Neuronal and Molecular Mechanisms Underlying Chronic Pain and Depression Comorbidity in the Paraventricular Thalamus.

Patients with chronic pain often develop comorbid depressive symptoms, which makes the pain symptoms more complicated and refractory. However, the underlying mechanisms are poorly known. Here, in a repeated complete Freund's adjuvant (CFA) male mouse model, we reported a specific regulatory role of the paraventricular thalamic nucleus (PVT) glutamatergic neurons, particularly the anterior PVT (PVA) neurons, in mediating chronic pain and depression comorbidity (CDC). Our c-Fos protein staining observed increased PVA neuronal activity in CFA-CDC mice. In wild-type mice, chemogenetic activation of PVA glutamatergic neurons was sufficient to decrease the 50% paw withdrawal thresholds (50% PWTs), while depressive-like behaviors evaluated with immobile time in tail suspension test (TST) and forced swim test (FST) could only be achieved by repeated chemogenetic activation. Chemogenetic inhibition of PVA glutamatergic neurons reversed the decreased 50% PWTs in CFA mice without depressive-like symptoms and the increased TST and FST immobility in CFA-CDC mice. Surprisingly, in CFA-CDC mice, chemogenetically inhibiting PVA glutamatergic neurons failed to reverse the decrease of 50% PWTs, which could be restored by rapid-onset antidepressant S-ketamine. Further behavioral tests in chronic restraint stress mice and CFA pain mice indicated that PVA glutamatergic neuron inhibition and S-ketamine independently alleviate sensory and affective pain. Molecular profiling and pharmacological studies revealed the 5-hydroxytryptamine receptor 1D (Htr1d) in CFA pain-related PVT engram neurons as a potential target for treating CDC. These findings identified novel CDC neuronal and molecular mechanisms in the PVT and provided insight into the complicated pain neuropathology under a comorbid state with depression and related drug development.

Multiple integrated social stress induces depressive-like behavioral and neural adaptations in female C57BL/6J mice.

Despite women representing most of those affected by major depression, preclinical studies have focused almost exclusively on male subjects, partially due to a lack of ideal animal paradigms. As the persistent need regarding the sex balance of neuroscience research and female-specific pathology of mental disorders surges, the establishment of natural etiology-based and systematically validated animal paradigms for depression with female subjects becomes an urgent scientific problem. This study aims to establish, characterize, and validate a "Multiple Integrated Social Stress (MISS)" model of depression in female C57BL/6J mice by manipulating and integrating daily social stressors that females are experiencing. Female C57BL/6J mice randomly experienced social competition failure in tube test, modified vicarious social defeat stress, unescapable overcrowding stress followed by social isolation on each day, for ten consecutive days. Compared with their controls, female MISS mice exhibited a relatively decreased preference for social interaction and sucrose, along with increased immobility in the tail suspension test, which could last for at least one month. These MISS mice also exhibited increased levels of blood serum corticosterone, interleukin-6 L and 1ß. In the pharmacological experiment, MISS-induced dysfunctions in social interaction, sucrose preference, and tail suspension tests were amended by systematically administrating a single dose of sub-anesthetic ketamine, a rapid-onset antidepressant. Compared with controls, MISS females exhibited decreased c-Fos activation in their anterior cingulate cortex, prefrontal cortex, nucleus accumbens and some other depression-related brain regions. Furthermore, 24 h after the last exposure to the paradigm, MISS mice demonstrated a decreased center zone time in the open field test and decreased open arm time in the elevated plus-maze test, indicating anxiety-like behavioral phenotypes. Interestingly, MISS mice developed an excessive nesting ability, suggesting a likely behavioral phenotype of obsessive-compulsive disorder. These data showed that the MISS paradigm was sufficient to generate pathological profiles in female mice to mimic core symptoms, serum biochemistry and neural adaptations of depression in clinical patients. The present study offers a multiple integrated natural etiology-based animal model tool for studying female stress susceptibility.

Chiral Recognition of Chiral (Hetero)Cyclic Derivatives Probed by Tetraaza Macrocyclic Chiral Solvating Agents via 1H NMR Spectroscopy.

In the field of chiral recognition, chiral cyclic organic compounds, especially heterocyclic organic compounds, have attracted little attention and have been rarely studied as chiral substrates by means of 1H NMR spectroscopy. In this paper, enantiomers of thiohydantoin derivatives, representing typical five-membered N,N-heterocycles, have been synthesized and utilized for assignment of absolute configuration and analysis of enantiomeric excess. All enantiomers have been successfully differentiated with the assistance of novel tetraaza macrocyclic chiral solvating agents (TAMCSAs) by 1H NMR spectroscopy. Surprisingly, unprecedented nonequivalent chemical shift values (up to 2.052 ppm) of the NH proton of substrates have been observed, a new milestone in the evaluation of enantiomers. To better understand the intermolecular interactions between host and guest, Job plots and theoretical calculations of (S)-G1 and (R)-G1 with TAMCSA 1a were investigated and revealed significant geometric differentiation between the diastereomers. In order to evaluate practical applications of the present systems in analyzing optical purity of chiral substrates, enantiomeric excesses of a typical substrate (G1) with different optical compositions in the presence of a representative TAMCSA (1a) can be accurately calculated based on the integration of the NH proton's signal peaks. Importantly, this work provides a significant breakthrough in exploring and developing the chiral recognition of chiral heterocyclic organic compounds by 1H NMR spectroscopy.

Ginsenoside Rg1 mitigates cerebral ischaemia/reperfusion injury in mice by inhibiting autophagy through activation of mTOR signalling.

Reperfusion injury, which is distinct from ischaemic injury, occurs when blood flow is restored in previously ischaemic brain tissue, further compromising neurons and other cells and worsening the injury. There is currently a lack of pharmaceutical agents and therapeutic interventions that specifically mitigate cerebral ischaemia/reperfusion (I/R) injury. Ginsenoside Rg1 (Rg1), a protopanaxatriol-type saponin isolated from Panax ginseng C. A. Meyer, has been found to protect against cerebral I/R injury, but its intricate protective mechanisms remain to be elucidated. Numerous studies have shown that autophagy plays a crucial role in protecting brain tissue during the I/R process and is emerging as a promising therapeutic strategy for effective treatment. In this study, we investigated whether Rg1 protected against I/R damage in vitro and in vivo by regulating autophagy. Both MCAO and OGD/R models were established. SK-N-AS and SH-SY5Y cells were subjected to OGD followed by reperfusion with Rg1 (4-32 µM). MCAO mice were injected with Rg1 (30 mg·kg-1·d-1. i.p.) for 3 days before and on the day of surgery. Rg1 treatment significantly mitigated ischaemia/reperfusion injury both in vitro and in vivo. Furthermore, we demonstrated that the induction of autophagy contributed to I/R injury, which was effectively inhibited by Rg1 in both in vitro and in vivo models of cerebral I/R injury. Rg1 inhibited autophagy through multiple steps, including impeding autophagy initiation, inducing lysosomal dysfunction and inhibiting cathepsin enzyme activities. We revealed that mTOR activation was pivotal in mediating the inhibitory effect of Rg1 on autophagy. Treatment with Torin-1, an autophagy inducer and mTOR-specific inhibitor, significantly reversed the impact of Rg1 on autophagy, decreasing its protective efficacy against I/R injury both in vitro and in vivo. In conclusion, our results suggest that Rg1 may serve as a promising drug candidate against cerebral I/R injury by inhibiting autophagy through activation of mTOR signalling.

Prenatal diagnosis of interrupted aortic arch using high-definition flow render mode and spatiotemporal image correlation.

OBJECTIVES: To evaluate the clinical utility of two dimensional (2D) ultrasound combined with spatiotemporal image correlation (STIC) in diagnosing interrupted aortic arch (IAA) in fetal life. METHODS: A total of 53 cases of fetal IAA were diagnosed using 2D ultrasound combined with STIC, and 53 normal fetuses of the same gestational week were selected. These cases were retrospectively analyzed to assess the utility of employing 2D ultrasound combined with STIC in the diagnosis of IAA. RESULTS: 2D ultrasound combined with STIC detected 22 cases of type A IAA, 24 cases of type B IAA, and seven cases of type C IAA. Furthermore, combining 2D ultrasound with STIC enabled dynamic visualization of the IAA, aiding in prenatal diagnosis. The diagnostic coincidence rate of IAA was found to be higher in the HD-flow combined with STIC than that in the 2D combined with HD-flow. CONCLUSION: HD-flow combined with STIC can assist in diagnosing fetal IAA, and this technique has important clinical value.

Optical design of low-location illumination based on asymmetric double freeform surfaces.

The development of optical optics for low-location road lighting is a challenging problem in providing high luminance and uniformity of illumination and meeting many other specific requirements. This study proposes an optical design method of low-location illumination based on an asymmetric double freeform surface lens. The ray emitted from the light source is refracted and reflected through the different surface types to the corresponding area of the receiving surface. In the design example, the road has dual-side mounted luminaires and a width of 6 m, and a height of 0.8 m. Simulation results indicate that, compared with conventional high-pole streetlights, the luminance uniformity had increased from 0.60 to 0.66, the illuminance uniformity had improved from 0.75 to 0.86, and the glare had been reduced.

In vitro drug screening models derived from different PC12 cell lines for exploring Parkinson's disease based on electrochemical signals of catecholamine neurotransmitters.

Gold nanostructures and a Nafion modified screen-printed carbon electrode (Nafion/AuNS/SPCE) were developed to assess the cell viability of Parkinson's disease (PD) cell models. The electrochemical measurement of cell viability was reflected by catecholamine neurotransmitter (represented by dopamine) secretion capacity, followed by a traditional tetrazolium-based colorimetric assay for confirmation. Due to the  capacity to synthesize, store, and release catecholamines as well as their unlimited homogeneous proliferation, and ease of manipulation, pheochromocytoma (PC12) cells were used for PD cell modeling. Commercial low-differentiated and highly-differentiated PC12 cells, and home-made nerve growth factor (NGF) induced low-differentiated PC12 cells (NGF-differentiated PC12 cells) were included in the modeling. This approach achieved sensitive and rapid determination of cellular modeling and intervention states. Notably, among the three cell lines, NGF-differentiated PC12 cells displayed the enhanced neurotransmitter secretion level accompanied with attenuated growth rate, incremental dendrites in number and length that were highly resemble with neurons. Therefore, it was selected as the PD-tailorable modeling cell line. In short, the electrochemical sensor can be used to sensitively determine the biological function of neuron-like PC12 cells with negligible destruction and to explore the protective and regenerative impact of various substances on nerve cell model.

HbA1c variability associated with dementia risk in people with type 2 diabetes.

INTRODUCTION: Although poor glycemic control is associated with dementia, it is unknown if variability in glycemic control, even in those with optimal glycosylated hemoglobin A1c (HbA1c) levels, increases dementia risk. METHODS: Among 171,964 people with type 2 diabetes, we evaluated the hazard of dementia association with long-term HbA1c variability using five operationalizations, including standard deviation (SD), adjusting for demographics and comorbidities. RESULTS: The mean baseline age was 61 years (48% women). Greater HbA1c SD was associated with greater dementia hazard (adjusted hazard ratio = 1.15 [95% confidence interval: 1.12, 1.17]). In stratified analyses, higher HbA1c SD quintiles were associated with greater dementia hazard among those with a mean HbA1c < 6% (P = 0.0004) or 6% to 8% (P < 0.0001) but not among those with mean HbA1c ≥ 8% (P = 0.42). DISCUSSION: Greater HbA1c variability is associated with greater dementia risk, even among those with HbA1c concentrations at ideal clinical targets. These findings add to the importance and clinical impact of recommendations to minimize glycemic variability. HIGHLIGHTS: We observed a cohort of 171,964 people with type 2 diabetes (mean age 61 years). This cohort was based in Northern California between 1996 and 2018. We examined the association between glycosylated hemoglobin A1c (HbA1c) variability and dementia risk. Greater HbA1c variability was associated with greater dementia hazard. This was most evident among those with normal-low mean HbA1c concentrations.

Acupuncture May Help to Prevent Chemotherapy-Induced Peripheral Neuropathy: A Randomized, Sham-Controlled, Single-Blind Study.

OBJECTIVE: This study investigated the efficacy of acupuncture in preventing chemotherapy-induced peripheral neuropathy (CIPN) in patients with colorectal cancer (CRC). METHODS: This single center, randomized, controlled, single-blind clinical trial randomly assigned patients with stage 3 CRC attending outpatient clinics in China Medical University Hospital to either verum or sham acupuncture treatment concurrently with chemotherapy. Primary outcomes were nerve conduction velocity (NCV) and touch thresholds of limb terminals. Secondary outcomes were total and subdomain scores on the Functional Assessment of Cancer Therapy-General (FACT-G), and scores on the FACT/GOG-Ntx subscale and the Brief Pain Inventory-Short Form (BPI-SF), at baseline, weeks 12, 36, and follow-up (week 48). RESULTS: Thirty-two patients met the inclusion criteria and received verum acupuncture (N = 16) or sham acupuncture (N = 16). Under the -intent-to-treat principle, 26 participants were analyzed. Significant changes from baseline for questionnaire scores and sensory NCV were observed in both study groups. Sham acupuncture was associated with significant reductions from baseline in motor NCV and sensory touch thresholds; no such changes were observed with verum acupuncture. No serious adverse events were reported. CONCLUSION: Prophylactic acupuncture may exert neuroprotective effects on mechanical or tactile touch thresholds during chemotherapy regimens in patients with CRC, with evidence of this protectiveness persisting at 6 months' follow-up. The lack of change in motor NCV values with verum acupuncture indicates neuroprotective effects. Sensory NCV values and patient-reported outcomes did not differ significantly between the study groups.

Tau as a biomarker of cognitive impairment and neuropsychiatric symptom in Alzheimer's disease.

The A/T/N research framework has been proposed for the diagnosis and prognosis of Alzheimer's disease (AD). However, the spatial distribution of ATN biomarkers and their relationship with cognitive impairment and neuropsychiatric symptoms (NPS) need further clarification in patients with AD. We scanned 83 AD patients and 38 cognitively normal controls who independently completed the mini-mental state examination and Neuropsychiatric Inventory scales. Tau, Aß, and hypometabolism spatial patterns were characterized using Statistical Parametric Mapping together with [18F]flortaucipir, [18F]florbetapir, and [18F]FDG positron emission tomography. Piecewise linear regression, two-sample t-tests, and support vector machine algorithms were used to explore the relationship between tau, Aß, and hypometabolism and cognition, NPS, and AD diagnosis. The results showed that regions with tau deposition are region-specific and mainly occurred in inferior temporal lobes in AD, which extensively overlaps with the hypometabolic regions. While the deposition regions of Aß were unique and the regions affected by hypometabolism were widely distributed. Unlike Aß, tau and hypometabolism build up monotonically with increasing cognitive impairment in the late stages of AD. In addition, NPS in AD were associated with tau deposition closely, followed by hypometabolism, but not with Aß. Finally, hypometabolism and tau had higher accuracy in differentiating the AD patients from controls (accuracy = 0.88, accuracy = 0.85) than Aß (accuracy = 0.81), and the combined three were the highest (accuracy = 0.95). These findings suggest tau pathology is superior over Aß and glucose metabolism to identify cognitive impairment and NPS. Its results support tau accumulation can be used as a biomarker of clinical impairment in AD.

Typical metabolic pattern of 18F-FDG PET in Anti-NMDAR encephalitis in the acute and subacute phases and its correlation with T2 FLAIR-MRI features.

BACKGROUND/AIMS: Early diagnosis of Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis with non-invasive imaging modalities benefiting is crucial to guarantee prompt treatments decision-making and good prognosis for patients. The present study aimed to explore the correlation of MRI features with brain metabolism characteristics of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) and to describe the metabolic patterns in Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis at acute and subacute phases. Twenty-four patients with anti-NMDAR encephalitis confirmed by serum and/or CSF tests at acute and subacute phases, 9 females and 15 males, with an age range of 6-80 years, were enrolled in this retrospective study as encephalitis group. 18F-FDG PET and MRI findings of all patients were investigated and interpreted with visual analysis. Chi-square test was performed to compare the diagnostic sensitivity between MRI and PET. Independent sample t-test was used to compare the standardized uptake value ratio (SUVR) of each ROI between the encephalitis group and control group, which consisted of 24 healthy volunteers of the same age and gender. RESULTS: There was no statistical difference in the diagnostic sensitivity between FDG PET (23/24, 95.83%) and MRI (18/24, 75.00%) in anti-NMDAR encephalitis patients (P > 0.05). Three categories of abnormalities shown on T2 FLAIR, including shallow of sulci and swelling of brain tissue, increased signal in the sulci, increased signal on brain gray matter or adjacent white matter presented hypermetabolism on PET, excepting increased signal in brain linear structure with hypometabolism of the basal ganglia on PET. We identified 19 brain regions with hypermetabolism and 16 brain regions with hypometabolism that exhibited statistically significant changes in SUVRs between anti-NMDAR encephalitis group and control group (FDR P < 0.05). CONCLUSION: Anteroposterior glucose metabolism gradient (frontal-temporal/parietal-occipital) is proved to be a typical pattern of anti-NMDAR encephalitis at the acute and subacute phases in both visual and statistical testing. Interestingly, the pattern is also commonly found in the anterior and posterior portions of the parietal lobe and cingular cortex, which may be a potential indicator for the diagnosis of this disorder. In addition, MRI is an important and reliable neuroimaging modality to assist in the correct evaluation of activity changes on individual 18F-FDG PET.

11C-methionine PET imaging characteristics in children with diffuse intrinsic pontine gliomas and relationship to survival and H3 K27M mutation status.

PURPOSE: This study aimed to describe 11C-methionine (11C-MET) PET imaging characteristics in patients with paediatric diffuse intrinsic pontine glioma (DIPG) and correlate them with survival and H3 K27M mutation status. METHODS: We retrospectively analysed 98 children newly diagnosed with DIPG who underwent 11C-MET PET. PET imaging characteristics evaluated included uptake intensity, uniformity, metabolic tumour volume (MTV), and total lesion methionine uptake (TLMU). The maximum, mean, and peak of the tumour-to-background ratio (TBR), calculated as the corresponding standardised uptake values (SUV) divided by the mean reference value, were also recorded. The associations between the PET imaging characteristics and clinical outcomes in terms of progression-free survival (PFS) and overall survival (OS) and H3 K27M mutation status were assessed, respectively. RESULTS: In univariate analysis, imaging characteristics significantly associated with shorter PFS and OS included a higher uniformity grade, higher TBRs, larger MTV, and higher TLMU. In multivariate analysis, larger MTV at diagnosis, shorter symptom duration, and no treatment were significantly correlated with shorter PFS and OS. The PET imaging features were not correlated with H3 K27M mutation status. CONCLUSION: Although several imaging features were significantly associated with PFS and OS, only MTV, indicating the size of the active tumour, was identified as a strong independent prognostic factor.

Surface Modification Functionalized Carbon Dots.

Carbon dots (CDs) smaller than 10 nm constitute a new type of fluorescent carbon-based nanomaterial. They have attracted much attention owing to their unique structures and excellent photoelectric properties. Primitive CDs usually comprise carbon and oxygen and are synthesized in one step from various natural products or synthetic organic compounds, usually via microwave or hydrothermal methods. However, the uniformity of surface functional groups often make CDs lack the diversity of active sites required for specific applications. Therefore, the functionalization of CDs by specific groups is a powerful strategy for improving their photophysical and photochemical properties. This paper reviews surface modification strategies to overcome these shortcomings. Functionalizing CDs using covalent or non-covalent modification can give them unique properties and broaden their applicability.

Spatiotemporal Investigation of Intercellular Heterogeneity via Multiple Photocaged Probes.

Intercellular heterogeneity occurs widely under both normal physiological environments and abnormal disease-causing conditions. Several attempts to couple spatiotemporal information to cell states in a microenvironment were performed to decipher the cause and effect of heterogeneity. Furthermore, spatiotemporal manipulation can be achieved with the use of photocaged/photoactivatable molecules. Here, we provide a platform to spatiotemporally analyze differential protein expression in neighboring cells by multiple photocaged probes coupled with homemade photomasks. We successfully established intercellular heterogeneity (photoactivable ROS trigger) and mapped the targets (directly ROS-affected cells) and bystanders (surrounding cells), which were further characterized by total proteomic and cysteinomic analysis. Different protein profiles were shown between bystanders and target cells in both total proteome and cysteinome. Our strategy should expand the toolkit of spatiotemporal mapping for elucidating intercellular heterogeneity.

Interictal HFO and FDG-PET correlation predicts surgical outcome following SEEG.

OBJECTIVE: This study aimed to investigate the quantitative relationship between interictal 18 F-fluorodeoxyglucose-positron emission tomography (FDG-PET) and interictal high-frequency oscillations (HFOs) from stereo-electroencephalography (SEEG) recordings in patients with refractory epilepsy. METHODS: We retrospectively included 32 patients. FDG-PET data were quantified through statistical parametric mapping (SPM) t test modeling with normal controls. Interictal SEEG segments with four, 10-min segments were selected randomly. HFO detection and classification procedures were automatically performed. Channel-based HFOs separating ripple (80-250 Hz) and fast ripple (FR; 250-500 Hz) counts were correlated with the surrounding metabolism T score at the individual and group level, respectively. The association was further validated across anatomic seizure origins and sleep vs wake states. We built a joint feature FR × T reflecting the FR and hypometabolism concordance to predict surgical outcomes in 28 patients who underwent surgery. RESULTS: We found a negative correlation between interictal FDG-PET and HFOs through the linear mixed-effects model (R2  = .346 and .457 for ripples and FRs, respectively, p < .001); these correlations were generalizable to different epileptogenic-zone lobar localizations and vigilance states. The FR × T inside the resection volume could be used as a predictor for surgical outcomes with an area under the curve of 0.81. SIGNIFICANCE: The degree of hypometabolism is associated with HFO generation rate, especially for FRs. This relationship would be meaningful for selection of SEEG candidates and for optimizing SEEG scheme planning. The concordance between FRs and hypometabolism inside the resection volume could provide prognostic information regarding surgical outcome.

Individualized discrimination of tumor progression from treatment-related changes in different types of adult-type diffuse gliomas using [11C]methionine PET.

PURPOSE: This study aimed to assess the ability of [11C]methionine (MET) PET in distinguishing between tumor progression (TP) and treatment-related changes (TRCs) among different types of adult-type diffuse gliomas according to the 2021 World Health Organization classification and predict overall survival (OS). METHODS: We retrospectively selected 113 patients with adult-type diffuse gliomas with suspected TP who underwent MET PET imaging. Maximum and mean tumor-to-background ratios (TBRmax, TBRmean) and metabolic tumor volume (MTV) were calculated. Diagnoses were verified by histopathology (n = 50) or by clinical/radiological follow-up (n = 63). The diagnostic performance of MET PET parameters was evaluated through receiver operating characteristic (ROC) analysis and area under the curve (AUC) calculation. Survival analysis employed the Kaplan-Meier method and Cox proportional-hazards regression. RESULTS: TP and TRCs were diagnosed in 76 (67%) and 37 (33%) patients, respectively. ROC analysis revealed TBRmax had the best performance in differentiating TP from TRCs with a cut-off of 1.96 in IDH-mutant astrocytoma (AUC, 0.87; sensitivity, 93%; specificity 69%), 1.80 in IDH-mutant and 1p/19q-codeleted oligodendroglioma (AUC, 0.96; sensitivity, 100%; specificity, 89%), and 2.13 in IDH wild-type glioblastoma (AUC, 0.89; sensitivity, 89%; specificity, 78%), respectively. On multivariate analysis, higher TBRmean and MTV were significantly correlated with shorter OS in all IDH-mutant gliomas, as well as in IDH-mutant astrocytoma subgroup. CONCLUSION: This work confirms that MET PET has varying diagnostic performances in distinguishing TP from TRCs within three types of adult-type diffuse gliomas, and highlights its high diagnostic accuracy in IDH-mutant and 1p/19q-codeleted oligodendroglioma and potential prognostic value for IDH-mutant gliomas, particularly IDH-mutant astrocytoma.

Cationic Divalent Metal Sites (M = Mn, Fe, Co) Operating as Both Nitrene-Transfer Agents and Lewis Acids toward Mediating the Synthesis of Three- and Five-Membered N-Heterocycles.

The tripodal compounds [(TMG3trphen)MII-solv](PF6)2 (M = Mn, Fe, Co; solv = MeCN, DMF) and bipodal analogues [(TMG2biphen)MII(NCMe)x](PF6)2 (x = 3 for Mn, Fe; x = 2 for Co) and [(TMG2biphen)MIICl2] have been synthesized with ligands that feature a triaryl- or diarylmethyl-amine framework and superbasic tetramethylguanidinyl residues (TMG). The dicationic M(II) sites mediate catalytic nitrene-transfer reactions between the imidoiodinane PhI═NTs (Ts = tosyl) and a panel of styrenes in MeCN to afford aziridines and low yields of imidazolines (upon MeCN insertion) with an order of productivity that favors the bipodal over the tripodal reagents and a metal preference of Fe > Co ≥ Mn. In CH2Cl2, the more acidic Fe(II) sites favor formation of 2,4-diaryl-N-tosylpyrrolidines by means of an in situ (3 + 2) cycloaddition of the initially generated 2-aryl-N-tosylaziridine with residual styrene. In the presence of ketone, 1,3-oxazolidines can be formed in practicable yields, involving a single-pot cycloaddition reaction of alkene, nitrene, and ketone (2 + 1 + 2). Mechanistic studies indicate that the most productive bipodal Fe(II) site mediates stepwise addition of nitrene to olefins to generate aziridines with good retention of stereochemistry and further enables aziridine ring opening to unmask a 1,3-zwitterion that can undergo cycloaddition with dipolarophiles (MeCN, alkene, ketone) to afford five-membered N-heterocycles.

Cyclometalated Half-Sandwich Ruthenium Complexes: Preparation, Structure, and Catalytic Synthesis of Phenolic Esters from Aryl Halides without Using External CO under Air.

A series of cyclometalated C,N-chelate half-sandwich ruthenium complexes based on N-heterocyclic ligands were prepared through a simple route with good yields. These air- and moisture-stable cyclometalated ruthenium complexes showed excellent catalytic efficiency in phenoxy carbonylation of aryl halides with phenyl formate derivatives as a CO source and phenol as a coupling partner under air. Ester products were obtained with high yields at room temperature and without the need for an inert atmosphere. The excellent catalytic activity, broad substrate range, and mild reaction conditions made this catalytic system potential for industrial production. In addition, DFT study has been carried out to elaborate the possible mechanism of this Ru-catalyzed reaction.

Dynamic Nomogram for Predicting the Risk of Perioperative Neurocognitive Disorders in Adults.

BACKGROUND: Simple and rapid tools for screening high-risk patients for perioperative neurocognitive disorders (PNDs) are urgently needed to improve patient outcomes. We developed an online tool with machine-learning algorithms using routine variables based on multicenter data. METHODS: The entire dataset was composed of 49,768 surgical patients from 3 representative academic hospitals in China. Surgical patients older than 45 years, those undergoing general anesthesia, and those without a history of PND were enrolled. When the patient's discharge diagnosis was PND, the patient was in the PND group. Patients in the non-PND group were randomly extracted from the big data platform according to the surgical type, age, and source of data in the PND group with a ratio of 3:1. After data preprocessing and feature selection, general linear model (GLM), artificial neural network (ANN), and naive Bayes (NB) were used for model development and evaluation. Model performance was evaluated by the area under the receiver operating characteristic curve (ROCAUC), the area under the precision-recall curve (PRAUC), the Brier score, the index of prediction accuracy (IPA), sensitivity, specificity, etc. The model was also externally validated on the multiparameter intelligent monitoring in intensive care (MIMIC) Ⅳ database. Afterward, we developed an online visualization tool to preoperatively predict patients' risk of developing PND based on the models with the best performance. RESULTS: A total of 1051 patients (242 PND and 809 non-PND) and 2884 patients (6.2% patients with PND) were analyzed on multicenter data (model development, test [internal validation], external validation-1) and MIMIC Ⅳ dataset (external validation-2). The model performance based on GLM was much better than that based on ANN and NB. The best-performing GLM model on validation-1 dataset achieved ROCAUC (0.874; 95% confidence interval [CI], 0.833-0.915), PRAUC (0.685; 95% CI, 0.584-0.786), sensitivity (72.6%; 95% CI, 61.4%-81.5%), specificity (84.4%; 95% CI, 79.3%-88.4%), Brier score (0.131), and IPA (44.7%), and of which the ROCAUC (0.761, 95% CI, 0.712-0.809), the PRAUC (0.475, 95% CI, 0.370-0.581), Brier score (0.053), and IPA (76.8%) on validation-2 dataset. Afterward, we developed an online tool (https://pnd-predictive-model-dynnom.shinyapps.io/ DynNomapp/) with 10 routine variables for preoperatively screening high-risk patients. CONCLUSIONS: We developed a simple and rapid online tool to preoperatively screen patients' risk of PND using GLM based on multicenter data, which may help medical staff's decision-making regarding perioperative management strategies to improve patient outcomes.

Comparative study on the gene expression of corticosterone metabolic enzymes in embryonic tissues between Tibetan and broiler chickens.

Glucocorticoids (GCs) are an essential mediator hormone that can regulate animal growth, behavior, the phenotype of offspring, and so on, while GCs in poultry are predominantly corticosterones. The biological activity of GCs is mainly regulated by the intracellular metabolic enzymes, including 11ß-hydroxysteroid dehydrogenases 1 (11ß-HSD1), 11ß-hydroxysteroid dehydrogenases 2 (11ß-HSD2), and 20-hydroxysteroid dehydrogenase (20-HSD). To investigate the embryonic mechanisms of phenotypic differences between breeds, we compared the expression of corticosterone metabolic enzyme genes in the yolk-sac membrane and chorioallantoic membrane (CAM). We described the tissue distribution and ontogenic patterns of corticosterone metabolic enzymes during embryonic incubation between Tibetan and broiler chickens. Forty fertilized eggs from Tibetan and broiler chickens were incubated under hypoxic and normoxic conditions, respectively. Real-time fluorescence quantitative PCR was used to examine the expression of 11ß-HSD1/2, and 20-HSD mRNA in embryonic tissues. The results showed that the expression levels of yolk-sac membrane mRNA of 11ß-HSD2 and 20-HSD in Tibetan chickens on E14 (embryonic day of 14) were significantly lower than those of broiler chickens (P < 0.05), and these genes expression of CAM in Tibetan chickens were higher than those of broiler chickens (P < 0.05). In addition, the three genes in the yolk-sac membrane and CAM were followed by a down-regulation on E18 (embryonic day of 18). The 11ß-HSD1 and 11ß-HSD2 genes followed a similar tissue-specific pattern: the expression level was more abundantly in the liver, kidney, and intestine, with relatively lower abundance in the hypothalamus and muscle, and the expression level of 20-HSD genes in all tissues tested was higher. In the liver, 20-HSD of both Tibetan and broiler chickens showed different ontogeny development patterns, and hepatic mRNA expression of 20-HSD in broiler chickens was significantly higher than that of Tibetan chickens of the same age from E14 to E18 (P < 0.05). This study preliminarily revealed the expression levels of cortisol metabolic genes in different tissues during the development process of Tibetan and broiler chicken embryos. It provided essential information for in-depth research of the internal mechanism of maternal GCs programming on offspring.