to recommended practices for CVC management. However, barriers of unrespect evidence-based recommendations need to be investigated in depth.

Demonstration of a Plasmonic Nonlinear Pseudodiode.

We demonstrate a nonlinear plasmonic metasurface that exhibits strongly asymmetric second-harmonic generation: nonlinear scattering is efficient upon excitation in one direction, and it is substantially suppressed when the excitation direction is reversed, thus enabling a diode-like functionality. A significant (approximately 10 dB) extinction ratio of SHG upon opposite excitations is measured experimentally, and those findings are substantiated with full-wave simulations. This effect is achieved by employing a combination of two commonly used metals─aluminum and silver─producing a material composition asymmetry that results in a bianisotropic response of the system, as confirmed by performing homogenization analysis and extracting an effective susceptibility tensor. Finally, we discuss the implications of our results from the more fundamental perspectives of reciprocity and time-reversal asymmetry.

Protein Dielectrophoresis with Gradient Array of Conductive Electrodes Sheds New Light on Empirical Theory.

Dielectrophoresis (DEP) is a versatile tool for the precise microscale manipulation of a broad range of substances. To unleash the full potential of DEP for the manipulation of complex molecular-sized particulates such as proteins requires the development of appropriate theoretical models and their comprehensive experimental verification. Here, we construct an original DEP platform and test the Hölzel-Pethig empirical model for protein DEP. Three different proteins are studied: lysozyme, BSA, and lactoferrin. Their molecular Clausius-Mossotti function is obtained by detecting their trapping event via the measurement of the fluorescence intensity to identify the minimum electric field gradient required to overcome dispersive forces. We observe a significant discrepancy with published theoretical data and, after a very careful analysis to rule out experimental errors, conclude that more sophisticated theoretical models are required for the response of molecular entities in DEP fields. The developed experimental platform, which includes arrays of sawtooth metal electrode pairs with varying gaps and produces variations of the electric field gradient, provides a versatile tool that can broaden the utilization of DEP for molecular entities.

Quadrupolar susceptibility modeling of substrated metasurfaces with application to the generalized Brewster effect.

We derive generalized sheet transition conditions (GSTCs) including dipoles and quadrupoles, using generalized functions (distributions). This derivation verifies that the GSTCs are valid for metasurfaces in non-homogeneous environments, such as for practical metasurfaces fabricated on a substrate. The inclusion of quadrupoles and modeling of spatial dispersion provides additional hyper-susceptibility components which serve as degrees of freedom for wave transformations. We leverage them to demonstrate a generalized Brewster effect with multiple angles of incidence at which reflection is suppressed, along with an "anti-Brewster" effect where transmission is suppressed.

Clinical features and outcomes of COVID-19 patients hospitalized for psychiatric disorders: a French multi-centered prospective observational study.

BACKGROUND: Patients with psychiatric disorders are exposed to high risk of COVID-19 and increased mortality. In this study, we set out to assess the clinical features and outcomes of patients with current psychiatric disorders exposed to COVID-19. METHODS: This multi-center prospective study was conducted in 22 psychiatric wards dedicated to COVID-19 inpatients between 28 February and 30 May 2020. The main outcomes were the number of patients transferred to somatic care units, the number of deaths, and the number of patients developing a confusional state. The risk factors of confusional state and transfer to somatic care units were assessed by a multivariate logistic model. The risk of death was analyzed by a univariate analysis. RESULTS: In total, 350 patients were included in the study. Overall, 24 (7%) were transferred to medicine units, 7 (2%) died, and 51 (15%) patients presented a confusional state. Severe respiratory symptoms predicted the transfer to a medicine unit [odds ratio (OR) 17.1; confidence interval (CI) 4.9-59.3]. Older age, an organic mental disorder, a confusional state, and severe respiratory symptoms predicted mortality in univariate analysis. Age >55 (OR 4.9; CI 2.1-11.4), an affective disorder (OR 4.1; CI 1.6-10.9), and severe respiratory symptoms (OR 4.6; CI 2.2-9.7) predicted a higher risk, whereas smoking (OR 0.3; CI 0.1-0.9) predicted a lower risk of a confusional state. CONCLUSION: COVID-19 patients with severe psychiatric disorders have multiple somatic comorbidities and have a risk of developing a confusional state. These data underline the need for extreme caution given the risks of COVID-19 in patients hospitalized for psychiatric disorders.

A hierarchical process model links behavioral aging and lifespan in C. elegans.

Aging involves a transition from youthful vigor to geriatric infirmity and death. Individuals who remain vigorous longer tend to live longer, and within isogenic populations of C. elegans the timing of age-associated vigorous movement cessation (VMC) is highly correlated with lifespan. Yet, many mutations and interventions in aging alter the proportion of lifespan spent moving vigorously, appearing to "uncouple" youthful vigor from lifespan. To clarify the relationship between vigorous movement cessation, death, and the physical declines that determine their timing, we developed a new version of the imaging platform called "The Lifespan Machine". This technology allows us to compare behavioral aging and lifespan at an unprecedented scale. We find that behavioral aging involves a time-dependent increase in the risk of VMC, reminiscent of the risk of death. Furthermore, we find that VMC times are inversely correlated with remaining lifespan across a wide range of genotypes and environmental conditions. Measuring and modelling a variety of lifespan-altering interventions including a new RNA-polymerase II auxin-inducible degron system, we find that vigorous movement and lifespan are best described as emerging from the interplay between at least two distinct physical declines whose rates co-vary between individuals. In this way, we highlight a crucial limitation of predictors of lifespan like VMC-in organisms experiencing multiple, distinct, age-associated physical declines, correlations between mid-life biomarkers and late-life outcomes can arise from the contextual influence of confounding factors rather than a reporting by the biomarker of a robustly predictive biological age.

Intramolecular Palladium-Catalyzed Carboamination for the Stereoselective Synthesis of Five-Membered Iminosugar C-Glycosides.

We report here a new method for the stereoselective synthesis of five-membered iminosugar C-glycosides using an intramolecular palladium-catalyzed carboamination. We have prepared efficiently two sugar-derived aminoalkenes, which were submitted to the carboamination conditions in the presence of different aryl bromides. A small library of protected iminosugars carrying a 1-C-arylmethyl substituent was obtained, and some of them were fully deprotected to yield original iminosugar C-glycosides. This methodology provides one of the shortest pathways to this family of molecules.

Synthesis of the aminocyclopentenediol fragment of queuosine by way of the stereoselective addition of an organometallic reagent to a N-t-butanesulfinyl glycosylamine.

An innovative, concise synthesis of the aminocyclopentenediol fragment of queuosine is reported. The synthesis is based on the stereocontrolled addition of a vinylGrignard·LiCl reagent to a t-butanesulfinyl L-ribofuranosylamine, followed by dehydrodeoxygenation to generate a second vinyl group and ring-closing metathesis to form the five-membered ring scaffold of the natural product. This approach has the potential for the development of a larger scale synthesis.

Trap-and-Track for Characterizing Surfactants at Interfaces.

Understanding the behavior of surfactants at interfaces is crucial for many applications in materials science and chemistry. Optical tweezers combined with trajectory analysis can become a powerful tool for investigating surfactant characteristics. In this study, we perform trap-and-track analysis to compare the behavior of cetyltrimethylammonium bromide (CTAB) and cetyltrimethylammonium chloride (CTAC) at water-glass interfaces. We use optical tweezers to trap a gold nanoparticle and statistically analyze the particle's movement in response to various surfactant concentrations, evidencing the rearrangement of surfactants adsorbed on glass surfaces. Our results show that counterions have a significant effect on surfactant behavior at the interface. The greater binding affinity of bromide ions to CTA+ micelle surfaces reduces the repulsion among surfactant head groups and enhances the mobility of micelles adsorbed on the interface. Our study provides valuable insights into the behavior of surfactants at interfaces and highlights the potential of optical tweezers for surfactant research. The development of this trap-and-track approach can have important implications for various applications, including drug delivery and nanomaterials.

SeSAM: software for automatic construction of order-robust linkage maps.

BACKGROUND: Genotyping and sequencing technologies produce increasingly large numbers of genetic markers with potentially high rates of missing or erroneous data. Therefore, the construction of linkage maps is more and more complex. Moreover, the size of segregating populations remains constrained by cost issues and is less and less commensurate with the numbers of SNPs available. Thus, guaranteeing a statistically robust marker order requires that maps include only a carefully selected subset of SNPs. RESULTS: In this context, the SeSAM software allows automatic genetic map construction using seriation and placement approaches, to produce (1) a high-robustness framework map which includes as many markers as possible while keeping the order robustness beyond a given statistical threshold, and (2) a high-density total map including the framework plus almost all polymorphic markers. During this process, care is taken to limit the impact of genotyping errors and of missing data on mapping quality. SeSAM can be used with a wide range of biparental populations including from outcrossing species for which phases are inferred on-the-fly by maximum-likelihood during map elongation. The package also includes functions to simulate data sets, convert data formats, detect putative genotyping errors, visualize data and map quality (including graphical genotypes), and merge several maps into a consensus. SeSAM is also suitable for interactive map construction, by providing lower-level functions for 2-point and multipoint EM analyses. The software is implemented in a R package including functions in C++. CONCLUSIONS: SeSAM is a fully automatic linkage mapping software designed to (1) produce a framework map as robust as desired by optimizing the selection of a subset of markers, and (2) produce a high-density map including almost all polymorphic markers. The software can be used with a wide range of biparental mapping populations including cases from outcrossing. SeSAM is freely available under a GNU GPL v3 license and works on Linux, Windows, and macOS platforms. It can be downloaded together with its user-manual and quick-start tutorial from ForgeMIA (SeSAM project) at https://forgemia.inra.fr/gqe-acep/sesam/-/releases.

Immune Profiling Demonstrates a Common Immune Signature of Delayed Acquired Immunodeficiency in Patients With Various Etiologies of Severe Injury.

OBJECTIVES: The host response plays a central role in the pathophysiology of sepsis and severe injuries. So far, no study has comprehensively described the overtime changes of the injury-induced immune profile in a large cohort of critically ill patients with different etiologies. DESIGN: Prospective observational cohort study. SETTING: Adult ICU in a University Hospital in Lyon, France. PATIENTS: Three hundred fifty-three septic, trauma, and surgical patients and 175 healthy volunteers were included in the REAnimation Low Immune Status Marker study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Extensive immune profiling was performed by assessing cellular phenotypes and functions, protein, and messenger RNA levels at days 1-2, 3-4, and 5-7 after inclusion using a panel of 30 standardized immune markers. Using this immunomonitoring panel, no specificity in the immune profile was observed among septic, trauma, and surgical patients. This common injury-induced immune response was characterized by an initial adaptive (i.e., physiologic) response engaging all constituents of the immune system (pro- and anti-inflammatory cytokine releases, and innate and adaptive immune responses) but not associated with increased risk of secondary infections. In contrary, the persistence in a subgroup of patients of profound immune alterations at the end of the first week after admission was associated with increased risk of secondary infections independently of exposure to invasive devices. The combined monitoring of markers of pro-/anti-inflammatory, innate, and adaptive immune responses allowed a better enrichment of patients with risk of secondary infections in the selected population. CONCLUSIONS: Using REAnimation Low Immune Status Marker immunomonitoring panel, we detected delayed injury-acquired immunodeficiency in a subgroup of severely injured patients independently of primary disease. Critically ill patients' immune status could be captured through the combined monitoring of a common panel of complementary markers of pro-/anti-inflammatory, innate, and adaptive immune responses. Such immune monitoring needs to be incorporated in larger study cohorts with more extensive immune surveillance to develop specific hypothesis allowing for identification of biological systems affecting altered immune function related to late infection in the setting of acute systemic injury.

Electromagnetic forces in the time domain.

We look beyond the standard time-average approach and investigate optical forces in the time domain. The formalism is developed for both the Abraham and Minkowski momenta, which appear to converge in the time domain. We unveil an extremely rich - and by far unexplored - physics associated with the dynamics of the optical forces, which can even attain negative values over short time intervals or produce low frequency dynamics that can excite mechanical oscillations in macroscopic objects under polychromatic illumination. The magnitude of this beating force is tightly linked to the average one. Implications of this work for transient optomechanics are discussed.

Tunable Approach to C-Linked Analogs of Glycosamines.

The synthesis of (1R)-2-amino-2-deoxy-ß-l-gulopyranosyl benzene and the α and ß forms of 2-amino-2-deoxy-l-idopyranosyl benzene derivatives was accomplished through stereospecific addition of tributylstannyllithium to readily available (SR)- or (SS)-N-tert-butanesulfinyl-arabinofuranosylamine building blocks, followed by stereoretentive Pd-catalyzed Migita-Kosugi-Stille cross-coupling, stereoselective reduction, and an activation-cyclization strategy. Application of this methodology paves the way to new three-dimensional chemical space and preparation of unknown (non-natural) and complex 2-amino-2-deoxy sugars of biological interest.

Pitfalls in the spectral measurements of polarization-altering metasurfaces.

The optical characterization of metasurfaces and nanostructures that alter the polarization of light is tricky and can lead to unphysical results, such as reflectance beyond unity. We track the origin of such pitfalls to the response of some typical optical components used in a commercial microscope or a custom-made setup. In particular, the beam splitter and some mirrors have different responses for both polarizations and can produce wrong results. A simple procedure is described to correct these erroneous results, based on the optical characterization of the different components in the optical setup. With this procedure, the experimental results match the numerical simulations perfectly. The methodology described here is simple and will enable the accurate spectral measurements of nanostructures and metasurfaces that alter the polarization of the incoming light.