Upconversion-Mediated Optogenetics for the Treatment of Surgery-Induced Postoperative Neurocognitive Dysfunction.

Perioperative neurocognitive disorder (PND) is a common complication in surgical patients. While many interventions to prevent PND have been studied, the availability of treatment methods is limited. Thus, it is crucial to delve into the mechanisms of PND, pinpoint therapeutic targets, and develop effective treatment approaches. In this study, reduced dorsal tenia tecta (DTT) neuronal activity was found to be associated with tibial fracture surgery-induced PND, indicating that a neuronal excitation-inhibition (E-I) imbalance could contribute to PND. Optogenetics in the DTT brain region was conducted using upconversion nanoparticles (UCNPs) with the ability to convert 808 nm near-infrared light to visible wavelengths, which triggered the activation of excitatory neurons with minimal damage in the DTT brain region, thus improving cognitive impairment symptoms in the PND model. Moreover, this noninvasive intervention to modulate E-I imbalance showed a positive influence on mouse behavior in the Morris water maze test, which demonstrates that UCNP-mediated optogenetics is a promising tool for the treatment of neurological imbalance disorders.

The feasibility of the posterior tibial nerve-flexor hallucis brevis pathway applied in neuromuscular monitoring: a multicentric, controlled, and prospective clinical trial.

This study aimed to investigate the clinical viability of utilizing the flexor hallucis brevis as an alternative site for neuromuscular monitoring compared to the conventional adductor pollicis. Patients were recruited from three medical centers. Cis-atracurium was administered, and two monitors were employed independently to assess neuromuscular blockade of the adductor pollicis and the ipsilateral flexor hallucis brevis, following a train of four (TOF) pattern until TOF ratios exceeded 0.9 or until the conclusion of surgery. Statistical analysis revealed significant differences in onset time, duration of no-twitch response, spontaneous recovery time, and total monitoring time between the two sites, with mean differences of -53.54 s, -2.49, 3.22, and 5.89 min, respectively (P < 0.001).The posterior tibial nerve-flexor hallucis brevis pathway presents a promising alternative for neuromuscular monitoring during anesthesia maintenance. Further investigation is warranted to explore its utility in anesthesia induction and recovery. Trial registration: The trial was registered at www.chictr.org.cn (20/11/2018, ChiCTR1800019651).

Validation of the Mindray VS9 Vital Signs Monitor in a combined adult and pediatric population according to ISO Standard 81060-2:2018.

We aimed to validate the accuracy of the Mindray VS9 Vital Signs Monitor, which features the Mindray TrueBP inflation algorithm for oscillometric blood pressure (BP) measurement, to check if it complies with the International Organization for Standardization Standard (ISO 81060-2:2018) in a combined adult and pediatric population. A total of 86 participants, including both adult and pediatric subjects, were recruited. The distribution of their ages, gender, BPs and limb sizes all complied with the requirement of the ISO standard. The inflation and deflation algorithms were validated independently using the same-arm sequential BP measurement method. For each subject, the BP was first determined by two independent observers using a mercury sphygmomanometer (R1). The BP of the subject was then determined by the third observer using the test equipment (T1). Then, using a mercury sphygmomanometer, two independent observers were asked to determine the subject's BP (R2) again. R1-T1-R2 were considered a valid pair of data. This cycle continued until 3 pairs of valid data were achieved. We collected 258 pairs of valid BP data for the validation of the inflation and deflation algorithms respectively. For validation Criterion 1, the mean ± SD of the differences between the readings obtained from the test device and reference BP was 0.0 ±â€…6.6/-1.8 ±â€…7.1 mmHg (systolic/diastolic) when the deflation algorithm was used, and 2.4 ±â€…6.3/ 0.3 ±â€…6.9 mmHg (systolic/diastolic) when the inflation algorithm was used. For validation Criterion 2, the SD of the averaged BP differences between the test device and the reference BP per subject was 5.35/6.33 mmHg (systolic/diastolic) when the deflation algorithm was used, and 5.17/5.75 mmHg (systolic/diastolic) when the inflation algorithm was used. The VS9 Vital Signs Monitor fulfilled all the criteria in the ISO Standard. Moreover, the inflation algorithm had a shorter Measure Time (by 7-21 s) and lower maximum inflation pressure (by 9.7-22 mmHg). The VS9 Vital Signs Monitor fulfilled all the requirements of the ISO Standard (ISO 81060-2:2018) in a combined adult and pediatric population and is recommended for clinical use.

Ginkgolide B Blocks Vascular Remodeling after Vascular Injury via Regulating Tgfß1/Smad Signaling Pathway.

Coronary artery disease (CAD) is the most prevalent cardiovascular disease worldwide, resulting in myocardial infarction (MI) and even sudden death. Following percutaneous coronary intervention (PCI), restenosis caused by vascular remodeling is always formed at the stent implantation site. Here, we show that Ginkgolide B (GB), a naturally occurring terpene lactone, effectively suppresses vascular remodeling and subsequent restenosis in wild-type mice following left carotid artery (LCA) injury. Additional experiments reveal that GB exerts a protective effect on vascular remodeling and further restenosis through modulation of the Tgfß1/Smad signaling pathway in vivo and in human vascular smooth muscle cells (HVSMAs) but not in human umbilical vein endothelial cells (HUVECs) in vitro. Moreover, the beneficial effect of GB is abolished after incubated with pirfenidone (PFD, a drug for idiopathic pulmonary fibrosis, IPF), which can inhibit Tgfß1. In Tgfß1-/- mice, treatment with pirfenidone capsules and Yinxingneizhi Zhusheye (including Ginkgolide B) fails to improve vascular remodeling and restenosis. In conclusion, our data identify that GB could be a potential novel therapeutic agent to block vessel injury-associated vascular remodeling and further restenosis and show significant repression of Tgfß1/Smad signaling pathway.

SerpinB1 is required for Rev-erbα-mediated protection against acute lung injury induced by lipopolysaccharide-in mice.

BACKGROUND AND PURPOSE: Acute lung injury (ALI) is a serious, life-threatening inflammation of the lungs that still lacks effective treatment. We previously showed that serine protease inhibitor B1 (SerpinB1) protects against ALI induced by orthotopic autologous liver transplantation. However, the role of SerpinB1 in lipopolysaccharide (LPS)-induced ALI and its regulatory mechanisms are not known. EXPERIMENTAL APPROACH: Wild-type (WT) and SerpinB1 knockout (KO) mice were treated with intratracheal LPS stimulation to induce ALI. Some of the WT and KO mice were injected i.p. with melatonin, a rhythm-related protein Rev-erbα agonist. The circadian rhythm in WT mice was disrupted by exposing mice to 24 h of continuous dark or light conditions after intratracheal LPS. Neutrophils were isolated from alveolar lavage fluid of WT and KO mice, and from human peripheral blood. Neutrophils were treated with LPS and melatonin. KEY RESULTS: Disruption of circadian rhythm by either 24-h dark or light conditions exacerbated LPS-induced ALI and decreased expression of Rev-erbα and SerpinB1 protein in lung, whereas melatonin treatment increased SerpinB1 expression and attenuated LPS-induced ALI in WT mice, but not in KO mice. In isolated neutrophils, Rev-erbα was co-localized with SerpinB1 and bound to its promoter to trigger SerpinB1 transcription. Furthermore, LPS stimulation increased formation of neutrophil extracellular traps, which was reversed by melatonin treatment in neutrophils from WT mice, but not from KO mice. CONCLUSION AND IMPLICATIONS: In mice, SerpinB1 is rhythmically regulated by Rev-erbα, and its down-regulation exacerbates LPS-induced ALI by inducing formation of neutrophil extracellular traps.

Protective role of nitric oxide donors on endothelium in ischemia-reperfusion injury: a meta-analysis of randomized controlled trials.

BACKGROUND: Decreased bioavailability of nitric oxide (NO) under hypoxic conditions can lead to endothelial dysfunction. NO supplementation may protect endothelial function in ischemia-reperfusion (IR) injury. Therefore, a meta-analysis of randomized controlled trials (RCTs) was performed to verify the protective effect of NO donors on endothelium in IR injury. METHODS: Medline, Embase, Cochrane Library, and Web of Science databases were searched from inception to April 1, 2023. The specific inclusion criteria were as follows: (1) RCTs; (2) trials comparing NO donors with placebo control groups; and (3) trials reporting the effects of these interventions on vascular endothelial functional outcomes in IR injury. Random-effects models were used to assess pooled effect sizes, which were expressed as standardized mean differences (SMD). RESULTS: Seven studies satisfied the inclusion criteria and consisted of a total of 149 participants. NO donors were protective of endothelial function in IR injury (SMD: - 1.60; 95% confidence interval [CI]: - 2.33, - 0.88, P < 0.0001; heterogeneity [I2 = 66%, P = 0.001]). Results of the subgroup analysis showed the following: absence of protective effect of NO donor use following ischemia on endothelial function in IR injury - 1.78 (95% CI: - 2.50, - 1.07) and loss of protective effect on endothelial function after prolonged NO donor use - 0.89 (95% CI: - 2.06, 0.28). CONCLUSION: The short-period use of NO donors before the onset of ischemia can protect endothelial function in IR injury.

Intertruncal versus classical approach to the ultrasound-guided supraclavicular brachial plexus block for upper extremity surgery: study protocol for a randomized non-inferiority trial.

BACKGROUND: Ultrasound-guided intertruncal approach (IA) to the supraclavicular block (SB) is recently proposed as a new approach for local anesthetic (LA) injection in terms of the classical approach (CA) at the level of the first rib. The CA-SB has been proven to result in satisfying sensorimotor block, but associate with a high risk of intraneural injection. The aim of this randomized non-inferiority study is to explore whether IA-SB can obtain similar block dynamics, as the CA-SB, but avoiding an intraneural injection during the whole nerve block procedure. METHODS: The total 122 patients undergoing elective upper extremity surgery will be randomly allocated to receive either an IA-SB or a CA-SB using a double-injection (DI) technique. In the IA-SB group, a portion of LA (15 mL) is injected accurately to the intertruncal plane between the middle and lower trunks under real-time ultrasound guidance; then, the remaining volume (10 mL) is carefully distributed to the other intertruncal plane between the upper and middle trunks. In the CA-SB group, the DI technique will be carried out as described in Tran's study. The primary outcome is the percentage of patients with a complete sensory blockade at 20 min with a predefined non-inferiority margin of - 5%. The secondary outcomes include the sensory-motor blockade of all 4 terminal nerves, onset times of the individual nerves within 30 min, block-related variables, and adverse events. DISCUSSION: The results will provide sensory-motor blockade-related parameters and safety of the ultrasound-guided intertruncal approach to the supraclavicular block, thereby promoting clinical practice. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000040199 . Registered on 25 November 2020.

B and T lymphocyte attenuator regulates autophagy in mycobacterial infection via the AKT/mTOR signal pathway.

The survivability of Mycobacterium tuberculosis (M.tb) in macrophages in granuloma is a predominant cause for tuberculosis (TB) infection and recurrence. However, the mechanism of mycobacterial clearance in macrophages still needs further study. Here, we explored a novel role of B and T lymphocyte Attenuator (BTLA) in macrophage-mediated host defense against mycobacterial infection. We found that the surface expression of BTLA was increased in CD14+ monocytes from active TB patients. The mRNA levels of BTLA were induced in human and mice monocytes/macrophages during Mycobacterium bovis BCG or M.tb H37Rv infection, as well as spleen and lung of H37Rv-infected mice. Furthermore, silencing of BTLA promoted the intracellular survival of BCG and H37Rv by suppressing the autophagy in macrophages but not effecting phagocytosis, reactive oxygen species (ROS) and apoptosis. Silence of BTLA reduced bacterial-autophagosome and bacterial-lysosome colocalization. Moreover, BTLA inhibited AKT and mTOR signaling substrates S6K and 4EBP1 phosphorylation in BCG and H37Rv infected macrophages, and BTLA-mediated AKT-mTOR signaling and intracellular BCG survival were reversed by PI3K inhibitors in macrophages. Finally, treatment with BTLA agonist ameliorated lung pathology and promoted autophagy and mycobacterial clearance during mycobacterial infection in vivo. These results demonstrate that BTLA promotes host defense against mycobacteria by enhancing autophagy, which may provide potential therapeutic interventions against tuberculosis.

TLT2 Suppresses Th1 Response by Promoting IL-6 Production in Monocyte Through JAK/STAT3 Signal Pathway in Tuberculosis.

The function of triggering receptor expressed on myeloid cell-like transcript 2 (TLT2) has not been characterized and their role in pulmonary tuberculosis (TB) remains unclear. In this study, we found that surface TLT2 was up-regulated in human monocytes of patients with active TB compared to healthy subjects. In vitro, TLT2 expression was induced in human monocyte cell line THP-1 cells after bacillus Calmette-Guérin (BCG) or Mycobacterium tuberculosis (Mtb) H37Rv infection. Knockdown of TLT2 by siRNA transfection suppressed IL-6 expression, whereas over-expression of TLT2 increased IL-6 production in THP-1 cells infected by H37Rv. TLT2+CD14+ monocytes produced higher level of IL-6 compared to TLT2- subset in active TB patients. Western blot and immunocoprecipitation revealed that TLT2 interacted with kinase JAK1/JAK2/Tyk2 to enhance STAT3 phosphorylation. Moreover, we showed that tyrosine residues 297 and 315 of TLT2 cytoplasmic domain were involved in STAT3 activation. In monocyte/CD4+ T cell co-culture assay, blockage of TLT2 fusion protein facilitated IFN-γ production by CD4+ T cells. Plate count assay showed that monocyte-mediated bacterial killing was promoted by TLT2 fusion protein. In vivo treatment with TLT-2 fusion protein reduced IL-6 production by macrophage but increased IFN-γ production by CD4+ T cell in H37Rv and BCG infected mice. Furthermore, TLT2 fusion protein attenuated inflammation, and reduced bacterial load in lung of infected mice. Together, these findings demonstrate that TLT2 negatively regulates Th1 response against mycobacterial infection, which promotes IL-6 production through JAK/STAT3 signal pathway.

Effects of landscape heterogeneity and breeding habitat diversity on rice frog abundance and body condition in agricultural landscapes of Yangtze River Delta, China.

Amphibians play a key role in structuring biological assemblages of agricultural landscapes, but they are threatened by global agricultural intensification. Landscape structure is an important variable influencing biodiversity in agricultural landscapes. However, in the Yangtze River Delta, where a "farmland-orchard-fishpond" agricultural pattern is common, the effects of landscape construction on anuran populations are unclear. In this study, we examined the effects of agricultural landscape parameters on the abundance and body condition of the rice frog (Fejervarya multistriata), which is a dominant anuran species in farmland in China. Employing a visual encounter method, we surveyed rice frog abundance for 3 years across 20 agricultural landscapes. We also calculated the body condition index (BCI) of 188 male frog individuals from these agricultural landscapes. Landscape variables, comprising landscape compositional heterogeneity (using the Shannon diversity index of all land cover types except buildings and roads), landscape configurational heterogeneity (using landscape edge density), breeding habitat diversity (using the number of 5 waterbody types available as breeding habitats), and areas of forest were also measured for each 1-km radius landscape. We found that the amount of forest in each agricultural landscape had a significant positive relationship with rice frog abundance, and breeding habitat diversity was positively related to the BCI of male rice frogs. However, body condition was negatively impacted by landscape configurational heterogeneity. Our results suggested the importance of nonagricultural habitats in agricultural landscapes, such as waterbodies and forest, to benefit rice frog population persistence.

Inhibition of the PI3K-Akt-mTOR signaling pathway in T lymphocytes in patients with active tuberculosis.

OBJECTIVES: To investigate PI3K-Akt-mTOR signaling pathway changes and the proliferation of FoxP3+Treg cells in patients with active tuberculosis. METHODS: We isolated PBMCs and CD4+CD25+FoxP3+Treg cells from peripheral blood collected from patients with active tuberculosis and healthy controls. We compared the proportion and MFI of PI3K-Akt-mTOR pathway components and PTEN by flow cytometry using specific cell-surface and intracellular markers. Moreover, we detected the specific secretory proteins ESAT-6 and Ag85B, cytokines IL-10, TGF-ß1 and IL-35 in serum by ELISA. RESULTS: Compared with healthy controls, the proportions of CD3+Akt+, CD3+p-Akt+, CD3+mTOR+, CD3+p-mTOR+ and CD3+PTEN+ cells, in the T lymphocyte population of patients with active tuberculosis, were decreased (p<0.05), while CD3+FoxP3+ cells were increased (p=0.013). Similarly, for CD4+CD25+FoxP3+Treg cells, the proportions of Akt+ cells, p-Akt+ cells, mTOR+ cells, p-mTOR+ cells and PTEN+ cells were decreased (p<0.05) in patients with active tuberculosis. Compared with healthy controls, the levels of ESAT-6 and Ag85B were higher in patients with active tuberculosis (p<0.001). Levels of IL-10 and TGF-ß1 were higher (p<0.001), whereas the level of IL-35 was lower (p<0.001). CONCLUSION: The PI3K-Akt-mTOR signaling pathway in T lymphocytes and CD4+CD25+FoxP3+Treg cells was inhibited, which could explain why M.tuberculosis can induce FoxP3+Treg cell to expand.

Intestinal NF-E2-related factor-2 expression and antioxidant activity changes in rats undergoing orthotopic liver autotransplantation.

Liver transplantation is known to trigger intestinal injuries. Oxidative damage that is induced by reactive oxygen species (ROS) plays a crucial role in ischemia-reperfusion injuries. NF-E2-related factor-2 (Nrf2) and its modulated antioxidant enzymes form the critical endogenous antioxidant system to scavenge ROS. The present study investigated the dynamic changes of intestinal ROS levels, Nrf2 expression and antioxidant enzyme activity following orthotopic liver autotransplantation (OLAT). Sprague-Dawley rats were randomly divided into five groups consisting of one sham group and four groups with rats that underwent OLAT and were evaluated following 4, 8, 16 and 24 h, respectively. The intestinal specimens were collected for histopathological examination and the detection of hydrogen peroxide (H2O2), hydroxyl radical (•OH), malondialdehyde (MDA), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) levels and the expression of Nrf2. The present study demonstrated that OLAT resulted in severe intestinal injury, which manifested as a significant change in the intestine pathological scores as early as 4 h and peaking at 8 h post-treatment. Oxidative stress was also revealed by the increase of the H2O2, •OH and MDA levels. Significant decreases were observed in the activity of SOD and CAT and a dramatic decrease occurred in the levels of GSH at 4 and 8 h post-treatment. All the parameters were restored gradually at 16 and 24 h post-treatment. The expression of Nrf2 in the intestinal tissues increased significantly at 4, 16 and 24 h following OLAT. The present study shows that an imbalance between oxidants and antioxidants contributes to intestinal oxidative injury, and that the upregulation of Nrf2 is not sufficient to withstand intestinal oxidative injury following OLAT.