Construction of 1,3,4-oxadiazolines bearing CF3-quaternary centers via amino-assisted [3 + 2] cycloadditions.

An amino-assisted [3 + 2] cycloaddition strategy of nitrile imines with o-aminotrifluoroacetophenones has been explored, thus providing functionalized 1,3,4-oxadiazolines bearing CF3-quaternary centers in good to excellent yields in the presence of K2CO3 under mild conditions. The amino groups located at the ortho-position of trifluoroacetophenone might play a crucial role in the present cyclization. The MTT assay shows that the 1,3,4-oxadiazoline derivatives could be potential candidates for the treatment of head and neck cancers.

Severity of acute gastrointestinal injury grade is a predictor of all-cause mortality in critically ill patients: a multicenter, prospective, observational study.

BACKGROUND: In 2012, the European Society of Intensive Care Medicine proposed a definition for acute gastrointestinal injury (AGI) based on current medical evidence and expert opinion. The aim of the present study was to evaluate the feasibility of using the current AGI grading system and to investigate the association between AGI severity grades with clinical outcome in critically ill patients. METHODS: Adult patients at 14 general intensive care units (ICUs) with an expected ICU stay ≥24 h were prospectively studied. The AGI grade was assessed daily on the basis of gastrointestinal (GI) symptoms, intra-abdominal pressures, and feeding intolerance (FI) in the first week of admission to the ICU. RESULTS: Among the 550 patients enrolled, 456 patients (82.9%) received mechanical ventilation, and 470 patients were identified for AGI. The distribution of the global AGI grade was 24.5% with grade I, 49.4% with grade II, 20.6% with grade III, and 5.5% with grade IV. AGI grading was positively correlated with 28- and 60-day mortality (P < 0.0001). Univariate Cox regression analysis showed that age, sepsis, diabetes mellitus, coronary artery disease, the use of vasoactive drugs, serum creatinine and lactate levels, mechanical ventilation, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, and the global AGI grade were significantly (P ≤ 0.02) associated with 60-day mortality. In a multivariate analysis including these variables, diabetes mellitus (HR 1.43, 95% CI 1.03-1.87; P = 0.05), the use of vasoactive drugs (HR 1.56, 95% CI 1.12-2.11; P = 0.01), serum lactate (HR 1.15, 95% CI 1.06-1.24; P = 0.03), global AGI grade (HR 1.65, 95% CI 1.28-2.12; P = 0.008), and APACHE II score (HR 1.04, 95% CI 1.02-1.06; P < 0.001) were independently associated with 60-day mortality. In a subgroup analysis of 402 patients with 7-day survival, in addition to clinical predictors and the AGI grade on the first day of ICU stay, FI within the first week of ICU stay had an independent and incremental prognostic value for 60-day mortality (χ2 = 41.9 vs. 52.2, P = 0.007). CONCLUSIONS: The AGI grading scheme is useful for identifying the severity of GI dysfunction and could be used as a predictor of impaired outcomes. In addition, these results support the hypothesis that persistent FI within the first week of ICU stay is an independent determinant for mortality. TRIAL REGISTRATION: Chinese Clinical Trial Registry identifier: ChiCTR-OCS-13003824 . Registered on 29 September 2013.

Phosphine-catalyzed [5+1] annulation of ß'-acetoxy allenoates: straightforward access to tetrahydroquinoline derivatives.

An unprecedented phosphine-catalyzed [5+1] annulation of ß'-acetoxy allenoates with 1,5-dinucleophiles has been developed, which provides novel and facile access to functionalized tetrahydroquinolines in good to high yields in the presence of PPh3 and K3PO4 under mild reaction conditions. Notably, it is the first report of ß'-acetoxy allenoates acting as C1 synthons in Lewis base-catalyzed annulation reactions.

Phosphine-Mediated Sequential [2+4]/[2+3] Annulation to Construct Pyrroloquinolines.

A domino [2+4]/[2+3] sequential annulation reaction of MBH carbonates with N-unprotected indoles has been developed to provide various pyrroloquinoline derivatives in ≤94% yield and 20:1 dr. The reaction could be either mediated by stoichiometric PCy3 or catalyzed by R3PO via PIII/PV═O redox cycling in the presence of phenylsilane. This method assembles polycyclic 1,7-fused indoles in one step diastereoselectively.

Emotional learning retroactively promotes memory integration through rapid neural reactivation and reorganization.

Neutral events preceding emotional experiences can be better remembered, likely by assigning them as significant to guide possible use in future. Yet, the neurobiological mechanisms of how emotional learning enhances memory for past mundane events remain unclear. By two behavioral studies and one functional magnetic resonance imaging study with an adapted sensory preconditioning paradigm, we show rapid neural reactivation and connectivity changes underlying emotion-charged retroactive memory enhancement. Behaviorally, emotional learning retroactively enhanced initial memory for neutral associations across the three studies. Neurally, emotional learning potentiated trial-specific reactivation of overlapping neural traces in the hippocampus and stimulus-relevant neocortex. It further induced rapid hippocampal-neocortical functional reorganization supporting such retroactive memory benefit, as characterized by enhanced hippocampal-neocortical coupling modulated by the amygdala during emotional learning, and a shift of hippocampal connectivity from stimulus-relevant neocortex to distributed transmodal prefrontal-parietal areas at post-learning rests. Together, emotional learning retroactively promotes memory integration for past neutral events through stimulating trial-specific reactivation of overlapping representations and reorganization of associated memories into an integrated network to foster its priority for future use.

NDI: A Platform-Independent Data Interface and Database for Neuroscience Physiology and Imaging Experiments.

Collaboration in neuroscience is impeded by the difficulty of sharing primary data, results, and software across labs. Here, we introduce Neuroscience Data Interface (NDI), a platform-independent standard that allows an analyst to use and create software that functions independently from the format of the raw data or the manner in which the data are organized into files. The interface is rooted in a simple vocabulary that describes common apparatus and storage devices used in neuroscience experiments. Results of analyses, and analyses of analyses, are stored as documents in a scalable, queryable database that stores the relationships and history among the experiment elements and documents. The interface allows the development of an application ecosystem where applications can focus on calculation rather than data format or organization. This tool can be used by individual labs to exchange and analyze data, and it can serve to curate neuroscience data for searchable archives.

Socioeconomic Disparities Affect Children's Amygdala-Prefrontal Circuitry via Stress Hormone Response.

BACKGROUND: The socioeconomic status (SES) of a family can affect almost all aspects of a child's life, including health and current and future achievement. The potential adverse effects of low SES on children's emotional development are thought to result from proximal factors such as stress. The underlying neurobiological mechanisms, however, remain elusive. METHODS: The effect of SES on children's integrative cortisol secretion and its modulations on emotion-related brain systems and connectivity were examined in children aged 6 to 12 years. In study 1, we investigated the relationship between SES and cortisol secretion in 239 children. In study 2, using resting-state and task-dependent functional magnetic resonance imaging in a subsample of 50 children, we investigated how SES affects children's amygdala-prefrontal functional organization through cortisol secretion. RESULTS: Children from lower SES exhibited lower cortisol secretion, considering basal cortisol, nocturnal cortisol activity during sleep, and cortisol awakening response, which mediated higher amygdala nuclei intrinsic functional connectivity with the medial and dorsolateral prefrontal cortex (PFC). Critically, these children also exhibited higher task-evoked ventromedial PFC activity through higher intrinsic connectivity of the centromedial amygdala with the medial PFC. They also exhibited higher functional coupling of the centromedial amygdala with the dorsolateral PFC when processing negative emotions. CONCLUSIONS: This study demonstrates that SES shapes children's amygdala-prefrontal circuitry through stress-sensitive cortisol secretion, with the most prominent effect in the centromedial amygdala's functional coordination with the ventromedial and dorsolateral PFC involved in processing negative emotions. Our findings provide important insight into the neurobiological etiology underlying how socioeconomic disparities shape children's emotional development.

Construction of CF3-Containing Tetrahydropyrano[3,2-b]indoles through DMAP-Catalyzed [4+1]/[3+3] Domino Sequential Annulation.

A [4+1]/[3+3] domino sequential annulation reaction of o-aminotrifluoroacetophenone derivatives and ß'-acetoxy allenoates enabled by DMAP has been reported. A variety of CF3-containing tetrahydropyrano[3,2-b]indoles were obtained as a single diastereomer in high yields (≤98%) under mild conditions. The reaction can build one C-N bond, one C-C bond, and one C-O bond sequentially in a single step. The synthetic utility was demonstrated with gram-scale reactions and various transformations of the products.

Erianin inhibits the oncogenic properties of hepatocellular carcinoma via inducing DNA damage and aberrant mitosis.

Natural compounds have been confirmed as one of the most feasible solutions for hard-to-treat cancers such as hepatocellular carcinoma (HCC). Erianin, a natural bibenzyl compound from Dendrobium chrysotoxum, has been recently discovered with anticancer property in cancer cells. However, the roles and the molecular mechanisms of erianin in HCC remain unknown. The present study evaluates the effect of erianin on human HCC cells by inhibiting cell proliferation, inducing apoptotic-related cell death and hampering tumorigenicity. Furthermore, it was found that erianin could cause irreparable DNA damage, induce G2/M arrest and deregulate mitotic regulators. It was also observed that many cells with damaged DNA induced by erianin could overcome G2/M arrest and enter mitosis, leading to abnormal mitosis, and subsequently mitotic catastrophe and apoptotic-related cell death. The present study confirmed that erianin could be a potential antitumor agent for HCC clinical treatment.

Prognostic Value of Prolonged Feeding Intolerance in Predicting All-Cause Mortality in Critically Ill Patients: A Multicenter, Prospective, Observational Study.

BACKGROUND: The 2012 European Society of Intensive Care Medicine (ESICM) guidelines provided a clear definition of feeding intolerance (FI). The study aimed to investigate the association between FI based on the current ESICM definition and clinical outcome and to further explore the effect of the duration of FI on mortality. METHODS: Adult patients from 14 general intensive care units (ICUs) with an expected ICU stay ≥24 hours were prospectively studied. Based on FI duration in the first week of admission to the ICU, FI was categorized as 7-day persistent feeding tolerance (FT), delayed FT, delayed FI, and 7-day persistent FI. The primary outcomes were 28-day and 60-day all-cause mortality. RESULTS: Of 499 patients, the prevalence of 3-day and 7-day persistent FI was 39.2% (n = 196) and 25.4% (n = 106), respectively. The patients with 3-day FT had lower risk of 28-day and 60-day mortality rates and higher prevalence in ventilator weaning and vasoactive medication on the seventh day of ICU admission than those with 3-day FI. Three-day FI remained an independent predictor for 60-day mortality. In a subgroup analysis including 418 patients with 7-day survival, compared with those with 7-day persistent FT, the odds ratios of 60-day mortality were 1.67, 1.97, and 2.62 in the patients with delayed FT, delayed FI, and 7-day persistent FI, respectively. CONCLUSION: FI was associated with increased mortality and longer duration of mechanical ventilation and vasoactive support. Prolonged or relapsing FI represented an incremental risk of adverse outcomes in critically ill patients.

DABCO-mediated [3+3] annulation of para-quinamines: access to functionalized 1,2,4-triazinone derivatives.

An unprecedented [3+3]-annulation of p-quinamines and nitrile imines was developed, affording a series of 1,2,4-triazinone derivatives in moderate to excellent yields with excellent diastereoselectivity. This cycloaddition expands the scope of p-quinamines to the construction of six-membered nitrogen-containing heterocyclic compounds.

Phosphine Sequentially Catalyzed Domino 1,6-Addition/Annulation: Access to Functionalized Chromans and Tetrahydroquinolines with an Ethynyl-Substituted All-Carbon Quaternary Center.

A novel phosphine sequentially catalyzed domino 1, 6-addition/annulation process has been developed using p-quinone methides ( p-QMs) and α-substituted allenoates which generates a series of chroman and tetrahydroquinoline derivatives containing an ethynyl-substituted all-carbon quaternary center with up to 97% yield and 20:1 dr. value. In this reaction, allenoates act as C2 synthons.

Sequential Phosphine-Catalyzed [4 + 2] Annulation of ß'-Acetoxy Allenoates: Enantioselective Synthesis of 3-Ethynyl-Substituted Tetrahydroquinolines.

The first enantioselective sequential phosphine-catalyzed (SPC as abbreviation) mode for the formation of tetrahydroquinolines with an ethynyl-substituted all-carbon quaternary stereogenic center is reported. In this SPC process, a novel [4 + 2] annulation process was devised employing α-substituted allenoates as C2 synthons (α-ß', 1,2-dipole) for the first time. 3-Ethynyl-substituted tetrahydroquinolines were readily prepared in good yields and high enantioselectivities.

Socioeconomic status disparities affect children's anxiety and stress-sensitive cortisol awakening response through parental anxiety.

Socioeconomic status (SES) disparities have profound impacts on child development and health, which are linked to negative emotions and alterations in the integrity of stress-sensitive hypothalamus-pituitary-adrenal (HPA)-axis system. However, its underlying psychophysiological mechanisms remain poorly understood. Here we investigate how family SES, in concert with parental anxiety, affects children's anxiety and their integrity of HPA-axis system in two studies involving a total of 1318 children and their parents. In Study 1 with a cohort of 1088 children and their parents, we found that low-SES children relative to high-SES ones experienced a higher level of anxiety mediated by increasing parental anxiety. In Study 2 with an independent cohort of 230 children and their parents, we found that low-SES children exhibited an increase in pre-bedtime basal cortisol but a decrease in cortisol awakening response (CAR). Structural equation modeling (SEM) further revealed that the association between low SES and children's reduced CAR was mediated by increased parental and child anxiety. Our findings suggest that low-SES children are more vulnerable to anxiety and altered HPA-axis integrity, most likely mediated through increased parental anxiety.

A phosphine mediated sequential annulation process of 2-tosylaminochalcones with MBH carbonates to construct functionalized aza-benzobicyclo[4.3.0] derivatives.

A novel phosphine mediated sequential annulation process to construct functionalized aza-benzobicyclo[4.3.0] derivatives has been developed involving a one-pot sequential catalytic and stoichiometric process, which generates a series of benzobicyclo[4.3.0] compounds containing one quaternary center with up to 94% yield and 20 : 1 dr value. In this reaction, MBH carbonates act as 1,2,3-C3 synthons.