Summary
Non‐typhoidal Salmonella enterica (NTS) are diverse and important bacterial pathogens consisting of more than 2600 different serovars, with varying host‐specificity. Here, we characterized ...the poultry‐associated serovars in Israel, analysed their resistome and illuminated the molecular mechanisms underlying common multidrug resistance (MDR) patterns. We show that at least four serovars including Infantis, Muenchen, Newport and Virchow present a strong epidemiological association between their temporal trends in poultry and humans. Worrisomely, 60% from all of the poultry isolates tested (n = 188) were multidrug resistant, mediated by chromosomal SNPs and different mobile genetics elements. A novel streptomycin‐azithromycin resistance island and previously uncharacterized versions of the mobilized Salmonella genomic island 1 (SGI1) were identified and characterized in S. Blockley and S. Kentucky isolates respectively. Moreover, we demonstrate that the acquisition of SGI1 does not impose fitness cost during growth under nutrient‐limited conditions or in the context of Salmonella infection in the mouse model. Overall, our data emphasize the role of the poultry production as a pool of specific epidemic MDR strains and autonomous genetic elements, which confer resistance to heavy metals and medically relevant antibiotics. These are likely to disseminate to humans via the food chain and fuel the increasing global antibiotic resistance crisis.
Replacement of the damaged scar tissue created by a myocardial infarction is the goal of cardiac tissue engineering. However, once the implanted tissue is in place, monitoring its function is ...difficult and involves indirect methods, while intervention necessarily requires an invasive procedure and available medical attention. To overcome this, methods of integrating electronic components into engineered tissues have been recently presented. These allow for remote monitoring of tissue function as well as intervention through stimulation and controlled drug release. Here, an improved hybrid microelectronic tissue construct capable of withstanding the dynamic environment of the beating heart without compromising electronic or mechanical functionality is reported. While the reported system is enabled to sense the function of the engineered tissue and provide stimulation for pacing, an electroactive polymer on the electronics enables it to release multiple drugs in parallel. It is envisioned that the integration of microelectronic devices into engineered tissues will provide a better way to monitor patient health from afar, as well as provide facile, more exact methods to control the healing process.
A freestanding hybrid microelectronic tissue construct capable of withstanding the motions of the heart without compromising electronic or mechanical functionality is introduced. The hybrid construct is capable of monitoring the function of the engineered cardiac tissue and providing electrical stimulation for pacing and controlled release of multiple drugs from a built in electroactive polymer.
Despite incremental improvements in the field of tissue engineering, no technology is currently available for producing completely autologous implants where both the cells and the scaffolding ...material are generated from the patient, and thus do not provoke an immune response that may lead to implant rejection. Here, a new approach is introduced to efficiently engineer any tissue type, which its differentiation cues are known, from one small tissue biopsy. Pieces of omental tissues are extracted from patients and, while the cells are reprogrammed to become induced pluripotent stem cells, the extracellular matrix is processed into an immunologically matching, thermoresponsive hydrogel. Efficient cell differentiation within a large 3D hydrogel is reported, and, as a proof of concept, the generation of functional cardiac, cortical, spinal cord, and adipogenic tissue implants is demonstrated. This versatile bioengineering approach may assist to regenerate any tissue and organ with a minimal risk for immune rejection.
Fatty tissues are extracted from patients and the cellular and a‐cellular materials are separated. While the cells are reprogrammed to induced pluripotent stem cells (iPSCs), the extracellular matrix is processed to a personalized, nonimmunogenic hydrogel. The iPSCs are encapsulated within the hydrogel and differentiated to engineer autologous cardiac, cortical, dopaminergic, spinal cord, and adipogenic implants.
In cardiac tissue engineering approaches to treat myocardial infarction, cardiac cells are seeded within three-dimensional porous scaffolds to create functional cardiac patches. However, current ...cardiac patches do not allow for online monitoring and reporting of engineered-tissue performance, and do not interfere to deliver signals for patch activation or to enable its integration with the host. Here, we report an engineered cardiac patch that integrates cardiac cells with flexible, freestanding electronics and a 3D nanocomposite scaffold. The patch exhibited robust electronic properties, enabling the recording of cellular electrical activities and the on-demand provision of electrical stimulation for synchronizing cell contraction. We also show that electroactive polymers containing biological factors can be deposited on designated electrodes to release drugs in the patch microenvironment on demand. We expect that the integration of complex electronics within cardiac patches will eventually provide therapeutic control and regulation of cardiac function.
Land plants are considered monophyletic, descending from a single successful colonization of land by an aquatic algal ancestor. The ability to survive dehydration to the point of desiccation is a key ...adaptive trait enabling terrestrialization. In extant land plants, desiccation tolerance depends on the action of the hormone abscisic acid (ABA) that acts through a receptor-signal transduction pathway comprising a PYRABACTIN RESISTANCE 1-like (PYL)–PROTEIN PHOSPHATASE 2C (PP2C)–SNF1-RELATED PROTEIN KINASE 2 (SnRK2) module. Early-diverging aeroterrestrial algae mount a dehydration response that is similar to that of land plants, but that does not depend on ABA: Although ABA synthesis is widespread among algal species, ABA-dependent responses are not detected, and algae lack an ABA-binding PYL homolog. This raises the key question of how ABA signaling arose in the earliest land plants. Here, we systematically characterized ABA receptor-like proteins from major land plant lineages, including a protein found in the algal sister lineage of land plants. We found that the algal PYL-homolog encoded by Zygnema circumcarinatum has basal, ligand-independent activity of PP2C repression, suggesting this to be an ancestral function. Similarly, a liverwort receptor possesses basal activity, but it is further activated by ABA. We propose that co-option of ABA to control a preexisting PP2C-SnRK2-dependent desiccation-tolerance pathway enabled transition from an all-or-nothing survival strategy to a hormone-modulated, competitive strategy by enabling continued growth of anatomically diversifying vascular plants in dehydrative conditions, enabling them to exploit their new environment more efficiently.
Type 1 diabetes (T1D) is a challenging autoimmune disease, characterized by an immune system assault on insulin-producing β-cells. As insulin facilitates glucose absorption into cells and tissues, ...β-cell deficiency leads to elevated blood glucose levels on one hand and target-tissues starvation on the other. Despite efforts to halt β-cell destruction and stimulate recovery, success has been limited. Our recent investigations identified Protease-Activated Receptor 2 (Par2) as a promising target in the battle against autoimmunity. We discovered that Par2 activation’s effects depend on its initial activation site: exacerbating the disease within the immune system but fostering regeneration in affected tissue.
We utilized tissue-specific Par2 knockout mice strains with targeted Par2 mutations in β-cells, lymphocytes, and the eye retina (as a control) in the NOD autoimmune diabetes model, examining T1D onset and β-cell survival.
We discovered that Par2 expression within the immune system accelerates autoimmune processes, while its presence in β-cells offers protection against β-cell destruction and T1D onset. This suggests a dual-strategy treatment for T1D: inhibiting Par2 in the immune system while activating it in β-cells, offering a promising strategy for T1D.
This study highlights Par2's potential as a drug target for autoimmune diseases, particularly T1D. Our results pave the way for precision medicine approaches in treating autoimmune conditions through targeted Par2 modulation.
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•Par2 identified as key in Type 1 diabetes, with contradicting roles.•Par2 knockout mice were used to solve Par2 functions on Type 1 diabetes.•Par2 dual modulation strategy suggested for Type 1 diabetes treatment.•Highlights Par2 as a promising therapeutic target in Type 1 diabetes.•Advances precision medicine for autoimmune diseases via Par2 dual modulation.
This paper presents a comparative study of entropy estimation in a large-alphabet regime. A variety of entropy estimators have been proposed over the years, where each estimator is designed for a ...different setup with its own strengths and caveats. As a consequence, no estimator is known to be universally better than the others. This work addresses this gap by comparing twenty-one entropy estimators in the studied regime, starting with the simplest plug-in estimator and leading up to the most recent neural network-based and polynomial approximate estimators. Our findings show that the estimators' performance highly depends on the underlying distribution. Specifically, we distinguish between three types of distributions, ranging from uniform to degenerate distributions. For each class of distribution, we recommend the most suitable estimator. Further, we propose a sample-dependent approach, which again considers three classes of distribution, and report the top-performing estimators in each class. This approach provides a data-dependent framework for choosing the desired estimator in practical setups.
ABSTRACT During the first few days after explosion, Type II supernovae (SNe) are dominated by relatively simple physics. Theoretical predictions regarding early-time SN light curves in the ...ultraviolet (UV) and optical bands are thus quite robust. We present, for the first time, a sample of 57 R-band SN II light curves that are well-monitored during their rise, with detections during the first 10 days after discovery, and a well-constrained time of explosion to within 1-3 days. We show that the energy per unit mass (E/M) can be deduced to roughly a factor of five by comparing early-time optical data to the 2011 model of Rabinak & Waxman, while the progenitor radius cannot be determined based on R-band data alone. We find that SN II explosion energies span a range of E/M = (0.2-20) × 1051 erg/(10 ), and have a mean energy per unit mass of erg/(10 ), corrected for Malmquist bias. Assuming a small spread in progenitor masses, this indicates a large intrinsic diversity in explosion energy. Moreover, E/M is positively correlated with the amount of 56Ni produced in the explosion, as predicted by some recent models of core-collapse SNe. We further present several empirical correlations. The peak magnitude is correlated with the decline rate ( ), the decline rate is weakly correlated with the rise time, and the rise time is not significantly correlated with the peak magnitude. Faster declining SNe are more luminous and have longer rise times. This limits the possible power sources for such events.
We report the discovery by the Palomar Transient Factory (PTF) of the transient source PTF11agg, which is distinguished by three primary characteristics: (1) bright, rapidly fading, optical transient ...emission; (2) a faint, blue-quiescent optical counterpart; and (3) an associated year-long, scintillating radio transient. The observed properties are all consistent with the population of long-duration gamma-ray bursts (GRBs), marking the first time such an outburst has been discovered in the distant universe independent of a high-energy trigger. We searched for possible high-energy counterparts to PTF11agg, but found no evidence for associated prompt emission. We therefore consider three possible scenarios to account for a GRB-like afterglow without a high-energy counterpart: an "untriggered" GRB, an "orphan" afterglow. While not definitive, we nonetheless speculate that PTF11agg may represent a new, more common class of relativistic outbursts lacking associated high-energy emission. If so, such sources will be uncovered in large numbers by future wide-field optical and radio transient surveys.
Most Type I superluminous supernovae (SLSNe-I) reported to date have been identified by their high peak luminosities and spectra lacking obvious signs of hydrogen. We demonstrate that these events ...can be distinguished from normal-luminosity SNe (including Type Ic events) solely from their spectra over a wide range of light-curve phases. We use this distinction to select 19 SLSNe-I and four possible SLSNe-I from the Palomar Transient Factory archive (including seven previously published objects). We present 127 new spectra of these objects and combine these with 39 previously published spectra, and we use these to discuss the average spectral properties of SLSNe-I at different spectral phases. We find that Mn ii most probably contributes to the ultraviolet spectral features after maximum light, and we give a detailed study of the O ii features that often characterize the early-time optical spectra of SLSNe-I. We discuss the velocity distribution of O ii, finding that for some SLSNe-I this can be confined to a narrow range compared to relatively large systematic velocity shifts. Mg ii and Fe ii favor higher velocities than O ii and C ii, and we briefly discuss how this may constrain power-source models. We tentatively group objects by how well they match either SN 2011ke or PTF12dam and discuss the possibility that physically distinct events may have been previously grouped together under the SLSN-I label.
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