Circuit-specific gene therapy reverses core symptoms in a primate Parkinson's disease model.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder. Its symptoms are typically treated with levodopa or dopamine receptor agonists, but its action lacks specificity due to the wide distribution of dopamine receptors in the central nervous system and periphery. Here, we report the development of a gene therapy strategy to selectively manipulate PD-affected circuitry. Targeting striatal D1 medium spiny neurons (MSNs), whose activity is chronically suppressed in PD, we engineered a therapeutic strategy comprised of a highly efficient retrograde adeno-associated virus (AAV), promoter elements with strong D1-MSN activity, and a chemogenetic effector to enable precise D1-MSN activation after systemic ligand administration. Application of this therapeutic approach rescues locomotion, tremor, and motor skill defects in both mouse and primate models of PD, supporting the feasibility of targeted circuit modulation tools for the treatment of PD in humans.

Tim-3 regulates the immunosuppressive function of decidual MDSCs via the Fyn-STAT3-C/EBPß pathway during Toxoplasma gondii infection.

Myeloid-derived suppressor cells (MDSCs) play a key role in maintaining maternal-fetal tolerance for a successful pregnancy, but the role of MDSCs in abnormal pregnancy caused by Toxoplasma gondii infection is unknown. Herein, we revealed a distinct mechanism by which T-cell immunoglobulin domain and mucin domain containing protein-3 (Tim-3), an immune checkpoint receptor that balances maternal-fetal tolerance during pregnancy, contributes to the immunosuppressive function of MDSCs during T. gondii infection. The expression of Tim-3 in decidual MDSCs was significantly downregulated following T. gondii infection. The proportion of monocytic MDSCs population, the inhibitory effect of MDSCs on T-cell proliferation, the levels of STAT3 phosphorylation, and the expression of functional molecules (Arg-1 and IL-10) in MDSCs were all decreased in T. gondii-infected pregnant Tim-3 gene knockout (Tim-3KO) mice compared with infected pregnant WT mice. After treatment with Tim-3-neutralizing Ab in vitro, the expression levels of Arg-1, IL-10, C/EBPß, and p-STAT3 were decreased, the interaction between Fyn and Tim-3 or between Fyn and STAT3 was weakened, and the binding ability of C/EBPß to the promoters of ARG1 and IL10 was decreased in human decidual MDSCs with T. gondii infection, while opposite results were observed following treatment with galectin-9 (a ligand for Tim-3). Inhibitors of Fyn and STAT3 also downregulated the expression of Arg-1 and IL-10 in decidual MDSCs and exacerbated adverse pregnancy outcomes caused by T. gondii infection in mice. Therefore, our studies discovered that the decrease of Tim-3 after T. gondii infection could downregulate the functional molecules of Arg-1 and IL-10 expression in decidual MDSCs through the Fyn-STAT3-C/EBPß signaling pathway and weaken their immunosuppressive function, which eventually contribute to the development of adverse pregnancy outcomes.

LncRNA LINC01703 promotes the proliferation, migration, and invasion of colorectal cancer by activating PI3K/AKT pathway.

The role of LINC01703 in cancers, especially in colorectal cancer (CRC), is still largely unclear. Bioinformatics prediction, real-time quantitative polymerase chain reaction (RT-qPCR), 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assay, colony formation assay, Transwell assays, in vivo animal experiments, IF, luciferase reporter assay, and Western blot were carried out for the exploration of the potential involvement and underlying molecular mechanisms of LINC01703 in CRC cells. The results showed that LINC01703 appeared upregulated in CRC and was linked to poor prognosis. LINC01703 acted as an oncogene in both in vitro and in vivo CRC cell environments. LINC01703 activated the PI3K/AKT signaling pathway by mediating the miR-205-5p/E2F1 axis in CRC. In summary, LINC01703 possesses an oncogenic function and can be a possible biomarker or target to treat CRC.

Virtual reality treatment could reduce anxiety for women undergoing cesarean section with spinal anesthesia: a randomized controlled trial.

PURPOSE: Cesarean section may result in adverse psychosocial and behavioral outcomes because women put considerable emphasis on the process of birth. Virtual reality treatment has been shown by many studies to reduce anxiety and improve patient satisfaction. Therefore, we designed a randomized controlled trial to investigate whether the application of virtual reality technology during cesarean section can reduce maternal anxiety and improve satisfaction. METHODS: We recruited 128 women undergoing elective cesarean delivery with proposed spinal anesthesia and randomly assigned them to either virtual reality or routine care. The virtual reality intervention was a virtual reality program tailored specifically for women undergoing cesarean section. Primary outcome was the change in anxiety score (change = preoperative-intraoperative score). Secondary outcomes included patient satisfaction score, requirement of intraoperative sedative and analgesic drugs, and respiratory rate. RESULTS: The change in anxiety score in the virtual reality group was significantly higher than that in the routine care group (30 [20, 47.5] vs 10 [- 10, 23.8], respectively; P < 0.001, with Hodges-Lehmann median difference estimate of 20 (95% confidence interval CI, 15-30)). There were no significant differences between the two groups in patient satisfaction scores, the requirement of intraoperative sedative and analgesic drugs, and respiratory rate and side effects. CONCLUSION: Virtual reality treatment could reduce the anxiety of women undergoing elective cesarean section, which is beneficial to the mother and baby. Trial registration This study was registered at the Chinese Clinical Trial Registry (ChiCTR2200061936) on July 11, 2022, and can be reached at https://www.chictr.org.cn/showprojEN.html?proj=173329.

Potential of metagenomic next-generation sequencing in detecting infections of ICU patients.

BACKGROUND: Due to the limitations of traditional microbiological detection techniques in evaluating complicated infections in ICU patients, it is necessary to explore novel and effective methods to improve the clinical detection of ICU patients' infections. OBJECTIVE: This study aimed to evaluate the efficiency and specificity of mNGS in screening pathogens in the blood, deep phlegm, urine, and other sample types of ICU patients exploring an effective method for infection detection. METHODS: A total of 56 ICU patients with 131 samples were included in this study. The sample types included blood, deep phlegm, urine, drainage, anal swabs, and other types. Samples were analyzed by both conventional detection method and mNGS tests. The diagnosis efficiency and consistency of the two methods were compared. The distribution of the identified pathogens was analyzed. Moreover, the clinical features of patients with mNGS-positive or mNGS-negative results were compared. RESULTS: The positive rate of mNGS was 81.7% (107/131) including 3.1% (4/131) weakly positive, while the positive rate of traditional detection was only 30.5%, including 29 strong positive results and 11 weak positive results. Additionally, there were 41 patients chose to adjust anti-infection strategies according to the results of mNGS, which significantly saved treatment costs. The mNGS-positive patients showed a shorter ICU hospitalization and higher intention to adjust anti-infection strategies than the mNGS-negative patients. CONCLUSION: mNGS is of great potential for the pathogen detection of ICU patients, and has a higher detection rate than traditional detection methods. Further clinical application investigations can be carried out to expand the application of mNGS.

Risk factors associated with intraoperative shivering during caesarean section: a prospective nested case-control study.

BACKGROUND: To study the incidence and risk factors of shivering in pregnant women during cesarean section. METHODS: We performed a prospective nested case-control study involving parturients scheduled for cesarean sections between July 2018 and May 2021. The overall incidence of intraoperative shivering and its potential risk factors were investigated. The potential risk factors evaluated were pain, anxiety, emergency surgery, transfer from the delivery room, epidural labor analgesia, membrane rupture, labor, and the timing of the surgery. Shivering and body temperature at different time points during the cesarean section were also recorded. The selected seven time points were: entering the operating room, post-anesthesia, post-disinfection, post-delivery, post-oxytocin, post additional hysterotonics, and before leaving the operating room. RESULTS: We analyzed 212 cesarean section parturients. The overall incidence of shivering was 89 (42.0%). Multivariate logistic regression showed that anxiety, emergency delivery, and transfer from the delivery room to the operating room increased the overall shivering incidence (odds ratio = 1.77, 2.90, and 3.83, respectively). The peak shivering incidence occurred after skin disinfection (63, 29.7%), and the lowest body temperature occurred after oxytocin treatment (36.24 ± 0.30 °C). Stratified analysis of surgery origin showed that emergency delivery was a risk factor for shivering (odds ratio = 2.99) in women transferred from the obstetric ward to the operating room. CONCLUSION: Shivering occurred frequently during cesarean sections, with the peak incidence occurring after skin disinfection. Anxiety, emergency delivery, and transfer from the delivery room to the operating room increased the risk of shivering development during cesarean sections. TRIAL REGISTRATION: The study protocol was registered online at China Clinical Registration Center (registration number: ChiCTR-ROC-17010532, Registered on 29 January 2017).

Prenatal Exposure to Ketamine Leads to Anxiety-Like Behaviors and Dysfunction in Bed Nucleus of Stria Terminalis.

BACKGROUND: Both the clinical and preclinical studies have suggested embryonic or infant exposure to ketamine, a general anesthetic, pose a great threat to the developing brain. However, it remains unclear how ketamine may contribute to the brain dysfunctions. METHODS: A mouse model of prenatal exposure to ketamine was generated by i.m. injection and continuous i.p. infusion of pregnant mice. Open field test and elevated plus maze test were used to analyze the behavioral alterations induced by ketamine. Immunostaining by c-Fos was used to map the neuron activity. Chemogenetic modulation of the neurons was used to rescue the abnormal neuron activity and behaviors. RESULTS: Here we show that mice prenatally exposed to ketamine displayed anxiety-like behaviors during adulthood, but not during puberty. C-Fos immunostaining identified abnormal neuronal activity in Bed Nucleus of the Stria Terminalis, the silencing of which by chemogenetics restores the anxiety-like behaviors. CONCLUSIONS: Taken together, these results demonstrate a circuitry mechanism of ketamine-induced anxiety-like behaviors.

Effect of epidural analgesia in trial of labor after cesarean on maternal and neonatal outcomes in China: a multicenter, prospective cohort study.

BACKGROUND: The trial of labor after cesarean section (TOLAC) is a relatively new technique in mainland of China, and epidural analgesia is one of the risk factors for uterine rupture. This study aimed to evaluate the effect of epidural analgesia on primary labor outcome [success rate of vaginal birth after cesarean (VBAC)], parturient complications and neonatal outcomes after TOLAC in Chinese multiparas based on a strictly uniform TOLAC indication, management and epidural protocol. METHODS: A total of 423 multiparas undergoing TOLAC were enrolled in this study from January 2017 to February 2018. Multiparas were divided into two groups according to whether they received epidural analgesia (study group, N = 263) or not (control group, N = 160) during labor. Maternal delivery outcomes and neonatal characteristics were recorded and evaluated using univariate analysis, multivariable logistic regression and propensity score matching (PSM). RESULTS: The success rate of VBAC was remarkably higher (85.55% vs. 69.38%, p < 0.01) in study group. Epidural analgesia significantly shortened initiating lactation period and declined Visual Analogue Score (VAS). It also showed more superiority in neonatal umbilical arterial blood pH value. After matching by PSM, multivariable logistic regression revealed that the correction of confounding factors including epidural analgesia, cervical Bishop score at admission and spontaneous onset of labor were still shown as promotion probability in study group (OR = 4.480, 1.360, and 10.188, respectively; 95%CI = 2.025-10.660, 1.113-1.673, and 2.875-48.418, respectively; p < 0.001, p = 0.003, and p < 0.001, respectively). CONCLUSIONS: Epidural analgesia could reduce labor pain, and no increased risk of postpartum bleeding or uterine rupture, as well as adverse effects in newborns were observed. The labor duration of multiparas was increased, but within acceptable range. In summary, epidural analgesia may be safe for both mother and neonate in the three studied hospitals. TRIAL REGISTRATION: Chineses Clinical Trial Register, ChiCTR-ONC-17010654. Registered February 16th, 2017.

Guest Exchange through Facilitated Transport in a Seemingly Impenetrable Hydrogen-Bonded Framework.

A new inclusion compound consisting of a guanidinium 1,3,5-tri(4-sulfophenyl)benzene (G3TSPHB) host framework containing isophorone guests that surround isolated and seemingly inaccessible pockets was amenable to guest exchange with hexafluorobenzene (HFB) through a single crystal-single crystal transformation (SCSCT). Single-crystal X-ray diffraction of intermediate transformation states, from the parent compound G3TSPHB·(isophorone)3.7·(methanol)5.4 to the final state G3TSPHB·(isophorone)3.1·(HFB)2·(methanol)2, indicated a crystal symmetry change from monoclinic to hexagonal prior to full incorporation of HFB. Optical microscopy during the SCSCT revealed the formation of lamellae, which expanded and then coalesced into a single crystal when the phase transformation was complete. In situ Raman microscopy revealed changes in the orientation of isophorone guests during the transformation that suggested a pathway for HFB entry into the host cavities. The SCSCT occurs more rapidly than expected on the basis of simple diffusion, consistent with facilitated transport along the lamellae interfaces and a reduction in the length scale for guest exchange.

Polymorphisms in the Th17 cell-related RORC gene are associated with spontaneous clearance of HCV in Chinese women.

BACKGROUND: Female gender and favorable IFNL3 genotypes are the primary independent predictors of spontaneous clearance of HCV infection. However, chronic hepatitis C infection occurs in numerous women carrying favorable IFNL3 genotypes, indicating that other host and/or virological factors contribute to the prognosis of infection. METHODS: A cohort of 137 anti-HCV-positive female Han Chinese cases, including 64 chronic HCV carriers and 73 HCV spontaneous resolvers, was recruited in the study. 111 SNPs in 23 genes encoding HCV co-receptors, transcription factors, Toll-like receptors, co-stimulating molecules, and cytokines were selected for SNP analysis. RESULTS: After comparison of genotypes and allelotype frequencies of 111 SNPs in 23 genes in the primary cohort, the SNPs rs9826 (P = 0.024 for CC/TT/CT; P = 0.015 for C allele/T allele) and rs1521177 (P = 0.017 for GG/TT/GT; P = 0.006 for G allele/T allele) in the RORC gene were significantly associated with spontaneous HCV clearance. In the sub-cohort carrying favorable IFNL3 genotypes (rs12979860CC, rs8099917 TT, rs12980275 AA), rs1521177 (genotype: P = 0.040; allelotype: P = 0.021) remained significantly associated with spontaneous HCV clearance. Importantly, the most common RORC haplotype rs9826-T/rs1521177-T was presented at significantly different frequencies in resolvers and carriers in both the primary cohort (P = 0.0027) and the IFNL3 favorable sub-cohort (P = 0.0117). CONCLUSIONS: This study indicates that genetic polymorphisms in human Th17-related RORC gene are associated with different natural prognosis of HCV infection. The RORC haplotype, rs9826-T/rs1521177-T, was favorable for spontaneous clearance of HCV infection.

Co-expression of LAG3 and TIM3 identifies a potent Treg population that suppresses macrophage functions in colorectal cancer patients.

Regulatory T (Treg) cells are critical suppressors of inflammation and are thought to exert mainly deleterious effects in cancers. In colorectal cancer (CRC), Foxp3+ Treg accumulation in tumors was associated with poor prognosis. Hence, we examined the circulating Treg cells in CRC patients. Compared to controls, CRC patients presented mild upregulations in CD4+ CD25+/hi T cells and in the more canonical CD4+ CD25+/hi Foxp3+ Treg cells in peripheral blood mononuclear cells. Both of these Treg populations could be roughly divided into lymphocyte activation gene 3 negative T cell immunoglobulin and mucin-domain containing-3 negative (LAG3- TIM3- ) and LAG3+ TIM3+ subsets. In CRC patients, the LAG3+ TIM3+ subset represented approximately half of CD4+ CD25+/hi T cells and greater than 60% of CD4+ CD25+/hi Foxp3+ Treg cells, which was significantly more frequent than in healthy controls. Compared to the LAG3- TIM3- CD4+ CD25+/hi T cells, the LAG3+ TIM3+ CD4+ CD25+/hi T cells presented considerably higher transforming growth factor-ß and slightly higher interleukin (IL)-10 secretion, together with higher cytotoxic T-lymphocyte associated protein 4 and Foxp3 expression levels. Notably, macrophages following incubation with LAG3- TIM3- CD4+ CD25+/hi T cells and LAG3+ TIM3+ CD4+ CD25+/hi T cells displayed different characteristics. Macrophages incubated with LAG3+ TIM3+ CD4+ CD25+/hi T cells presented lower expression of major histocompatibility complex class II, CD80, CD86, and tumor necrosis factor-α but higher expression of IL-10, than macrophages incubated with LAG3- TIM3- CD4+ CD25+/hi T cells. Together, our investigations demonstrated that CRC patients presented an enrichment of circulating Treg cells, in which the LAG3+ TIM3+ subset exhibited more potent expression of inhibitory molecules, and furthermore, the LAG3+ TIM3+ Treg cells could suppress the proinflammatory activation of macrophages more potently than the LAG3- TIM3- Treg cells.

RhIII-Catalyzed Synthesis of Isoquinolones and 2-Pyridones via Annulation of N-Methoxyamides and Nitroalkenes.

The Rh(III)-catalyzed synthesis of 4-substituted isoquinolones and 2-pyridones by the annulation of N-methoxyamides and nitroalkenes has been developed. Both aliphatic and aromatic nitroalkenes were effective inputs. Annulations also proceeded for aromatic, alkenyl, and heteroaromatic C-H bond starting materials. Moreover, benzoic acid provided a novel nitrodihydroisocoumarin. The structure and relative stereochemistry of this compound, which is an oil at room temperature, was determined unambiguously by single crystal X-ray diffraction of its inclusion complex with a hydrogen-bonded host framework.

Resveratrol Suppresses Gut-Derived NLRP3 Inflammasome Partly through Stabilizing Mast Cells in a Rat Model.

BACKGROUND: Inflammatory responses induced by intestinal ischemia-reperfusion (IIR) lead to serious systemic organ dysfunction and pose a challenge for current treatment. This study aimed at investigating the effects of resveratrol on IIR-induced intestinal injury and its influence on mast cells (MCs) in rats. METHODS: Rats subjected to intestinal ischemia for 60 min and 4 h of IIR were investigated. Animals were randomly divided into five groups (n = 8 per group): sham, IIR, resveratrol (RESV, 15 mg/kg/day for 5 days before operation) + IIR, cromolyn sodium (CS, MC membrane stabilizer) + IIR, and RESV + compound 48/80 (CP, MC agonist) + IIR. RESULTS: Intestinal injury and increased proinflammatory cytokines including tumor necrosis factor-α, interleukin-1ß, and interleukin-18 were observed in the IIR group. Intestinal MC-related tryptase and ß-hexosaminidase levels were also increased after rats were subjected to IIR accompanied by activation of NLRP3 inflammasomes. Interestingly, pretreatment with resveratrol significantly suppressed the activities of proinflammatory cytokines and attenuated intestinal injury. Resveratrol also reduced MC and NLRP3 inflammasome activation, which was consistent with the effects of cromolyn sodium. However, the protective effects of resveratrol were reversed by the MC agonist compound 48/80. CONCLUSIONS: In summary, these findings reveal that resveratrol suppressed IIR injury by stabilizing MCs, preventing them from degranulation, accompanied with intestinal mucosa NLRP3 inflammasome inhibition and intestinal epithelial cell apoptosis reduction.

Single bolus low-dose of ketamine does not prevent postpartum depression: a randomized, double-blind, placebo-controlled, prospective clinical trial.

PURPOSE: Postpartum depression is a common complication of childbirth. In the last decade, it has been suggested that subdissociative-dose ketamine is a fast-acting antidepressant. We aimed to investigate the efficacy of low-dose ketamine administered during caesarean section in preventing postpartum depression. METHODS: Using a randomized, double-blind, placebo-controlled design, 330 parturients who were scheduled to undergo caesarean section were enrolled in this trial. The parturients were randomly assigned to receive intravenous ketamine (0.25 mg/kg diluted to 10 mL with 0.9% saline) or placebo (10 mL of 0.9% saline) within 5 min following clamping of the neonatal umbilical cord. The primary outcome was the degree of depression, which was evaluated using the Edinburgh Postnatal Depression Scale (EPDS) (a threshold of 9/10 was used) at 3 days and 6 weeks after delivery. The secondary outcome was the numeric rating scale score of pain at 3 day and 6 week postpartum. RESULTS: No significant differences were found in the prevalence of postpartum depression between the two groups at 3 days and 6 weeks after delivery. The pain scores measured at 3 days postoperatively were not significantly different between the groups, whereas the scores measured at 6 week postpartum were significantly reduced in the treatment group compared with the saline group (P = 0.014). CONCLUSIONS: Intra-operative low-dose ketamine (0.25 mg/kg) does not have a preventive effect on postpartum depression.

Comparison of Intrathecal Dexmedetomidine with Morphine as Adjuvants in Cesarean Sections.

To compare the effects of intrathecal dexmedetomidine and intrathecal morphine as supplements to bupivacaine in cesarean sections under spinal anesthesia. Full-term parturients (n=120) undergoing elective cesarean sections under spinal anesthesia were randomly allocated into three groups: Group B received 10 mg bupivacaine, Group BD received 10 mg bupivacaine plus 5 µg dexmedetomidine, and Group BM received 10 mg bupivacaine plus 100 µg morphine. The onset and regression time of sensory and motor blockade, postoperative analgesia, and side effects were recorded. Group BD showed quicker onset time and a longer sensory and motor blockade than other groups (BD vs. B and BD vs. BM, p<0.05). The mean time of sensory regression to the S1 segment was 253.21±42.79 min in group BD, 192.50±40.62 min in group BM and 188.33±37.62 min in group B (p<0.001). Group BD showed an analgesia duration (time to requirement of first rescue analgesic) (17.59±6.23 h) similar to that of group BM (16.78±5.90 h) but longer than that of group B (3.53±1.68 h) (p<0.001). The incidence of pruritus was significantly higher in group BM compared with groups BD and B (p<0.001). Less shivering was observed in group BD than in groups BM and B (p=0.009). So intrathecal dexmedetomidine (5 µg) prolonged the motor and sensory blockade, provided a similar analgesic effect and reduced pruritus and shivering compared with morphine (100 µg) in cesarean sections.

Intrathecal dexmedetomidine as adjuvant to ropivacaine in hysteroscopic surgery: a prospective, randomized control study.

BACKGROUND: To compare the effects and side effects of intrathecal ropivacaine supplemented with dexmedetomidine and fentanyl in hysteroscopic surgery under spinal anesthesia. METHODS: Female patients (n = 108) undergoing operative hysteroscopic procedures under spinal anesthesia were randomly allocated to the following groups for subarachnoid drug delivery: R (n = 36) received 7.5 mg ropivacaine; RD (n = 36) received 7.5 mg ropivacaine plus 5 µg dexmedetomidine; RF (n = 36) received 7.5 mg ropivacaine plus 15 µg fentanyl. The onset and regression time of sensory and motor blockade, together with the postoperative analgesia and side effects were recorded. RESULTS: There was no significant difference as to sensory and motor onset time between groups. RD had significantly longer sensory and motor blockade time than RF and R. The mean time of sensory regression to the S1 segment was 191.25 ± 40.24 minutes in RD, 149.86 ± 37.46 minutes in RF, and 139.44 ± 38.97 minutes in R (RD vs. R and RD vs. RF, p < 0.001). The regression time of motor blockade to Bromage score 0 was 146.31 ± 40.72 minutes in RD, 80.28 ± 41.18 minutes in RF, and 84.94 ± 26.11 minutes in R (RD vs. R and RD vs. RF, p < 0.001). RD produced similar analgesia effect with RF, (2 hour visual analog scale (VAS) was 0.00 ± 0.00 and 0.31 ± 0.79, respectively) better than the R group (1.35 ± 1.65, p < 0.005). No pruritus occurred in the RD group, while the rate was 36.1% in the RF group. However, the RD group produced milder postsurgical hypotension (RD vs. R and RD vs. RF, p < 0.05). CONCLUSION: Intrathecal dexmedetomidine (5 µg) produced prolonged motor and sensory blockade and less pruritus compared with fentanyl (15 µg) in hysteroscopic surgery.

Nitrogen analogues of Thiele's hydrocarbon.

A series of bis[N,N-di-(4-methoxylphenyl)amino]arene dications 1(2+) -3(2+) have been synthesized and characterized. Their electronic structures were investigated by various experiments assisted by theoretical calculations. It was found that they are singlets in the ground state and that their diradical character is dependent on the bridging moiety. 3(2+) has a smaller singlet-triplet energy gap and its excited triplet state is thermally readily accessible. The work provides a nitrogen analogue of Thiele's hydrocarbon with considerable diradical character.

Ketamine administered to pregnant rats in the second trimester causes long-lasting behavioral disorders in offspring.

Commonly used anesthetic agents, e.g. ketamine, may be neurotoxic to the developing brain but there has been little attention to the neurobehavioral consequences for offspring when used for maternal anesthesia. We hypothesize that treatment of pregnant rats with ketamine during the second trimester would affect brain development of the offspring. Pregnant rats on gestational day 14, about equal to midtrimester pregnancy in humans, received a sedative dose of ketamine intravenously for 2h. Brain hippocampal morphology of their pups at postnatal days 0 (P0) and P30 was examined by Nissl-staining and the characteristics of dendrites were determined using the Golgi-Cox staining, while cell proliferation in subventricular zone (SVZ) and dentate gyrus (DG) was labeled with bromodeoxyuridine (BrdU). Their neurobehavioral functions were tested at P25-30 after which the NR1 and NR2 subunits of N-methyl-d-aspartate (NMDA) receptor, brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD-95) in the hippocampus were analyzed by western blot. When pregnant rats were exposed to ketamine, there was neuronal loss, pyramidal neuronal abnormality and reduced cell proliferation in the hippocampus of offspring. These morphological abnormalities were associated with depression- and anxiety-like behaviors, and impaired memory up to young adult age. The treatment further caused NR2A receptor subunit up-regulation and NR2B receptor subunit, BDNF and PSD-95 down-regulation. These data suggest that maternal anesthesia with ketamine during the fetal brain development period can cause fetal brain damage and subsequent neurobehavioral abnormality, which is likely associated with the imbalanced expression of NMDA receptor subunits.

Gene expression analysis of colorectal cancer by bioinformatics strategy.

BACKGROUND/AIMS: We used bioinformatics technology to analyze gene expression profiles involved in colorectal cancer tissue samples and healthy controls. METHODOLOGY: In this paper, we downloaded the gene expression profile GSE4107 from Gene Expression Omnibus (GEO) database, in which a total of 22 chips were available, including normal colonic mucosa tissue from normal healthy donors (n=10), colorectal cancer tissue samples from colorectal patients (n=33). To further understand the biological functions of the screened DGEs, the KEGG pathway enrichment analysis were conducted. Then we built a transcriptome network to study differentially co-expressed links. RESULTS: A total of 3151 DEGs of CRC were selected. Besides, total 164 DCGs (Differentially Coexpressed Gene, DCG) and 29279 DCLs (Differentially Co-expressed Link, DCL) were obtained. Furthermore, the significantly enriched KEGG pathways were Endocytosis, Calcium signaling pathway, Vascular smooth muscle contraction, Linoleic acid metabolism, Arginine and proline metabolism, Inositol phosphate metabolism and MAPK signaling pathway. CONCLUSION: Our results show that the generation of CRC involves multiple genes, TFs and pathways. Several signal and immune pathways are linked to CRC and give us more clues in the process of CRC. Hence, our work would pave ways for novel diagnosis of CRC, and provided theoretical guidance into cancer therapy.

Bioinformatics Approach to Identify the Pathogenetic Link of Gut Microbiota-Derived Short-Chain Fatty Acids and Ischemic Stroke.

Stroke is a life-threatening condition that impairs the arteries and causes neurological impairment. The incidence of stroke is increasing year by year with the arrival of the aging population. Thus, there is an urgent need for early stroke diagnosis. Short-chain fatty acids (SCFAs) can modulate the central nervous system and directly and indirectly impact behavioral and cognitive functions. This study aimed to investigate the connection between SCFA metabolism and stroke development via bioinformatic analysis. Initially, the Gene Set Enrichment Analysis (GSEA) and immune cell infiltration analysis were performed based on RNA data from stroke patients to comprehend the mechanisms governing stroke pathogenesis. The functional analysis, including Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Protein-Protein Interaction (PPI), was performed based on the Differentially Expressed Gene (DEG) selected by the limma package. 1220 SCFA metabolism-related genes screened from Genecards databases were intersected with 242 genes in main modules determined by Weighted Gene Co-Expression Network Analysis (WGCNA), and the final 10 SCFA key genes were obtained. GO analysis revealed that these genes were involved in immune response processes. Through lasso regression analyses, we established a stroke early diagnosis model and selected 6 genes with diagnostic value. The genes were validated by the area under curve (AUC) values and had a relatively good diagnostic performance. Finally, 4 potential therapeutic drugs targeting these genes were predicted using the Drug Signatures Database (DSigDB) via Enrichr. In conclusion, this paper analyzes the involvement of SCFAs in the complex gut-brain axis mechanism, which contributes to developing new targets for treating central nervous system diseases and provides new ideas for early ischemic stroke diagnosis.