The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an unprecedented public health crisis. Because of the novelty ...of the virus, there are currently no SARS-CoV-2-specific treatments or vaccines available. Therefore, rapid development of effective vaccines against SARS-CoV-2 are urgently needed. Here, we developed a pilot-scale production of PiCoVacc, a purified inactivated SARS-CoV-2 virus vaccine candidate, which induced SARS-CoV-2-specific neutralizing antibodies in mice, rats, and nonhuman primates. These antibodies neutralized 10 representative SARS-CoV-2 strains, suggesting a possible broader neutralizing ability against other strains. Three immunizations using two different doses, 3 or 6 micrograms per dose, provided partial or complete protection in macaques against SARS-CoV-2 challenge, respectively, without observable antibody-dependent enhancement of infection. These data support the clinical development and testing of PiCoVacc for use in humans.
Oxytocin (OT) is a great facilitator of social life but, although its effects on socially relevant brain regions have been extensively studied, OT neuron activity during actual social interactions ...remains unexplored. Most OT neurons are magnocellular neurons, which simultaneously project to the pituitary and forebrain regions involved in social behaviors. In the present study, we show that a much smaller population of OT neurons, parvocellular neurons that do not project to the pituitary but synapse onto magnocellular neurons, is preferentially activated by somatosensory stimuli. This activation is transmitted to the larger population of magnocellular neurons, which consequently show coordinated increases in their activity during social interactions between virgin female rats. Selectively activating these parvocellular neurons promotes social motivation, whereas inhibiting them reduces social interactions. Thus, parvocellular OT neurons receive particular inputs to control social behavior by coordinating the responses of the much larger population of magnocellular OT neurons.
Integrin-mediated force application induces a conformational change in latent TGF-β1 that leads to the release of the active form of the growth factor from the extracellular matrix (ECM). Mechanical ...activation of TGF-β1 is currently understood as an acute process that depends on the contractile force of cells. However, we show that ECM remodeling, preceding the activation step, mechanically primes latent TGF-β1 akin to loading a mechanical spring. Cell-based assays and unique strain devices were used to produce a cell-derived ECM of controlled organization and prestrain. Mechanically conditioned ECM served as a substrate to measure the efficacy of TGF-β1 activation after cell contraction or direct force application using magnetic microbeads. The release of active TGF-β1 was always higher from prestrained ECM as compared with unorganized and/or relaxed ECM. The finding that ECM prestrain regulates the bioavailability of TGF-β1 is important to understand the context of diseases that involve excessive ECM remodeling, such as fibrosis or cancer.
Hexavalent chromium (Cr(VI)), the most toxic valence state of chromium, is widely present in industrial effluents and wastes. Although previous study has reported that Cr(VI) can cause cytomembrane ...structure impairment by aggravating lipid peroxidation in the heart, the detailed mechanism of Cr(VI)-induced heart dysfunction is still unclear. Sesn2, a novel antioxidant and stress-inducible molecule, is evidenced to protect against various cardiometabolic diseases such as atherosclerosis and cardiomyopathy. To define the potential mechanism of heart dysfunction induced by chronic Cr(VI) exposure, Wistar rats were intraperitoneal injected with potassium dichromate (K2Cr2O7) for 35 d in the present study. The data showed that chronic K2Cr2O7 exposure caused dose-dependently hematological variations, oxidative stress, dysfunction, and disorganized structure of heart, cardiomyocyte apoptosis, ATP depletion, and mitochondria impairment in rats. In addition, the expressions of Drp1 and Bax were increased by K2Cr2O7. However, the suppression of Mfn2, PGC-1α, Sesn2, nuclear Nrf2, HO-1, and NQO1 protein levels was observed in K2Cr2O7-treated rat hearts. In conclusion, these results demonstrate that chronic K2Cr2O7 exposure dose-dependently causes heart dysfunction, and the molecular mechanism of this event is associated with the loss of Sesn2 mediated mitochondrial function and energy supply impairment.
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•Chronic exposure to Cr(VI) dose-dependently induces heart dysfunction in rats.•ATP depletion and mitochondria impairment take part in Cr(VI)-induced heart injury.•Chronic exposure to Cr(VI) inhibits Sesn2 activity in rat heart.•Inhibition of Sesn2 induces impairment of mitochondrial function and energy supply.
Hexavalent chromium induced heart dysfunction via Sesn2-mediated impairment of mitochondrial function and energy supply.
Abstract Hydrogel-based bioadhesives have emerged as alternatives for sutureless wound closure, since they can mimic the composition and physicochemical properties of the extracellular matrix. ...However, they are often associated with poor mechanical properties, low adhesion to native tissues, and lack antimicrobial properties. Herein, a new sprayable, elastic, and biocompatible composite hydrogel, with broad-spectrum antimicrobial activity, for the treatment of chronic wounds is reported. The composite hydrogels were engineered using two ECM-derived biopolymers, gelatin methacryloyl (GelMA) and methacryloyl-substituted recombinant human tropoelastin (MeTro). MeTro/GelMA composite hydrogel adhesives were formed via visible light-induced crosslinking. Additionally, the antimicrobial peptide Tet213 was conjugated to the hydrogels, instilling antimicrobial activity against Gram (+) and (−) bacteria. The physical properties (e.g. porosity, degradability, swellability, mechanical, and adhesive properties) of the engineered hydrogel can be fine-tuned by varying the ratio of MeTro/GelMA and the final polymer concentration. The hydrogels supported in vitro mammalian cellular growth in both two-dimensional and three dimensional cultures. The subcutaneous implantation of the hydrogels in rats confirmed their biocompatibility and biodegradation in vivo . The engineered MeTro/GelMA-Tet213 hydrogels can be used for sutureless wound closure strategies to prevent infection and promote healing of chronic wounds.
Metal–organic frameworks (MOFs) are a class of hybrid materials self-assembled from organic bridging ligands and metal ion/cluster connecting points. The combination of a variety of organic linkers, ...metal ions/clusters, and structural motifs can lead to an infinite array of new materials with interesting properties for many applications. In this Forum Article, we discuss the design and applications of MOFs in chemical sensing and biological imaging. The first half of this article focuses on the development of MOFs as chemical sensors by highlighting how unique attributes of MOFs can be utilized to enhance sensitivity and selectivity. We also discuss some of the issues that need to be addressed in order to develop practically useful MOF sensors. The second half of this article focuses on the design and applications of nanoscale MOFs (NMOFs) as imaging contrast agents. NMOFs possess several interesting attributes, such as high cargo loading capacity, ease of postmodification, tunable size and shape, and intrinsic biodegradability, to make them excellent candidates as imaging contrast agents. We discuss the use of representative NMOFs in magnetic resonance imaging (MRI), X-ray computed tomography (CT), and optical imaging. Although still in their infancy, we believe that the compositional tunability and mild synthetic conditions of NMOF imaging agents should greatly facilitate their further development for clinical translation.
Life on Earth emerged in a hydrogen sulfide (H2S)-rich environment eons ago and with it protein persulfidation mediated by H2S evolved as a signaling mechanism. Protein persulfidation ...(S-sulfhydration) is a post-translational modification of reactive cysteine residues, which modulate protein structure and/or function. Persulfides are difficult to label and study due to their reactivity and similarity with cysteine. Here, we report a facile strategy for chemoselective persulfide bioconjugation using dimedone-based probes, to achieve highly selective, rapid, and robust persulfide labeling in biological samples with broad utility. Using this method, we show persulfidation is an evolutionarily conserved modification and waves of persulfidation are employed by cells to resolve sulfenylation and prevent irreversible cysteine overoxidation preserving protein function. We report an age-associated decline in persulfidation that is conserved across evolutionary boundaries. Accordingly, dietary or pharmacological interventions to increase persulfidation associate with increased longevity and improved capacity to cope with stress stimuli.
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•Dimedone Switch method is a versatile, chemoselective persulfide labeling approach•Protein persulfidation is an evolutionarily conserved modification of cysteine thiols•Persulfidation waves rescue cysteines from overoxidation caused by ROS•Persulfidation decreases with aging, increases with caloric restriction, and extends lifespan
Zivanovic et al. develop a robust method for chemoselective persulfide labeling using dimedone-based probes to show that persulfidation is an evolutionarily conserved post-translational modification used by the cells to protect proteins from overoxidation caused by different stressors. Higher persulfidation levels, caused by pharmacological or dietary interventions, lead to better resistance to oxidative stress and longer life.
Key points
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The diversity of cellular targets of direct current stimulation (DCS), including somas, dendrites and axon terminals, determine the modulation of synaptic efficacy.
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Axon terminals of ...cortical pyramidal neurons are two–three times more susceptible to polarization than somas.
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DCS in humans results in current flow dominantly parallel to the cortical surface, which in animal models of cortical stimulation results in synaptic pathway‐specific modulation of neuronal excitability.
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These results suggest that somatic polarization together with axon terminal polarization may be important for synaptic pathway‐specific modulation of DCS, which underlies modulation of neuronal excitability during transcranial DCS.
Transcranial direct current stimulation (tDCS) is a non‐invasive brain stimulation technique to modulate cortical excitability. Although increased/decreased excitability under the anode/cathode electrode is nominally associated with membrane depolarization/hyperpolarization, which cellular compartments (somas, dendrites, axons and their terminals) mediate changes in cortical excitability remains unaddressed. Here we consider the acute effects of DCS on excitatory synaptic efficacy. Using multi‐scale computational models and rat cortical brain slices, we show the following. (1) Typical tDCS montages produce predominantly tangential (relative to the cortical surface) direction currents (4–12 times radial direction currents), even directly under electrodes. (2) Radial current flow (parallel to the somatodendritic axis) modulates synaptic efficacy consistent with somatic polarization, with depolarization facilitating synaptic efficacy. (3) Tangential current flow (perpendicular to the somatodendritic axis) modulates synaptic efficacy acutely (during stimulation) in an afferent pathway‐specific manner that is consistent with terminal polarization, with hyperpolarization facilitating synaptic efficacy. (4) Maximal polarization during uniform DCS is expected at distal (the branch length is more than three times the membrane length constant) synaptic terminals, independent of and two–three times more susceptible than pyramidal neuron somas. We conclude that during acute DCS the cellular targets responsible for modulation of synaptic efficacy are concurrently somata and axon terminals, with the direction of cortical current flow determining the relative influence.
Transplanted multipotent mesenchymal stromal cells (MSCs) improve functional recovery in rats after traumatic brain injury (TBI). In this study the authors tested a novel hypothesis that systemic ...administration of cell-free exosomes generated from MSCs promotes functional recovery and neurovascular remodeling in rats after TBI.
Two groups of 8 Wistar rats were subjected to TBI, followed 24 hours later by tail vein injection of 100 μg protein of exosomes derived from MSCs or an equal volume of vehicle (phosphate-buffered saline). A third group of 8 rats was used as sham-injured, sham-treated controls. To evaluate cognitive and sensorimotor functional recovery, the modified Morris water maze, modified Neurological Severity Score, and foot-fault tests were performed. Animals were killed at 35 days after TBI. Histopathological and immunohistochemical analyses were performed for measurements of lesion volume, neurovascular remodeling (angiogenesis and neurogenesis), and neuroinflammation.
Compared with the saline-treated group, exosome-treated rats with TBI showed significant improvement in spatial learning at 34-35 days as measured by the modified Morris water maze test (p < 0.05), and sensorimotor functional recovery (i.e., reduced neurological deficits and foot-fault frequency) was observed at 14-35 days postinjury (p < 0.05). Exosome treatment significantly increased the number of newly generated endothelial cells in the lesion boundary zone and dentate gyrus and significantly increased the number of newly formed immature and mature neurons in the dentate gyrus as well as reducing neuroinflammation.
The authors demonstrate for the first time that MSC-generated exosomes effectively improve functional recovery, at least in part, by promoting endogenous angiogenesis and neurogenesis and by reducing inflammation in rats after TBI. Thus, MSC-generated exosomes may provide a novel cell-free therapy for TBI and possibly for other neurological diseases.
Periprosthetic infection is considered the main cause of implant failure, which is expected to be solved by fabricating an antibacterial coating on the surface of the implant. Nevertheless, systemic ...antibiotic treatment still represents the mainstream method for preventing infection, and few antibacterial coatings are applied clinically. This is because the externally introduced traditional antibacterial coatings suffer from the risk of invalidation and tissue toxicity induced by the consumption of antibacterial agents, degradation, and shedding. In this work, we proposed a rapid photo-sonotherapy by creating an oxygen deficiency on a titanium (Ti) implant through sulfur (S)-doping (Ti–S–TiO2–x ), which endowed the implants with great sonodynamic and photothermal ability. Without introducing an external antibacterial coating, it reached a high antibacterial efficiency of 99.995% against Staphylococcus aureus under 15 min near-infrared light and ultrasound treatments. Furthermore, bone infection was successfully treated after combination treatments, and improved osseointegration was observed. Importantly, the S-doped Ti implant immersed in water for 6 months showed an unchanged structure and properties, suggesting that the Ti implant with intrinsic modification showed stable antibacterial performance under exogenous stimuli with a high antibacterial performance in vivo. This photo-sonotherapy based on sulfur doping is also promising for cancer therapy with biosafety.
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