The origin of different bending stiffness between double-stranded RNA and DNA revealed by magnetic tweezers and simulations.

The subtle differences in the chemical structures of double-stranded (ds) RNA and DNA lead to significant variations in their biological roles and medical implications, largely due to their distinct biophysical properties, such as bending stiffness. Although it is well known that A-form dsRNA is stiffer than B-form dsDNA under physiological salt conditions, the underlying cause of this difference remains unclear. In this study, we employ high-precision magnetic-tweezer experiments along with molecular dynamics simulations and reveal that the relative bending stiffness between dsRNA and dsDNA is primarily determined by the structure- and salt-concentration-dependent ion distribution around their helical structures. At near-physiological salt conditions, dsRNA shows a sparser ion distribution surrounding its phosphate groups compared to dsDNA, causing its greater stiffness. However, at very high monovalent salt concentrations, phosphate groups in both dsRNA and dsDNA become fully neutralized by excess ions, resulting in a similar intrinsic bending persistence length of approximately 39 nm. This similarity in intrinsic bending stiffness of dsRNA and dsDNA is coupled to the analogous fluctuations in their total groove widths and further coupled to the similar fluctuation of base-pair inclination, despite their distinct A-form and B-form helical structures.

Universality in RNA and DNA deformations induced by salt, temperature change, stretching force, and protein binding.

Nucleic acid deformations play important roles in many biological processes. The physical understanding of nucleic acid deformation by environmental stimuli is limited due to the challenge in the precise measurement of RNA and DNA deformations and the complexity of interactions in RNA and DNA. Magnetic tweezers experiments provide an excellent opportunity to precisely measure DNA and RNA twist changes induced by environmental stimuli. In this work, we applied magnetic tweezers to measure double-stranded RNA twist changes induced by salt and temperature changes. We observed RNA unwinds when lowering salt concentration, or increasing temperature. Our molecular dynamics simulations revealed the mechanism: lowering salt concentration or increasing temperature enlarges RNA major groove width, which causes twist decrease through twist-groove coupling. Combining these results with previous results, we found some universality in RNA and DNA deformations induced by three different stimuli: salt change, temperature, and stretching force. For RNA, these stimuli first modify the major groove width, which is transduced into twist change through twist-groove coupling. For DNA, these stimuli first modify diameter, which is transduced into twist change through twist-diameter coupling. Twist-groove coupling and twist-diameter coupling appear to be utilized by protein binding to reduce DNA and RNA deformation energy cost upon protein binding.

Exploring the induction of endometrial epithelial cell apoptosis in clinical-type endometritis in yaks through the cyt-c/caspase-3 signaling axis.

Endometritis is a significant contributor to reduced productivity in yaks in Tibet, China. The Cyt-c/Caspase-3 signaling axis plays a crucial role in the mitochondrial pathway that triggers cell apoptosis due to endogenous factors. In this study, we examined the endometrial epithelial tissue of yaks with endometritis using pathological examination, immunohistochemical analysis, TUNEL staining, qRT-PCR, and Western blot. The results indicated significant changes in the apoptotic factors of the Cyt-c/Caspase-3 signaling axis. The expression levels of Bak1, Bax, Cyt-c, Apaf-1, Caspase-9, and Caspase-3 were significantly increased (P < 0.05), while the expression level of Bcl-2 was significantly decreased. Immunohistochemistry results revealed significant increase in Bak1, Bax, Cyt-c, Apaf-1, Caspase-9, and Caspase-3 expression in the cytoplasm compared to the healthy group, except for Bcl-2, which showed a significant decrease. Pathological section analysis demonstrated that clinical endometritis in yaks led to structural damage, bleeding, congestion, and inflammatory cell infiltration in the endometrial epithelium. Our study findings indicated that clinical endometritis in yaks can modulate apoptosis of endometrial epithelial cells via the Cyt-c/Caspase-3 signaling pathway, resulting in different levels of damage. This research is pioneering in exploring cell apoptosis induced by clinical endometritis in yaks, offering novel insights and potential strategies for the future prevention and treatment of endometritis in yaks.

Metagenomic analysis for exploring the potential of Lactobacillus yoelii FYL1 to mitigate bacterial diarrhea and changes in the gut microbiota of juvenile yaks.

Diarrhea in calves is a common disease that results in poor nutrient absorption, poor growth and early death which leads to productivity and economic losses. Therefore, it is important to explore the methods to reduce diarrhea in yak's calves. Efficacy of lactic acid bacteria (LAB) for improvement of bacterial diarrhea is well recognized. For this purpose, two different doses (107 CFU, 1011 CFU) of Lactobacillus yoelii FYL1 isolated from yaks were fed to juvenile yaks exposed to E. coli O78. After a trial period of ten days fresh feces and intestinal contents of the experimental yaks were collected and metagenomics sequencing was performed. It was found that feeding a high dose of Lactobacillus yoelii FYL1 decreased abundance of phylum Firmicutes in the E. coli O78 infected group whereas, it was high in animals fed low dose of Lactobacillu yoelii FYL1. Results also revealed that counts of bacteria from the family Oscillospiraceae, genus Synergistes and Megasphaera were higher in control group whereas, order Bifidobacteriales and family Bifidobacteriaceae were higher in infected group. It was observed that bacterial counts for Pseudoruminococcus were significantly (P < 0.05) higher in animals of group that were given high dose of Lactobacillus yoelii FYL1 (HLAB). Compared to infected group multiple beneficial bacterial genera such as Deinococus and Clostridium were found higher in the animals that were given a low dose of Lactobacillus yoelii FYL1 (LLAB). The abundance of pathogenic bacterial genera that included Parascardovia, Bacteroides and Methanobrevibacter was decreased (P < 0.05) in the lower dose treated group. The results of functional analysis revealed that animals of LLAB had a higher metabolism of terpenoids and polyketides compared to animals of infected group. Virus annotation also presented a significant inhibitory effect of LLAB on some viruses (P < 0.05). It was concluded that L. yoelii FYL1 had an improved effect on gut microbiota of young yaks infected with E. coli O78. This experiment contributes to establish the positive effects of LAB supplementation while treating diarrhea.

Optogenetic activation of spinal microglia triggers chronic pain in mice.

Spinal microglia are highly responsive to peripheral nerve injury and are known to be a key player in pain. However, there has not been direct evidence showing that selective microglial activation in vivo is sufficient to induce chronic pain. Here, we used optogenetic approaches in microglia to address this question employing CX3CR1creER/+: R26LSL-ReaChR/+ transgenic mice, in which red-activated channelrhodopsin (ReaChR) is inducibly and specifically expressed in microglia. We found that activation of ReaChR by red light in spinal microglia evoked reliable inward currents and membrane depolarization. In vivo optogenetic activation of microglial ReaChR in the spinal cord triggered chronic pain hypersensitivity in both male and female mice. In addition, activation of microglial ReaChR up-regulated neuronal c-Fos expression and enhanced C-fiber responses. Mechanistically, ReaChR activation led to a reactive microglial phenotype with increased interleukin (IL)-1ß production, which is likely mediated by inflammasome activation and calcium elevation. IL-1 receptor antagonist (IL-1ra) was able to reverse the pain hypersensitivity and neuronal hyperactivity induced by microglial ReaChR activation. Therefore, our work demonstrates that optogenetic activation of spinal microglia is sufficient to trigger chronic pain phenotypes by increasing neuronal activity via IL-1 signaling.

Association between postoperative nadir platelet count and postoperative cardiovascular complications following septal myectomy in patients with hypertrophic cardiomyopathy: a retrospective cohort study.

BACKGROUND: Platelet count is associated with cardiovascular risk and mortality in several cardiovascular diseases, but the association of the nadir platelet counts post-septal myectomy with the cardiovascular complication risk in hypertrophic obstructive cardiomyopathy patients remains unclear. METHODS: This retrospective cohort study reviewed all adult patients who underwent septal myectomy at a single tertiary referral center over a 5-year period. Postoperative nadir platelet count was defined as the lowest platelet count in the first 4 postoperative days or until hospital discharge. The composite outcome included cardiovascular death, myocardial infarction, heart failure, malignant arrhythmia, cardiac tamponade, and major bleeding events within 30 days postoperatively. Univariable and multivariable logistic regression and restricted cubic spline models were used to assess the association between postoperative nadir platelet count and the 30-day postoperative cardiovascular complication risk. RESULTS: Among the 113 enrolled patients, 23 (20.4%) developed cardiovascular events within 30 days postoperatively. The incidence of postoperative cardiovascular complications was significantly higher in patients with a nadir platelet count ≤ 99 × 109/L than in those with a nadir platelet count > 99 × 109/L (33.3% vs. 7.1%, crude risk ratio: 4.67, 95% confidence interval: 1.69-12.85, P < 0.001). Multivariable logistic regression revealed that postoperative nadir platelet count was negatively associated with 30-day postoperative cardiovascular complications (adjusted odds ratio: 0.97; 95% confidence interval: 0.95-0.99; P = 0.005) and the association was linear (Pnonlinearity = 0.058) after full adjustment. The association between nadir platelet count and cardiovascular complications within 30 days post-surgery was consistent in all predefined subgroups (Pinteraction > 0.05). CONCLUSION: The postoperative nadir platelet count was significantly associated with the 30-day post-myectomy risk of cardiovascular complications in hypertrophic obstructive cardiomyopathy patients. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov (NCT04275544).

A role of prefrontal cortico-hypothalamic projections in wake promotion.

Ventromedial prefrontal cortex (vmPFC) processes many critical brain functions, such as decision-making, value-coding, thinking, and emotional arousal/recognition, but whether vmPFC plays a role in sleep-wake promotion circuitry is still unclear. Here, we find that photoactivation of dorsomedial hypothalamus (DMH)-projecting vmPFC neurons, their terminals, or their postsynaptic DMH neurons rapidly switches non-rapid eye movement (NREM) but not rapid eye movement sleep to wakefulness, which is blocked by photoinhibition of DMH outputs in lateral hypothalamus (LHs). Chemoactivation of DMH glutamatergic but not GABAergic neurons innervated by vmPFC promotes wakefulness and suppresses NREM sleep, whereas chemoinhibition of vmPFC projections in DMH produces opposite effects. DMH-projecting vmPFC neurons are inhibited during NREM sleep and activated during wakefulness. Thus, vmPFC neurons innervating DMH likely represent the first identified set of cerebral cortical neurons for promotion of physiological wakefulness and suppression of NREM sleep.

5-Methyl-cytosine stabilizes DNA but hinders DNA hybridization revealed by magnetic tweezers and simulations.

5-Methyl-cytosine (5mC) is one of the most important DNA modifications and plays versatile biological roles. It is well known that 5mC stabilizes DNA duplexes. However, it remains unclear how 5mC affects the kinetics of DNA melting and hybridization. Here, we studied the kinetics of unzipping and rezipping using a 502-bp DNA hairpin by single-molecule magnetic tweezers. Under constant loading rates, 5mC increases the unzipping force but counterintuitively decreases the rezipping force at various salt and temperature conditions. Under constant forces, the non-methylated DNA hops between metastable states during unzipping and rezipping, which implies low energy barriers. Surprisingly, the 5mC DNA can't rezip after fully unzipping unless much lower forces are applied, where it rezips stochastically in a one-step manner, which implies 5mC kinetically hinders DNA hybridization and high energy barriers in DNA hybridization. All-atom molecular dynamics simulations reveal that the 5mC kinetically hinders DNA hybridization due to steric effects rather than electrostatic effects caused by the additional methyl groups of cytosines. Considering the possible high speed of DNA unzipping and zipping during replication and transcription, our findings provide new insights into the biological roles of 5mC.

Association of adherence to the enhanced recovery after surgery pathway and outcomes after laparoscopic total gastrectomy.

OBJECTIVE: The current study used a composite outcome to investigate whether applying the ERAS protocol would enhance the recovery of patients undergoing laparoscopic total gastrectomy (LTG). EXPOSURES: Laparoscopic total gastrectomy and perioperative interventions were the exposure. An ERAS clinical pathway consisting of 14 items was implemented and assessed. Patients were divided into either ERAS-compliant or non-ERAS-compliant group according the adherence above 9/14 or not. MAIN OUTCOMES AND MEASURES: The primary study outcome was a composite outcome called 'optimal postoperative recovery' with the definition as below: discharge within 6 days with no sever complications and no unplanned re-operation or readmission within 30 days postoperatively. Univariate logistic regression analysis and multivariate logistic regression analysis were used to model optimal postoperative recovery and compliance, adjusting for patient-related and disease-related characteristics. RESULTS: A total of 252 patients were included in this retrospective study, 129 in the ERAS compliant group and 123 in the non-ERAS-compliant group. Of these, 79.07% of the patients in ERAS compliant group achieved optimal postoperative recovery, whereas 61.79% of patients in non-ERAS-compliant group did (P = 0.0026). The incidence of sever complications was lower in the ERAS-compliant group (1.55% vs. 6.5%, P = 0.0441). No patients in ERAS compliant group had unplanned re-operation, whereas 5.69% (7/123) of patients in non-ERAS-compliant group had (p = 0.006). The median length of the postoperative hospital stay was shorter in the in the ERAS compliant group (5.51 vs. 5.68 days, P = 0.01). Both logistic (OR 2.01, 95% CI 1.21-3.34) and stepwise regression (OR 2.07, 95% CI 1.25-3.41) analysis showed that high overall compliance with the ERAS protocol facilitated optimal recovery in such patients. In bivariate analysis of compliance for patients who had an optimal postoperative recovery, carbohydrate drinks (p = 0.0196), early oral feeding (P = 0.0043), early mobilization (P = 0.0340), and restrictive intravenous fluid administration (P < 0.0001) were significantly associated with optimal postoperative recovery. CONCLUSIONS AND RELEVANCE: Patients with higher ERAS compliance (almost 70% of the accomplishment) suffered less severe postoperative complications and were more likely to achieve optimal postoperative recovery.

Spatial and temporal alterations of developing oligodendrocytes induced by repeated sevoflurane exposure in neonatal mice.

The general anesthesia associated with long-term cognitive impairment has been causing the concern of the whole society. In particular, repeated anesthetic exposures may affect executive function, processing speed, and fine motor skills, which all directly depended on the functions of oligodendrocytes, myelin, and axons. However, the underlying mechanisms are still largely unknown. To investigate the spatial and temporal alterations in oligodendrocytes in the corpus callosum (CC) and hippocampus following repeated sevoflurane exposures (3%, for 2 h) from postnatal day 6 (P6) to P8, we used immunofluorescence, Western blot, and a battery of behavioral tests. As previously stated, we confirmed that early anesthetic exposures hampered both cognitive and motor performance during puberty in the rotarod and banes tests. Intriguingly, we discovered that the proliferation of oligodendrocyte progenitor cells (OPCs) was immediately enhanced after general anesthesia in the CC and hippocampus from P8 to P32. From P8 through P15, the overall oligodendrocyte population remained constant. However, along with the structural myelin abnormalities, the matured oligodendrocytes statistically reduced in the CC (from P15) and hippocampus (from P32). Administration of clemastine, which could induce OPC differentiation and myelin formation, significantly increased matured oligodendrocytes and promoted myelination and cognition. Collectively, we first demonstrated the bi-directional influence of early sevoflurane exposures on oligodendrocyte maturation and proliferation, which contributes to the cognitive impairment induced by general anesthesia. These findings illustrated the dynamic changes in oligodendrocytes in the developing brain following anesthetic exposures, as well as possible therapeutic strategies for multiple general anesthesia associated cognitive impairment.

Characterization, estimation of virulence and drug resistance of diarrheagenic escherichia coli (DEC) isolated from Tibetan pigs.

In this study, we collected feces of Tibetan piglets from Nyingchi area for isolation, culture, identification, virulence gene analysis and drug resistance analysis of Escherichia Coli. The results demonstrated a 41.3% isolation rate of Diarrheagenic Escherichia Coli from Tibetan pigs with the main phylogenetic groups: group A (68.6%) and group B2 (15.7%). Typical E.coli accounted for 76.5%. The highest detection rates of porcine virulence genes were E.coli heat-resistant enterotoxin STb (58.82%) and F107 fimbrial subunit (23.53%). The highest detection rates of virulence genes from Tibetan pigs were fimC (80.39%) and ompA (76.47%). A drug sensitivity test showed that Diarrheagenic Escherichia Coli from Tibetan pigs had high drug resistance rates to mezlocillin, doxycycline and gentamicin. This study comprehensively analyzed the species composition, virulence and drug resistance of Diarrheagenic Escherichia Coli from Tibetan pigs, which provided a clearer and more targeted idea for the prevention and treatment of yellow and white dysentery in Tibetan pigs in the future.

Association Between Loop Diuretics and Mortality in Patients With Cardiac Surgery-Associated Acute Kidney Injury: A Retrospective Propensity Score-Weighted Analysis.

BACKGROUND: Although loop diuretics (LDs) have been widely used in clinical practice, their effect on mortality when administered to patients experiencing cardiac surgery-associated acute kidney injury (CS-AKI) remains unknown. The study aimed to investigate the effectiveness of LD use in patients with CS-AKI. METHODS: Patients who underwent cardiac surgery with AKI were identified from the Medical Information Mart for Intensive Care III. Postoperative LD use in intensive care units (ICUs) was exposure. There were 2 primary outcome measures, the in-hospital mortality and ICU mortality; both were treated as time-to-event data and were analyzed via multivariable Cox proportional hazard models. Inverse probability weighting (IPW) was used to minimize bias. RESULTS: The study enrolled a total of 5478 patients, with a median age of 67 years, among which 2205 (40.3%) were women. The crude in-hospital and ICU mortality rates were significantly lower in the LD use group (525 of 4150 [12.7%] vs 434 of 1328 [32.7%], P < .001; 402 of 4150 [9.69%] vs 333 of 1328 [25.1%], P < .001). Adjusted hazard ratios suggested significant reductions in both in-hospital (hazard ratio [HR], 0.428; 95% confidence interval [CI], 0.374-0.489) and ICU mortality (HR, 0.278; 95% CI, 0.238-0.327). The IPW data showed a similar reduction, in-hospital mortality (HR, 0.434; 95% CI, 0.376-0.502) and ICU mortality (HR, 0.296; 95% CI, 0.251-0.349). Such association may act differently for patients with different fluid balance (P value for interaction < .001). CONCLUSIONS: LD use is associated with lower hospital and ICU mortality in CS-AKI patients in general. Patients under different conditions showed diverse responses toward such treatment indicating that personalized management is needed.

Ventral Tegmental Area Glutamatergic Neurons Facilitated Emergence From Isoflurane Anesthesia Involves Excitation of Lateral Septum γ-Aminobutyric Acid-ergic Neurons in Mice.

BACKGROUND: Ventral tegmental area (VTA) glutamatergic neurons promote wakefulness in the sleep-wake cycle; however, their roles and neural circuit mechanisms during isoflurane (ISO) anesthesia remain unclear. METHODS: Fiber photometry and in vivo electrophysiology were used to observe the changes in neuronal or terminal activity during ISO anesthesia and arousal processes. Optogenetic and anesthesia behaviors were used to investigate the effects of VTA glutamatergic neurons and their projections to the lateral septum (LS) during ISO anesthesia and arousal. Anterograde and retrograde tracings were performed to identify the connections between VTA glutamatergic neurons and the LS. RESULTS: Population activity and firing rates of VTA glutamatergic neurons decreased during ISO anesthesia (ISO: 95% confidence interval [CI], 0.83-2.06 Spikes.s-1 vs wake: 95% CI, 3.53-7.83 Spikes.s-1; P =.0001; n = 34 from 4 mice). Optogenetic activation of VTA glutamatergic neurons reduced the burst-suppression ratio in electroencephalography (laser: 95% CI, 13.09%-28.76% vs pre: 95% CI, 52.85%-71.59%; P =.0009; n = 6) and facilitated emergence (ChR2: 95% CI, 343.3-388.0 seconds vs mCherry: 95% CI, 447.6-509.8 seconds; P < .0001; n = 11/12) from ISO anesthesia. VTA glutamatergic neurons monosynaptically innervated LS γ-aminobutyric acid (GABA)-ergic neurons. The activity of VTA glutamatergic terminals in the LS decreased during ISO anesthesia, and optogenetic activation of the VTA glutamatergic terminals in the LS facilitated emergence from ISO anesthesia. Furthermore, optogenetic activation of VTA glutamatergic terminals increased the firing rates of LS γ-aminobutyric acid-ergic (GABAergic) neurons (laser: 95% CI, 0.85-4.03 Spikes.s-1 vs pre: 95% CI, 0.24-0.78 Spikes.s-1; P =.008; n = 23 from 4 mice) during ISO anesthesia. CONCLUSIONS: VTA glutamatergic neurons facilitated emergence from ISO anesthesia involving excitation of LS GABAergic neurons.

Effects of intra-operative administration of subanesthetic s-ketamine on emergence from sevoflurane anesthesia: a randomized double-blind placebo-controlled study.

BACKGROUND: Ketamine is administered in the perioperative period for its benefits in analgesia, anti-agitation and anti-depression when administered at a small dose. However, it is not clear whether the intra-operative administration of ketamine would affect emergence under sevoflurane anesthesia. To investigate this effect, we designed this trial. METHODS: In this randomized, double-blind, placebo-controlled study, we enrolled 44 female patients aged 18-60 who were scheduled to elective laparoscopic gynecological surgeries. All patients were randomly assigned to saline or s-ketamine group. In s-ketamine group, patients received 0.125 mg/kg s-ketamine 30 min after the start of surgery. In saline group, patients were administered the same volume of saline. Sevoflurane and remifentanil were used to maintain general anesthesia. The primary outcome was emergence time. We also assessed postoperative agitation, cognitive function, and delirium. In addition, we collected and analyzed prefrontal electroencephalogram (EEG) during and after general anesthesia. RESULTS: There were no significant differences in emergence time between s-ketamine group and saline group (10.80 ± 3.77 min vs. 10.00 ± 2.78 min, P = 0.457). Neither postoperative agitation (4 [3, 4] vs. 4 [3, 4], P = 0.835) nor cognitive function (25.84 ± 2.69 vs. 25.55 ± 2.19, P = 0.412) differed between groups. No postoperative delirium was observed in either group. Subanesthetic s-ketamine resulted in active EEG with decreased power of slow (-0.35 ± 1.13 dB vs. -1.63 ± 1.03 dB, P = 0.003), delta (-0.22 ± 1.11 dB vs. -1.32 ± 1.09 dB, P = 0.011) and alpha (-0.31 ± 0.71 dB vs. -1.71 ± 1.34 dB, P = 0.0003) waves and increased power of beta-gamma bands (-0.30 ± 0.89 dB vs. 4.20 ± 2.08 dB, P < 0.0001) during sevoflurane anesthesia, as well as an increased alpha peak frequency (-0.16 ± 0.48 Hz vs. 0.31 ± 0.73 Hz, P = 0.026). EEG patterns did not differ during the recovery period after emergence between groups. CONCLUSION: Ketamine administered during sevoflurane anesthesia had no apparent influence on emergence time in young and middle-aged female patients undergoing laparoscopic surgery. Subanesthetic s-ketamine induced an active prefrontal EEG pattern during sevoflurane anesthesia but did not raise neurological side effects after surgery. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR2100046479 (date: 16/05/2021).

Association of intraoperative cerebral and somatic tissue oxygen saturation with postoperative acute kidney injury in adult patients undergoing multiple valve surgery.

BACKGROUND: The association between tissue oxygenation with postoperative acute kidney injury (AKI) in adult patients undergoing multiple valve surgery has not been specifically studied. METHODS: In this prospective exploratory cohort study, 99 patients were enrolled. The left forehead, the left forearm, the left upper thigh, and the left renal region tissue oxygen saturation using near-infrared spectroscopy were monitored. The association between each threshold and AKI was assessed. The relative and absolute thresholds were < 70%, < 75%, < 80%, < 85%, < 90%, < 95%, and < 100% baseline, and baseline-standard deviation (SD), -1.5 SD, -2 SD, -2.5 SD, and -3 SD. Multivariate logistic regression analysis was adopted to explore the association. RESULTS: AKI occurred in 53 (54%) patients. The absolute value-based SrrO2 thresholds associated with AKI were baseline-3 SD (odds ratio [OR], 4.629; 95% confidence interval [CI], 1.238-17.314; P = 0.023) and baseline-2.5 SD (OR, 2.842; 95% CI, 1.025-7.881; P = 0.045) after adjusting for the potential confounders, those are renal region tissue oxygen saturation of 55% and 60%, but not statistically significant after correcting for multiple testing (corrected P = 0.114 and 0.179, respectively). CONCLUSION: The SrrO2 desaturation, defined as < baseline - 2.5 SD or < baseline - 3 SD, may be associated with AKI. The thresholds need to be verified in future large-scale studies. TRIAL REGISTRATIONS: The study was registered at ClinicalTrials.gov, first trial registration: 26/10/2017, identifier: NCT03323203.

Esketamine increases neurotransmitter releases but simplifies neurotransmitter networks in mouse prefrontal cortex.

General anesthesia induces a profound but reversible unconscious state, which is accompanied by changes in various neurotransmitters in the cortex. Unlike the "brain silencing" effect of γ-aminobutyric acid (GABA) receptor potentiator anesthesia, ketamine anesthesia leads the brain to a paradoxical active state with higher cortical activity, which is manifested as dissociative anesthesia. However, how the overall neurotransmitter network evolves across conscious states after ketamine administration remains unclear. Using in vivo microdialysis, high-performance liquid chromatography-mass spectrometry (HPLC-MS) analysis, and electroencephalogram (EEG) recording technique, we continuously measured the concentrations of six neurotransmitters and the EEG signals during anesthesia with esketamine, an S-enantiomer of ketamine racemate. We found that there was an increase in the release of five cortical neurotransmitters after the administration of esketamine. The correlation of cortical neurotransmitters was dynamically simplified along with behavioral changes until full recovery after anesthesia. The esketamine-increased gamma oscillation power was positively correlated only with the concentration of 5-hydroxytryptamine (5-HT) in the medial prefrontal cortex. This study suggests that the transformation of the neurotransmitter network rather than the concentrations of neurotransmitters could be more indicative of the consciousness shift during esketamine anesthesia.NEW & NOTEWORTHY In this study, we found that esketamine significantly increased the cortical concentration of multiple neurotransmitters in mice. However, esketamine dynamically simplified the overall network of cortical neurotransmitters at different behavioral states during the perianesthesia period. The concentration of 5-HT in the medial prefrontal cortex (mPFC) was highly correlated with the esketamine-increased gamma oscillation. These findings suggested that the transformation of the neurotransmitter network rather than the concentrations of neurotransmitters could be more indicative of the consciousness shift during esketamine anesthesia.

Pioglitazone attenuates ischaemic stroke aggravation by blocking PPARγ reduction and inhibiting chronic inflammation in diabetic mice.

Diabetes can cause vascular remodelling and is associated with worse outcome after ischaemic stroke. Pioglitazone is a commonly used anti-diabetic agent. However, it is not known whether pioglitazone use before ischaemia could reduce brain ischaemic injury. Pioglitazone was administered to 5-week-old db+ or db/db mice. Cerebral vascular remodelling was examined at the age of 9 weeks. Expression of peroxisome proliferator-activated receptor-γ (PPARγ), p-PPARγ (S112 and S273), nucleotide-binding domain (NOD)-like receptor protein 3 (Nlrp3), interleukin-1ß (IL-1ß) and tumour necrosis factor-α (TNF-α) was evaluated in the somatosensory cortex of mice. Neurological outcome was evaluated 24 h after brain ischaemia. Results showed that early pioglitazone treatment provided a long-lasting effect of euglycaemia but enhanced hyperlipidaemia in the db/db mice. Diabetic mice exhibited increased vascular tortuosity, narrower middle cerebral artery (MCA) width and IgG leakage in the brain. These changes were blocked by early pioglitazone treatment. In diabetic animals, PPARγ expression was reduced, and p-PPARγ at S273 but not S112, Nlrp3, IL-1ß and TNF-α were increased in the somatosensory cortex. PPARγ decrease and Nlrp3 increase were mainly in the neurons of the diabetic brain, which was reversed by early pioglitazone treatment. Pioglitazone attenuated the aggravated neurological outcome after stroke in diabetic mice. But this protective effect was abolished through restoring cerebral inflammation by intracerebroventricular administration of IL-1ß and TNF-α in pioglitazone-treated diabetic mice before MCAO. In summary, early pioglitazone treatment attenuates cerebral vascular remodelling and ischaemic brain injury possibly via blocking chronic neuroinflammation in the db/db mice.

Meta-analysis on the prevalence of bovine hydatid disease in China from 2000 to 2021.

Cystic Echinococcosis (hydatidosis) is caused by the larval stage of Echinococcus spp. It is an animal-borne zoonotic parasitic disease with local epidemic and natural foci, which is very common in northwest China. In recent years, a considerable attention has been paid to the epidemic investigation of hydatid disease in humans and sheep, but there are few large-scale epidemic investigation and data analysis of bovine hydatid disease. We systematically reviewed and analyzed the prevalence of bovine hydatid disease (2000-2021) in China for the first time. Several databases including CNKI, Wanfang, VIP Chinese periodical database, Baidu Library, PubMed and ScienceDirect were used to search 57 articles and 72 sets of valid data about bovine hydatid disease in China from 2000 to 2021. We used the random effect model in META package of R software, and PAS for rate conversion. The subgroup analysis and univariate meta regression analysis were used to reveal the factors leading to the heterogeneity of the study. The total prevalence rate of bovine hydatid disease in China from 2000 to 2021 is estimated to be 17.27% (10898/63113). According to the analysis of sampling years, the lowest positive rate since 2016 is 7.54% (1503/19929). The highest prevalence rate of bovine hydatid disease is 53.93% (4340/8048). The infection rate of bovine liver accounted for the highest proportion of the total infections, 45.2% (2040/4507). We also assessed the effects of different geographical and climatic factors on the prevalence of bovine hydatid disease. The results showed that the prevalence rate of hydatid disease was higher in cold and humid areas. Although the infection rate of bovine hydatid disease has declined in recent years, it is still necessary to carry out long-term surveillance and control of hydatid disease, cut off the infection route and reduce the risk of infection in high-risk areas.

Complete genome analysis of Lactobacillus fermentum YLF016 and its probiotic characteristics.

Lactobacillus fermentum (L. fermentum) YLF016 is a well-characterized probiotic with several favorable characteristics. This study aimed to analyze the probiotic characteristics of L. fermentum and uncover the genes implicated in its potential probiotic ability on the base of its genomics features. The complete genome of L. fermentum YLF016 was found to have a circular chromosome of 2,094,354 bp, and 51.46% G + C content without any plasmid. Its chromosome contained 2,130 predicted protein-encoding genes, 58 tRNA, and 15 rRNA-encoding genes. Also, it was found to have many other probiotic properties, such as a high survival rate in the gastrointestinal tract with strong adherence to intestinal cells, antibacterial activity against pathogens, and antioxidant activity. Moreover, the genome sequence analysis demonstrated specific genes coding for carbon metabolism pathway, genetic adaption, stress resistance, and adhesive ability. Further analysis revealed its non-hemolytic activity and its non-functional ability of virulence factors. In conclusion, L. fermentum YLF016 possesses many valuable probiotic properties that refer to its potential probiotic ability.

Multivalent Cations Reverse the Twist-Stretch Coupling of RNA.

When stretched, both DNA and RNA duplexes change their twist angles through twist-stretch coupling. The coupling is negative for DNA but positive for RNA, which is not yet completely understood. Here, our magnetic tweezers experiments show that the coupling of RNA reverses from positive to negative by multivalent cations. Combining with the previously reported tension-induced negative-to-positive coupling reversal of DNA, we propose a unified mechanism of the couplings of both RNA and DNA based on molecular dynamics simulations. Two deformation pathways are competing when stretched: shrinking the radius causes positive couplings but widening the major groove causes negative couplings. For RNA whose major groove is clamped by multivalent cations and canonical DNA, their radii shrink when stretched, thus exhibiting positive couplings. For elongated DNA whose radius already shrinks to the minimum and canonical RNA, their major grooves are widened when stretched, thus exhibiting negative couplings.