Dominant activities of fear engram cells in the dorsal dentate gyrus underlie fear generalization in mice.

Over-generalized fear is a maladaptive response to harmless stimuli or situations characteristic of posttraumatic stress disorder (PTSD) and other anxiety disorders. The dorsal dentate gyrus (dDG) contains engram cells that play a crucial role in accurate memory retrieval. However, the coordination mechanism of neuronal subpopulations within the dDG network during fear generalization is not well understood. Here, with the Tet-off system combined with immunostaining and two-photon calcium imaging, we report that dDG fear engram cells labeled in the conditioned context constitutes a significantly higher proportion of dDG neurons activated in a similar context where mice show generalized fear. The activation of these dDG fear engram cells encoding the conditioned context is both sufficient and necessary for inducing fear generalization in the similar context. Activities of mossy cells in the ventral dentate gyrus (vMCs) are significantly suppressed in mice showing fear generalization in a similar context, and activating the vMCs-dDG pathway suppresses generalized but not conditioned fear. Finally, modifying fear memory engrams in the dDG with "safety" signals effectively rescues fear generalization. These findings reveal that the competitive advantage of dDG engram cells underlies fear generalization, which can be rescued by activating the vMCs-dDG pathway or modifying fear memory engrams, and provide novel insights into the dDG network as the neuronal basis of fear generalization.

Alternate levels versus all levels mini-plate fixation in C3-6 cervical laminoplasty: a retrospective comparative study.

OBJECTIVE: The purpose of this study is to compare radiological and clinical outcomes between alternate levels (C4 and C6) and all levels mini-plate fixation in C3-6 unilateral open-door laminoplasty. METHODS: Ninety-six patients who underwent C3-6 unilateral open-door laminoplasty with alternate levels mini-plate fixation (54 patients in group A) or all levels mini-plate fixation (42 patients in group B) between September 2014 and September 2019 were reviewed in this study. Radiologic and clinical outcomes were assessed. Clinical results included Visual Analogue Scale (VAS) of axial neck pain and Japanese Orthopedic Association (JOA) score. Radiographic results included cervical range of motion (ROM), cervical curvature index (CCI), and the spinal canal expansive parameters including open angle, anteroposterior diameter (APD), and Pavlov`s ratio. RESULTS: There was no significant difference in VAS, JOA score, ROM, and CCI between two groups. There was no significant difference in canal expansion postoperatively between two groups. However, open angle, APD, and Pavlov`s ratio in group A decreased significantly during the follow-up. In group B, APD, Pavlov`s ratio, and open angle were maintained until the final follow-up. There was no hardware failure or lamina reclosure occurred in both groups during the follow-up. The mean cost of group B was higher than that of group A. CONCLUSIONS: Despite the differences in the maintenance of canal expansion, alternate levels mini-plate fixation can achieve similar clinical outcomes as all levels mini-plate fixation in C3-6 unilateral open-door laminoplasty. As evidenced in this study, we believe C3-6 laminoplasty with alternate levels (C4 and C6) mini-plate fixation is an economical, effective, and safe treatment method.

Biocompatible Electrical and Optical Interfaces for Implantable Sensors and Devices.

Implantable bioelectronics hold tremendous potential in the field of healthcare, yet the performance of these systems heavily relies on the interfaces between artificial machines and living tissues. In this paper, we discuss the recent developments of tethered interfaces, as well as those of non-tethered interfaces. Among them, systems that study neural activity receive significant attention due to their innovative developments and high relevance in contemporary research, but other functional types of interface systems are also explored to provide a comprehensive overview of the field. We also analyze the key considerations, including perforation site selection, fixing strategies, long-term retention, and wireless communication, highlighting the challenges and opportunities with stable, effective, and biocompatible interfaces. Furthermore, we propose a primitive model of biocompatible electrical and optical interfaces for implantable systems, which simultaneously possesses biocompatibility, stability, and convenience. Finally, we point out the future directions of interfacing strategies.

Deep brain stimulation in the lateral habenula reverses local neuronal hyperactivity and ameliorates depression-like behaviors in rats.

Deep brain stimulation (DBS) is a promising therapy for treatment-resistant depression, while mechanisms underlying its therapeutic effects remain poorly defined. Increasing evidence has revealed an intimate association between the lateral habenula (LHb) and major depression, and suggests that the LHb might be an effective target of DBS therapy for depression. Here, we found that DBS in the LHb effectively decreased depression-like behaviors in rats experienced with chronic unpredictable mild stress (CUMS), a well-accepted paradigm for modeling depression in rodents. In vivo electrophysiological recording unveiled that CUMS increased neuronal burst firing, as well as the proportion of neurons showing hyperactivity to aversive stimuli in the LHb. Nevertheless, DBS downregulated local field potential power, reversed the CUMS-induced increase of LHb burst firing and neuronal hyperactivity to aversive stimuli, and decreased the coherence between LHb and ventral tegmental area (VTA). Our results demonstrate that DBS in the LHb exerts antidepressant-like effects and reverses local neural hyperactivity, supporting the LHb as a target of DBS therapy for depression.

Advances in Natural Polymer-Based Transdermal Drug Delivery Systems for Tumor Therapy.

As an alternative to traditional oral and intravenous injections with limited efficacy, transdermal drug delivery (TDD) has shown great promise in tumor treatment. Over the past decade, natural polymers have been designed into various nanocarriers due to their excellent biocompatibility, biodegradability, and easy availability, providing more options for TDD. In addition, surface functionalization modification of the rich functional groups of natural polymers, which in turn are developed into targeted and stimulus-responsive functional materials, allows precise delivery of drugs to tumor sites and release of drugs in response to specific stimuli. It not only improves the treatment efficiency of tumor but also reduces the toxic and side effects to normal tissues. Therefore, the development of natural polymer-based TDD (NPTDD) systems has great potential in tumor therapy. In this review, the mechanism of NPTDD systems such as penetration enhancers, nanoparticles, microneedles, hydrogels and nanofibers prepared from hyaluronic acid, chitosan, sodium alginate, cellulose, heparin and protein, and their applications in tumor therapy are overviewed. This review also outlines the future prospects and current challenges of NPTDD systems for local treatment tumors.

Subharmonic instabilities in Kerr microcombs.

We report experimental observation of subharmonic mode excitation in primary Kerr optical frequency combs generated using crystalline whispering-gallery mode resonators. We show that the subcombs can be controlled and span a single or multiple free spectral ranges around the primary comb modes. In the spatial domain, the resulting multiscale combs correspond to an amplitude modulation of intracavity roll patterns. We perform a theoretical analysis based on eigenvalue decomposition that evidences the mechanism leading to the excitation of these combs.

Research on Development 3D Ground Penetrating Radar Acquisition and Control Technology for Road Underground Diseases with Dual-Band Antenna Arrays.

This paper describes the development of a new 3D ground-penetrating radar (GPR) acquisition and control technology for road underground diseases with dual-band antenna arrays. The 3D GPR system can be mounted on a vehicle-loading device and used by vehicles to detect road underground diseases at regular speeds. Compared with existing 3D GPR systems, this new type of 3D GPR has the following design features: it has dual-band antenna arrays, including a 16-channel 400 MHz antenna array and an 8-channel 200 MHz antenna array, which not only improves the detection efficiency, but also effectively balances the detection depth and detection resolution. A novel antenna switching method for time division step multiplexing (TDSM) is realized via field programmable gate array (FPGA), which not only avoids the crosstalk of antenna echo signals of different frequencies, but also ensures the interval of the same antenna working time. By combining the advantages of the FPGA and micro-control unit (MCU), and utilizing the high-speed transmission of the network port, the high-speed real-time transmission of the 3D GPR echo data is achieved. Finally, the integration of all software and hardware verified the correctness of the system, with good results.

HCN2 Channels in the Ventral Hippocampal CA1 Regulate Nociceptive Hypersensitivity in Mice.

Chronic pain is a significant health problem worldwide. Recent evidence has suggested that the ventral hippocampus is dysfunctional in humans and rodents, with decreased neuronal excitability and connectivity with other brain regions, parallel pain chronicity, and persistent nociceptive hypersensitivity. But the molecular mechanisms underlying hippocampal modulation of pain remain poorly elucidated. In this study, we used ex vivo whole-cell patch-clamp recording, immunofluorescence staining, and behavioral tests to examine whether hyperpolarization-activated cyclic nucleotide-gated channels 2 (HCN2) in the ventral hippocampal CA1 (vCA1) were involved in regulating nociceptive perception and CFA-induced inflammatory pain in mice. Reduced sag potential and firing rate of action potentials were observed in vCA1 pyramidal neurons from CFA-injected mice. Moreover, the expression of HCN2, but not HCN1, in vCA1 decreased in mice injected with CFA. HCN2 knockdown in vCA1 pyramidal neurons induced thermal hypersensitivity, whereas overexpression of HCN2 alleviated thermal hyperalgesia induced by intraplantar injection of CFA in mice. Our findings suggest that HCN2 in the vCA1 plays an active role in pain modulation and could be a promising target for the treatment of chronic pain.

The impact of climate disaster on international trade: Evidence from developed and developing countries.

A climate disaster can be devastating, but its challenges and losses provide some opportunities to other countries. Therefore, in this paper, we examine the impact of climate risk on international trade with a particular focus on developed and developing countries. Using a large sample of 160 countries between 2006 and 2019, we find that climate disaster is positively associated with high international trade. An increase in the climate disaster index will lead to an increase of about 5.9% in imports as a proportion of GDP. This is significant given that the mean of imports of the sample countries is 48%. Regarding the flow of trade, importation is likely to increase by about 6.7% and export to decrease by 0.65% after the occurrence of climate disasters in developing countries. Conversely, we did not find significant changes in imports and a weak association with exports for developed countries. We attribute this differential impact of climate disasters between developed and developing countries to the preparedness and risk mitigation mechanism in developed countries. The result suggests that the long-term effect of climate disasters increasing overall international trade is due to increasing imports in developing countries. Additional analyses demonstrate the robustness of these results to different model specifications and measurements of variables. Our results imply that climate change and its associated natural disasters offer more trade opportunities for developed countries than developing countries, highlighting the climate injustices between the high and low climate change contributors.

Suppression of ventral hippocampal CA1 pyramidal neuronal activities enhances water intake.

Thirst is an important interoceptive response and drives water consumption. The hippocampus actively modulates food intake and energy metabolism, but direct evidence for the exact role of the hippocampus in modulating drinking behaviors is lacking. We observed decreased number of c-Fos-positive neurons in the ventral hippocampal CA1 (vCA1) after water restriction or hypertonic saline injection in rats. Suppressed vCA1 neuronal activities under the hypertonic state were further confirmed with in vivo electrophysiological recording, and the level of suppression paralleled both the duration and the total amount of water consumption. Chemogenetic inhibition of vCA1 pyramidal neurons increased water consumption in rats injected with both normal and hypertonic saline. These findings suggest that suppression of vCA1 pyramidal neuronal activities enhances water intake.

On-Chip Cell-Cell Interaction Monitoring at Single-Cell Level by Efficient Immobilization of Multiple Cells in Adjustable Quantities.

In recent decades, cell immobilization using microfluidic chips has facilitated significant advancements in biological analyses at the single-cell level. However, the efficient capture of multiple cells as a cluster in adjustable quantities for cell-cell interaction has not been achieved. In this paper, aiming to monitor the cell-cell interaction at the single-cell level, we proposed a novel method for the efficient immobilization of adjustable quantities of cells on the basis of passive hydrodynamics so that different cell-cell interaction patterns could be generated. Experiments were conducted to characterize the key geometric parameters of the chip to optimize the efficiency of trapping different quantities of cells. In the microfluidic chips optimized for immobilizing one to five cells, the trapping success rates (TSRs) were up to 97%, 87%, 84%, 58%, and 54%, respectively. Furthermore, the throughput was over 200 cells min-1 with a minimum cell density of 350 cells mm-2. Finally, in the experiments of applying the proposed multicell immobilization chips to cell-cell interaction monitoring, calcein-AM transfer between multiple cells under different patterns has been studied through quantifying the local fluorescent intensity. The results demonstrated that the proposed method could be a promising opportunity in the widening field of biological research at the single-cell level.

Topology-Controlled Photonic Cavity Based on the Near-Conservation of the Valley Degree of Freedom.

We demonstrate a novel path to localizing topologically nontrivial photonic edge modes along their propagation direction. Our approach is based on the near-conservation of the photonic valley degree of freedom associated with valley-polarized edge states. When the edge state is reflected from a judiciously oriented mirror, its optical energy is localized at the mirror surface because of an extended time delay required for valley index flipping. The degree of energy localization at the resulting topology-controlled photonic cavity is determined by the valley-flipping time, which is in turn controlled by the geometry of the mirror. Intuitive analytic descriptions of the "leaky" and closed topology-controlled photonic cavities are presented, and two specific designs-one for the microwave and the other for the optical spectral ranges-are proposed.

Correlation between the migration scale index and the number of new confirmed coronavirus disease 2019 cases in China.

In late December 2019, patients of atypical pneumonia due to an unidentified microbial agent were reported in Wuhan, Hubei Province, China. Subsequently, a novel coronavirus was identified as the causative pathogen which was named SARS-CoV-2. As of 12 February 2020, more than 44 000 cases of SARS-CoV-2 infection have been confirmed in China and continue to expand. Provinces, municipalities and autonomous regions of China have launched first-level response to major public health emergencies one after another from 23 January 2020, which means restricting movement of people among provinces, municipalities and autonomous regions. The aim of this study was to explore the correlation between the migration scale index and the number of confirmed coronavirus disease 2019 (COVID-19) cases and to depict the effect of restricting population movement. In this study, Excel 2010 was used to demonstrate the temporal distribution at the day level and SPSS 23.0 was used to analyse the correlation between the migration scale index and the number of confirmed COVID-19 cases. We found that since 23 January 2020, Wuhan migration scale index has dropped significantly and since 26 January 2020, Hubei province migration scale index has dropped significantly. New confirmed COVID-19 cases per day in China except for Wuhan gradually increased since 24 January 2020, and showed a downward trend from 6 February 2020. New confirmed COVID-19 cases per day in China except for Hubei province gradually increased since 24 January 2020, and maintained at a high level from 24 January 2020 to 4 February 2020, then showed a downward trend. Wuhan migration scale index from 9 January to 22 January, 10 January to 23 January and 11 January to 24 January was correlated with the number of new confirmed COVID-19 cases per day in China except for Wuhan from 22 January to 4 February. Hubei province migration scale index from 10 January to 23 January and 11 January to 24 January was correlated with the number of new confirmed COVID-19 cases per day in China except for Hubei province from 22 January to 4 February. Our findings suggested that people who left Wuhan from 9 January to 22 January, and those who left Hubei province from 10 January to 24 January, led to the outbreak in the rest of China. The 'Wuhan lockdown' and the launching of the first-level response to this major public health emergency may have had a good effect on controlling the COVID-19 epidemic. Although new COVID-19 cases continued to be confirmed in China outside Wuhan and Hubei provinces, in our opinion, these are second-generation cases.

A novel fluorescent probe based on naphthalimide for imaging nitroreductase (NTR) in bacteria and cells.

A nitroreductase (NTR) responsive fluorescent probe, Na-NO2, comprising p-nitrobenzyl as the unique recognition group and 1,8-naphthalimide as fluorophore, was synthesized. Na-NO2 showed remarkable fluorescence "turn-on" signal in the presence of NTR under DMSO/H2O (1:19, v/v) buffered with PBS (pH = 7) solution in the presence of NADH (300 µM). Furthermore, the probe has a low detection limit down to 3.4 ng/mL and it is very sensitive towards the NTR in Escherichia coli (E. coli), Staphylococcus aureus (S. aureus), normal and tumor cells such as HL-7702, HepG-2 and MCF-7.

Anterior cingulate cortex modulates the affective-motivative dimension of hyperosmolality-induced thirst.

Neuroimaging studies have shown that the anterior cingulate cortex (ACC) is consistently activated by thirst and may underlie the affective motivation of drinking behaviour demanded by thirst. But direct evidence for this hypothesis is lacking. The present study evaluated potential correlations between ACC neuronal activity and drinking behaviour in rats injected with different concentrations of saline. We observed an increased number of c-Fos-positive neurons in the ACC after injection of hypertonic saline, indicating strong ACC neuronal activation under hyperosmotic thirst. Increased firing rates of putative ACC pyramidal neurons preceded drinking behaviour and positively correlated with both the total duration of drinking and the total amount of water consumed. Chemogenetic inhibition of ACC pyramidal neurons changed drinking behaviour from an explosive and short-lasting pattern to a gradual but more persistent pattern, without affecting either the total duration of drinking or the total amount of water consumed. Together, these findings support a role of the ACC in modulating the affective-motivative dimension of hyperosmolality-induced thirst.

GSH-responsive anti-mitotic cell penetrating peptide-linked podophyllotoxin conjugate for improving water solubility and targeted synergistic drug delivery.

Podophyllotoxin (PPT) is a chemotherapeutic agent which has shown significant anti-cancer effects through inhibiting microtubule assembly. However, because of the poor water solubility and obvious side effects, PPT cannot be used in clinical cancer therapy. In order to solve these problems, a novel glutathione-responsive PPT conjugate has been synthesized in which PPT was linked to an anti-mitotic cell penetrating peptide (PRA) via a disulfide linkage. In particular, the as-prepared PPT-PRA conjugate can self-assemble into vesicle in water, furthermore, another anti-cancer drug (doxorubicin was chosen as an example) can be loaded in the vesicle for synergistic drug delivery. For better cancer cells targeting, the vesicle was then modified with folic acid (FA). The results indicated that the as-prepared FA modified drug-loaded vesicle not only could overcome the poor water solubility and side effects of PPT but also exhibited targeted toxicity and synergistic therapeutic effect.

In Situ Formation of Homogeneous Tellurium Nanodots in Paclitaxel-Loaded MgAl Layered Double Hydroxide Gated Mesoporous Silica Nanoparticles for Synergistic Chemo/PDT/PTT Trimode Combinatorial Therapy.

A folic acid (FA) functional drug delivery system (MT@L-PTX@FA) based on in situ formation of tellurium nanodots (Te NDs) in paclitaxel (PTX)-loaded MgAl layered double hydroxide (LDHs) gated mesoporous silica nanoparticles (MSNs) has been designed and fabricated for targeted chemo/PDT/PTT trimode combinatorial therapy. X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HRTEM), N2 adsorption-desorption, Fourier transform infrared (FT-IR) spectra, and UV-vis spectra were used to demonstrate the successful fabrication of MT@L-PTX@FA. In particular, the in situ generated Te NDs showed a homogeneous ultrasmall size. Reactive oxygen species (ROS) generation, photothermal effects, and photostability evaluations indicated that the in situ generated homogeneous Te NDs could serve as the phototherapeutic agent, converting the photon energy to ROS and heat under near-infrared (NIR) irradiation efficiently. The drug-release test revealed that MT@L-PTX@FA showed an apparent sustained release character in a pH-sensitive manner. In addition, cell imaging experiments demonstrated that MT@L-PTX@FA could selectively enter into cancer cells owing to the function of FA and release of PTX efficiently for chemotherapy for the reason that the low intracellular pH would dissolve MgAl LDHs to Mg2+ and Al3+. Cytotoxicity tests also indicated that MT@L-PTX@FA exhibited enhanced therapeutic effect in cancer cells under NIR irradiation, benefiting from the synergy based on targeted chemo/PDT/PTT trimode combinatorial therapy. The preliminary results reported here will shed new light on the future design and applications of nanosystems for synergistic combinatorial therapy.

Adult Hippocampal Neurogenesis along the Dorsoventral Axis Contributes Differentially to Environmental Enrichment Combined with Voluntary Exercise in Alleviating Chronic Inflammatory Pain in Mice.

Cognitive behavioral therapy, such as environmental enrichment combined with voluntary exercise (EE-VEx), is under active investigation as an adjunct to pharmaceutical treatment for chronic pain. However, the effectiveness and underlying mechanisms of EE-VEx remain unclear. In mice with intraplantar injection of complete Freund's adjuvant, our results revealed that EE-VEx alleviated perceptual, affective, and cognitive dimensions of chronic inflammatory pain. These effects of EE-VEx on chronic pain were contingent on the occurrence of adult neurogenesis in the dentate gyrus in a functionally dissociated manner along the dorsoventral axis: neurogenesis in the ventral dentate gyrus participated in alleviating perceptual and affective components of chronic pain by EE-VEx, whereas neurogenesis in the dorsal dentate gyrus was involved in EE-VEx's cognitive-enhancing effects. Chronic inflammatory pain was accompanied by decreased levels of brain-derived neurotrophic factor (BDNF) in the dentate gyrus, which were reversed by EE-VEx. Overexpression of BDNF in the dentate gyrus mimicked the effects of EE-VEx. Our results demonstrate distinct contribution of adult hippocampal neurogenesis along the dorsoventral axis to EE-VEx's beneficial effects on different dimensions of chronic pain.SIGNIFICANCE STATEMENT Environmental enrichment combined with voluntary exercise (EE-VEx) is under active investigation as an adjunct to pharmaceutical treatment for chronic pain, but its effectiveness and underlying mechanisms remain unclear. In a mouse model of inflammatory pain, the present study demonstrates that the beneficial effects of EE-VEx on chronic pain depend on adult neurogenesis with a dorsoventral dissociation along the hippocampal axis. Adult neurogenesis in the ventral dentate gyrus participates in alleviating perceptual and affective components of chronic pain by EE-VEx, whereas that in the dorsal pole is involved in EE-VEx's cognitive-enhancing effects in chronic pain.

Increased expression of CaV3.2 T-type calcium channels in damaged DRG neurons contributes to neuropathic pain in rats with spared nerve injury.

Ion channels are very important in the peripheral sensitization in neuropathic pain. Our present study aims to investigate the possible contribution of CaV3.2 T-type calcium channels in damaged dorsal root ganglion neurons in neuropathic pain. We established a neuropathic pain model of rats with spared nerve injury. In these model rats, it was easy to distinguish damaged dorsal root ganglion neurons (of tibial nerve and common peroneal nerve) from intact dorsal root ganglion neurons (of sural nerves). Our results showed that CaV3.2 protein expression increased in medium-sized neurons from the damaged dorsal root ganglions but not in the intact ones. With whole cell patch clamp recording technique, it was found that after-depolarizing amplitudes of the damaged medium-sized dorsal root ganglion neurons increased significantly at membrane potentials of -85 mV and -95 mV. These results indicate a functional up-regulation of CaV3.2 T-type calcium channels in the damaged medium-sized neurons after spared nerve injury. Behaviorally, blockade of CaV3.2 with antisense oligodeoxynucleotides could significantly reverse mechanical allodynia. These results suggest that CaV3.2 T-type calcium channels in damaged medium-sized dorsal root ganglion neurons might contribute to neuropathic pain after peripheral nerve injury.

A Rhodamine B-based fluorescent probe for imaging Cu2+ in maize roots.

A new Rhodamine B-based fluorescent probe (RBO) is successfully designed and synthesized, which is a higher selective and sensitive chemosensor for Cu2+ than other ions. Under physiological conditions (pH = 7.0), the non emission RBO displays a rapid fluorescence increase together with a color change after addition of Cu2+ and the detection limit is down to 28nM, which can clearly illustrate the distribution of Cu2+ with the help of laser scanning confocal microscope in plant tissues. Eventually, it confirmed that the Cu2+ accumulates mostly in the vascular cylinder and very less in the epidermal cells of maize roots, which is important to understand how the plants take up, transport and store in the Cu2+.