In response to replication hindrances, DNA replication forks frequently stall and are remodelled into a four-way junction. In such a structure the annealed nascent strand is thought to resemble a DNA ...double-strand break and remodelled forks are vulnerable to nuclease attack by MRE11 and DNA2. Proteins that promote the recruitment, loading and stabilisation of RAD51 onto single-stranded DNA for homology search and strand exchange in homologous recombination (HR) repair and inter-strand cross-link repair also act to set up RAD51-mediated protection of nascent DNA at stalled replication forks. However, despite the similarities of these pathways, several lines of evidence indicate that fork protection is not simply analogous to the RAD51 loading step of HR. Protection of stalled forks not only requires separate functions of a number of recombination proteins, but also utilises nucleases important for the resection steps of HR in alternative ways. Here we discuss how fork protection arises and how its differences with HR give insights into the differing contexts of these two pathways.
The integrity of genomes is constantly threatened by problems encountered by the replication fork. BRCA1, BRCA2 and a subset of Fanconi anaemia proteins protect stalled replication forks from ...degradation by nucleases, through pathways that involve RAD51. The contribution and regulation of BRCA1 in replication fork protection, and how this role relates to its role in homologous recombination, is unclear. Here we show that BRCA1 in complex with BARD1, and not the canonical BRCA1-PALB2 interaction, is required for fork protection. BRCA1-BARD1 is regulated by a conformational change mediated by the phosphorylation-directed prolyl isomerase PIN1. PIN1 activity enhances BRCA1-BARD1 interaction with RAD51, thereby increasing the presence of RAD51 at stalled replication structures. We identify genetic variants of BRCA1-BARD1 in patients with cancer that exhibit poor protection of nascent strands but retain homologous recombination proficiency, thus defining domains of BRCA1-BARD1 that are required for fork protection and associated with cancer development. Together, these findings reveal a BRCA1-mediated pathway that governs replication fork protection.
The ability to differentiate stimuli predicting positive or negative outcomes is critical for survival, and perturbations of emotional processing underlie many psychiatric disease states. Synaptic ...plasticity in the basolateral amygdala complex (BLA) mediates the acquisition of associative memories, both positive and negative. Different populations of BLA neurons may encode fearful or rewarding associations, but the identifying features of these populations and the synaptic mechanisms of differentiating positive and negative emotional valence have remained unknown. Here we show that BLA neurons projecting to the nucleus accumbens (NAc projectors) or the centromedial amygdala (CeM projectors) undergo opposing synaptic changes following fear or reward conditioning. We find that photostimulation of NAc projectors supports positive reinforcement while photostimulation of CeM projectors mediates negative reinforcement. Photoinhibition of CeM projectors impairs fear conditioning and enhances reward conditioning. We characterize these functionally distinct neuronal populations by comparing their electrophysiological, morphological and genetic features. Overall, we provide a mechanistic explanation for the representation of positive and negative associations within the amygdala.
Over the past decade, carbon dots have ignited a burst of interest in many different fields, including nanomedicine, solar energy, optoelectronics, energy storage, and sensing applications, owing to ...their excellent photoluminescence properties and the easiness to modify their optical properties through doping and functionalization. In this review, the synthesis, structural and optical properties, as well as photoluminescence mechanisms of carbon dots are first reviewed and summarized. Then, we describe a series of designs for carbon dot-based sensors and the different sensing mechanisms associated with them. Thereafter, we elaborate on recent research advances on carbon dot-based sensors for the selective and sensitive detection of a wide range of analytes, including heavy metals, cations, anions, biomolecules, biomarkers, nitroaromatic explosives, pollutants, vitamins, and drugs. Lastly, we provide a concluding perspective on the overall status, challenges, and future directions for the use of carbon dots in real-life sensing.
This work reports an interferometric optical microfiber sensor functionalized with nitrogen- and sulfur-codoped carbon dots (CDs) for the detection of ferric ions (Fe3+). Compared to other CD-based ...ferric ion sensors, the sensing mechanism of this presented sensor is dependent on the refractive index modulations due to selective Fe3+ adsorption onto the CD binding sites at the tapered region. This is the first study in which CD-based sensing was performed at the solid phase as a chelator, which does not rely on its fluorescence properties. The detection performance of the proposed sensor is not only comparable to a conventional fluorescence-based CD nanoprobe sensor but also capable of delivering quantitative analysis results and ease of translation to a sensor device for on-site detection. The presented sensor exhibits Fe3+ detection sensitivity of 0.0061 nm/(μg/L) in the linear detection range between 0 and 300 μg/L and a detection limit of 0.77 μg/L based on the Langmuir isotherm model. Finally, the potential use of the CD-functionalized optical microfiber sensor in the real environmental and biological Fe3+ monitoring applications has also been validated in this work.
•The working mechanisms and practical applications of SERS-based ultrasensitive detection are illustrated.•A systematic classification on the recent multiple strategies for ultra-high SERS detection ...sensitivity is presented.•A detailed analysis on the up-to-date applications in vitro and in vivo is outlined.•Optimal reference guidelines for specific detection or monitoring of analytes in highly diluted solutions are highlighted.
Ultrasensitive detection of chemicals and biological analytes in trace or single molecular level is highly desirable in both scientific and technological fields, e.g., analytical chemistry, life science, materials science, biomedical diagnostics, and forensic science, etc. With high sensitivity, high specificity, narrow line-widths, and multiplexed non-destructive testing capabilities, surface enhanced Raman scattering (SERS)-based sensing is the most promising approach to monitor targeted analytes in the vicinity of nanostructured surface. An insight into the recent advances of SERS-based ultrasensitive sensing platform can provide an effective reference guideline to develop an optimal detection approach for arising real-world applications. Many SERS-based review articles mainly focus on the fundamental theory of SERS, nanostructured plasmonic SERS sensors, and single molecule SERS detection. However, no comprehensive review article targeting SERS-based ultrasensitive detection strategies, their working mechanisms and illustrative practical applications has been reported yet. Hence, it is important to project the latest SERS-based ultrasensitive detection research in a review, which will present a reference guideline to develop an optimal detection approach for specific detection or monitoring of analytes in highly diluted solutions. We present a systematic classification and discussion on the recent multiple strategies to achieve ultra-high SERS detection sensitivity. We also outline a detailed analysis on the up-to-date applications in vitro and in vivo. Finally, we also discuss a new trend in SERS-based ultrasensitive sensing applications.
Recently, carbon allotropes have received tremendous research interest and paved a new avenue for optical fiber sensing technology. Carbon allotropes exhibit unique sensing properties such as large ...surface to volume ratios, biocompatibility, and they can serve as molecule enrichers. Meanwhile, optical fibers possess a high degree of surface modification versatility that enables the incorporation of carbon allotropes as the functional coating for a wide range of detection tasks. Moreover, the combination of carbon allotropes and optical fibers also yields high sensitivity and specificity to monitor target molecules in the vicinity of the nanocoating surface. In this review, the development of carbon allotropes-based optical fiber sensors is studied. The first section provides an overview of four different types of carbon allotropes, including carbon nanotubes, carbon dots, graphene, and nanodiamonds. The second section discusses the synthesis approaches used to prepare these carbon allotropes, followed by some deposition techniques to functionalize the surface of the optical fiber, and the associated sensing mechanisms. Numerous applications that have benefitted from carbon allotrope-based optical fiber sensors such as temperature, strain, volatile organic compounds and biosensing applications are reviewed and summarized. Finally, a concluding section highlighting the technological deficiencies, challenges, and suggestions to overcome them is presented.
Among the hallmark phenotypes reported in individuals with fragile X syndrome (FXS) are deficits in attentional function, inhibitory control, and cognitive flexibility, a set of cognitive skills ...thought to be associated with the prefrontal cortex (PFC). However, despite substantial clinical research into these core deficits, the PFC has received surprisingly little attention in preclinical research, particularly in animal models of FXS. In this study, we sought to investigate the molecular, cellular, and behavioral consequences of the loss of the fragile X mental retardation protein in the PFC of Fmr1 KO mice, a mouse model of FXS. We identify a robust cognitive impairment in these mice that may be related to the deficits in cognitive flexibility observed in individuals with FXS. In addition, we report that levels of proteins involved in synaptic function, including the NMDA receptor subunits NR1, NR2A, and NR2B; the scaffolding proteins PSD-95 and SAPAP3; and the plasticity-related gene Arc, are decreased in the prefrontal cortex of Fmr1 KO mice and are partly correlated with behavioral performance. Finally, we report that expression of c-Fos, a marker of neuronal activity, is decreased in the PFC of Fmr1 KO mice. Together, these data suggest that Fmr1 KO mice may represent a valuable animal model for the PFC-associated molecular, cellular, and behavioral abnormalities in FXS and that this model may be useful for testing the efficacy of therapeutic strategies aimed at treating the cognitive impairments in FXS.
Views on the clinical presentation and symptomatology of celiac disease have evolved alongside advances in disease detection and understanding of disease pathogenesis. Although historically regarded ...as a pediatric illness characterized by malabsorption, it is now better viewed as an immune illness of gluten-specific T cells with systemic manifestations affecting all ages. Its broad presentation, including frequent extraintestinal manifestations and asymptomatic disease, contributes to suboptimal disease detection. Adverse symptoms greatly impact patient quality of life and can result from chronic gluten exposure in untreated disease or those poorly responsive to the gluten-free diet. They can also present as acute symptoms after episodic gluten exposure. Functional gastrointestinal disease is a common comorbidity. Biomarkers like interleukin-2 that are highly sensitive and specific for celiac disease highlight a role for gluten-specific T cells in acute gluten symptomatology. A mechanistic understanding of symptoms will inform approaches to better measure and treat them effectively.
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