The role of spinal GABAB receptors in cancer-induced bone pain in rats

Cancer-induced bone pain (CIBP) remains a major challenge in advanced cancer patients due to our lack of understanding of its mechanisms. Previous studies have demonstrated the vital role of GABAB receptors (GABABRs) in regulating nociception and various neuropathic pain models have shown diminished activity of GABABRs. However, the role of spinal GABABRs in CIBP remains largely unknown. In this study, we investigated the specific cellular mechanisms of GABABRs in the development and maintenance of CIBP in rats. Our behavioral results show that both acute and chronic intrathecal treatment with baclofen, a GABABR agonist, significantly attenuated CIBP-induced mechanical allodynia and ambulatory pain. The expression levels of GABABRs were significantly decreased in a time-dependent manner and colocalized mostly with neuron and a minority with astrocyte and microglia. Chronic treatment with baclofen restored the expression of GABABRs and markedly inhibited the activation of cAMP-dependent protein kinase (PKA) and the cAMP-response element-binding protein (CREB) signaling pathway

STAT1 as a downstream mediator of ERK signaling contributes to bone cancer pain by regulating MHC II expression in spinal microglia

Major histocompatibility class II (MHC II)-specific activation of CD4+ T helper cells generates specific and persistent adaptive immunity against tumors. Emerging evidence demonstrates that MHC II is also involved in basic pain perception; however, little is known regarding its role in the development of cancer-induced bone pain (CIBP). In this study, we demonstrate that MHC II expression was markedly induced on the spinal microglia of CIBP rats in response to STAT1 phosphorylation. Mechanical allodynia was ameliorated by either pharmacological or genetic inhibition of MHC II upregulation, which was also attenuated by the inhibition of pSTAT1 and pERK but was deteriorated by intrathecal injection of IFNγ. Furthermore, inhibition of ERK signaling decreased the phosphorylation of STAT1, as well as the production of MHC II in vivo and in vitro. These findings suggest that STAT1 contributes to bone cancer pain as a downstream mediator of ERK signaling by regulating MHC II expression in spinal microglia

Disruption of the GABAergic system contributes to the development of perioperative neurocognitive disorders after anesthesia and surgery in aged mice

Aims: Perioperative neurocognitive disorders (PND) are associated with cognitive impairment in the preoperative or postoperative period, and neuroinflammation is thought to be the most important mechanisms especially during the postoperative period. The GABAergic system is easily disrupted by neuroinflammation. This study investigated the impact of the GABAergic system on PND after anesthesia and surgery. Methods: An animal model of laparotomy with inhalation anesthesia in 16-month old mice was addressed. Effects of the GABAergic system were assessed using biochemical analysis. Pharmacological blocking of α5GABAARs or P38 mitogen-activated protein kinase (MAPK) was applied to investigate the effect of the GABAergic system. Results: After laparotomy, the hippocampus-dependent memory and long-term potentiation were impaired, the levels of IL-6, IL-1β and TNF-α upregulated in the hippocampus, the concentration of GABA decreased, and the protein levels of the surface α5GABAARs up-regulated. Pharmacological blocking of α5GABAARs with L655,708 alleviated laparotomy induced cognitive deficits. A further study found that the P38 MAPK signaling pathway was involved and pharmacological blocking with SB203,580 alleviated memory dysfunction. Conclusions: Anesthesia and surgery caused neuroinflammation in the hippocampus, which consequently disrupted the GABAergic system, increased the expressions of surface α5GABAARs especially through the P38 MAPK signaling pathway, and eventually led to hippocampus-dependent memory dysfunctions

A Novel Role of VEGFC in Cerebral Ischemia With Lung Injury

Cerebral ischemia (CI) is a severe brain injury resulting in a variety of motor impairments combined with secondary injury in remote organs, especially the lung. This condition occurs due to insufficient blood supply to the brain during infancy. However, it has a molecular linkage that needs to be thoroughly covered. Here, we report on the role of vascular endothelial growth factor C (VEGFC) in lung injury induced by CI. The middle cerebral artery occlusion (MCAO) was depended to establish the animal model of CI. Rats were used and brain ischemia was confirmed through TTC staining. Serum was used for protein chip analysis to study the proteomic interaction. Immunohistochemistry analyses were used to quantify and locate the VEGFC in the lung and brain. The role of VEGFC was detected by siVEGFC technology in SY5Y, HUCEV, and A549 cell lines, under normal and oxygen glucose deprivation (OGD) conditions in vitro. As a result, the TTC staining demonstrated that the model of brain ischemia was successfully established, and MPO experiments reported that lung damage was induced in MCAO rats. VEGFC levels were up-regulated in serum. On the other hand, immunohistochemistry showed that VEGFC increased significantly in the cytoplasm of neurons, the endothelium of small trachea and the lung cells of CI animals. On a functional level, siVEGFC effectively inhibited the proliferation of SY5Y cells and decreased the viability of HUVEC cells in normal cell lines. But under OGD conditions, siVEGFC decreased the growth of HUVEC and increased the viability of A549 cells, while no effect was noticed on SYSY cells. Therefore, we confirmed the different role of VEGFC played in neurons and lung cells in cerebral ischemia-reperfusion injury. These findings may contribute to the understanding the molecular linkage of brain ischemia and lung injury, which therefore provides a new idea for the therapeutic approach to cerebral ischemia-reperfusion

Selection of Pru p 3 hypoallergenic peach and nectarine varieties

To the Editor, Peach is an important fruit consumed worldwide. However, it is also one of the most frequently reported allergenic fruits.1 Component diagnosis of peach allergy indicates Pru p 1, Pru p 2, Pru p 3, Pru p 4, Pru p 7, and Pru p 9 are involved.2, 3 Pru p 3 is the dominant allergen responsible for severe allergic reaction,4 and it is considered to be the primary sensitizer to other LTPs in Mediterranean and Central Europe.5 The levels of Pru p 3 differ between varieties.6 To date, measurement of Pru p 3 in a limited number of peach and nectarines from Spain, United States, and Italy has been reported.7 Significant variation of allergen concentration in processed foods containing peach has also been observed.8 The content of Pru p 3 of peach/nectarine determines the potential risk for peach allergic patients. China is the origin of peach with representative genetic diversity to be explored for hypoallergenic varieties.9 A core collection of 103 varieties cultivated in Jiaxing, Zhejiang Province were selected to represent this diversity, including 23 nectarines and 80 peach varieties (with fruit hair, round or flat, 77 cultivated, three wild) (Table S1). The soluble solid content (SSC), ripening date, and peach aroma intensity were recorded. Specific methods are detailed in the Supporting Information. Pru p 3 was quantified by ELISA based on our previous research.6info:eu-repo/semantics/publishedVersio

Substantial transition to clean household energy mix in rural China

The household energy mix has significant impacts on human health and climate, as it contributes greatly to many health- and climate-relevant air pollutants. Compared to the well-established urban energy statistical system, the rural household energy statistical system is incomplete and is often associated with high biases. Via a nationwide investigation, this study revealed high contributions to energy supply from coal and biomass fuels in the rural household energy sector, while electricity comprised ∼20%. Stacking (the use of multiple sources of energy) is significant, and the average number of energy types was 2.8 per household. Compared to 2012, the consumption of biomass and coals in 2017 decreased by 45% and 12%, respectively, while the gas consumption amount increased by 204%. Increased gas and decreased coal consumptions were mainly in cooking, while decreased biomass was in both cooking (41%) and heating (59%). The time-sharing fraction of electricity and gases (E&G) for daily cooking grew, reaching 69% in 2017, but for space heating, traditional solid fuels were still dominant, with the national average shared fraction of E&G being only 20%. The non-uniform spatial distribution and the non-linear increase in the fraction of E&G indicated challenges to achieving universal access to modern cooking energy by 2030, particularly in less-developed rural and mountainous areas. In some non-typical heating zones, the increased share of E&G for heating was significant and largely driven by income growth, but in typical heating zones, the time-sharing fraction was <5% and was not significantly increased, except in areas with policy intervention. The intervention policy not only led to dramatic increases in the clean energy fraction for heating but also accelerated the clean cooking transition. Higher income, higher education, younger age, less energy/stove stacking and smaller family size positively impacted the clean energy transition

Ground calibration of Gamma-Ray Detectors of GECAM-C

As a new member of GECAM mission, GECAM-C (also named High Energy Burst Searcher, HEBS) was launched onboard the SATech-01 satellite on July 27th, 2022, which is capable to monitor gamma-ray transients from $\sim$ 6 keV to 6 MeV. As the main detector, there are 12 gamma-ray detectors (GRDs) equipped for GECAM-C. In order to verify the GECAM-C GRD detector performance and to validate the Monte Carlo simulations of detector response, comprehensive on-ground calibration experiments have been performed using X-ray beam and radioactive sources, including Energy-Channel relation, energy resolution, detection efficiency, SiPM voltage-gain relation and the non-uniformity of positional response. In this paper, the detailed calibration campaigns and data analysis results for GECAM-C GRDs are presented, demonstrating the excellent performance of GECAM-C GRD detectors.Comment: third versio

Synchrotron Radiation Dominates the Extremely Bright GRB 221009A

The brightest Gamma-ray burst, GRB 221009A, has spurred numerous theoretical investigations, with particular attention paid to the origins of ultra-high energy TeV photons during the prompt phase. However, analyzing the mechanism of radiation of photons in the $\sim$MeV range has been difficult because the high flux causes pile-up and saturation effects in most GRB detectors. In this letter, we present systematic modeling of the time-resolved spectra of the GRB using unsaturated data obtained from Fermi/GBM (precursor) and SATech-01/GECAM-C (main emission and flare). Our approach incorporates the synchrotron radiation model, which assumes an expanding emission region with relativistic speed and a global magnetic field that decays with radius, and successfully fits such a model to the observational data. Our results indicate that the spectra of the burst are fully in accordance with a synchrotron origin from relativistic electrons accelerated at a large emission radius. The lack of thermal emission in the prompt emission spectra supports a Poynting-flux-dominated jet composition.Comment: 12 pages, 6 figures, 2 tables. Accepted for publication in ApJ

Calibration of the Timing Performance of GECAM-C

As a new member of the Gravitational wave high-energy Electromagnetic Counterpart All-sky Monitor (GECAM) after GECAM-A and GECAM-B, GECAM-C (originally called HEBS), which was launched on board the SATech-01 satellite on July 27, 2022, aims to monitor and localize X-ray and gamma-ray transients from $\sim$ 6 keV to 6 MeV. GECAM-C utilizes a similar design to GECAM but operates in a more complex orbital environment. In this work, we utilize the secondary particles simultaneously produced by the cosmic-ray events on orbit and recorded by multiple detectors, to calibrate the relative timing accuracy between all detectors of GECAM-C. We find the result is 0.1 $\mu \rm s$, which is the highest time resolution among all GRB detectors ever flown and very helpful in timing analyses such as minimum variable timescale and spectral lags, as well as in time delay localization. Besides, we calibrate the absolute time accuracy using the one-year Crab pulsar data observed by GECAM-C and Fermi/GBM, as well as GECAM-C and GECAM-B. The results are $2.02\pm 2.26\ \mu \rm s$ and $5.82\pm 3.59\ \mu \rm s$, respectively. Finally, we investigate the spectral lag between the different energy bands of Crab pulsar observed by GECAM and GBM, which is $\sim -0.2\ {\rm \mu s\ keV^{-1}}$.Comment: submitte