The 14-subunit metazoan-specific Integrator contains an endonuclease that cleaves nascent RNA transcripts. Here, we identified a complex containing Integrator and protein phosphatase 2A core enzyme (PP2A-AC), termed INTAC. The 3.5-angstrom-resolution structure reveals that nine human Integrator subunits and PP2A-AC assemble into a cruciform-shaped central scaffold formed by the backbone and shoulder modules, with the phosphatase and endonuclease modules flanking the opposite sides. As a noncanonical PP2A holoenzyme, the INTAC complex dephosphorylates the carboxy-terminal repeat domain of RNA polymerase II at serine-2, -5, and -7 and thus regulates transcription. Our study extends the function of PP2A to transcriptional regulation and reveals how dual enzymatic activities—RNA cleavage and RNA polymerase II dephosphorylation—are structurally and functionally integrated into the INTAC complex.

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The coronavirus disease 2019 (COVID-19) pandemic has imposed both physical and psychological burdens on healthcare workers (HCWs). What is more, few studies have focused on the gender differences in mental health problems (MHPs) among HCWs during such an outbreak. Thus, the current study investigated the prevalence and gender differences of various MHPs among HCWs in China during the COVID-19 outbreak. This nationwide survey was conducted online from January 29 to February 3, 2020. General information was collected by questions about socio-demographics, work-related factors, and living situations. Depressive, anxiety, stress, and insomnia symptoms were assessed by the Patient Health Questionnaire-9, the Generalized Anxiety Disorder-7, the Impact of Event Scale-Revised, and the Insomnia Severity Index, respectively. Among the 2198 contacted HCWs, 1563 (71.1%) responded with valid data, of whom 1293 (82.7%) were females. The prevalences of depressive, anxiety, stress, and insomnia symptoms in participants were 50.7%, 44.7%, 52.5%, and 36.1%, respectively. Female HCWs had significantly higher scores in all four scales ( p < 0.001) and higher prevalences in all MHPs involved (range, odds ratio [OR] 1.55–1.97). After adjusting for potential confounders, female HCWs still had higher risks for all MHPs involved than males (range, adjusted OR 1.36–1.96). HCWs present high prevalences of depressive, anxiety, stress, and insomnia symptoms during the COVID-19 outbreak. Furthermore, female HCWs are more vulnerable to all MHPs involved. These findings highlight the need for timely, special care and support for HCWs during the outbreak, especially for females.

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PurposeTo identify bioactive equivalent combinatorial components (BECCs) in herbal medicines. The exact composition of effective components in herbal medicines is often elusive due to the lack of adequate screening methodology. Herein, we propose a hypothesis that BECCs accounting for the whole efficacy of original herbal medicines could be discovered from a complex mixture of constituents.MethodsWe developed a bioactive equivalence oriented feedback screening method and applied it to discover the BECCs from an herbal preparation Cardiotonic Pill (CP). The operations include chemical profiling of CP, followed by an iterative loop of determining, collecting and evaluating candidate BECCs.ResultsA combination of 18 compounds was identified as BECCs from CP, which accounts for 15.0% (w/w) of original CP. We have demonstrated that the BECCs were as effective as CP in cell models and in a rat model of myocardial infarction.ConclusionsThis work answers the key question of which are real bioactive components for CP that have been used in clinic for many years, and provides a promising approach for discovering BECCs from herbal medicines. More importantly, the BECCs could be extended to improve quality control of herbal products and inspire an herbal medicines based discovery of combinatorial therapeutics.Electronic supplementary materialThe online version of this article (doi:10.1007/s11095-013-1283-1) contains supplementary material, which is available to authorized users.

Background:Cognitive impairment is a key feature of treatment-resistant depression (TRD) and can be related to the anterior cingulate cortex (ACC) function. Repetitive transcranial magnetic stimulation (rTMS) as an antidepressant intervention has increasingly been investigated in the last two decades. However, no studies to date have investigated the association between neurobiochemical changes within the anterior cingulate and executive dysfunction measured in TRD being treated with rTMS.Methods:Thirty-two young depressed patients with treatment-resistant unipolar depression were enrolled in a double-blind, randomized study [active (n=18) vs. sham (n=14)]. ACC metabolism was investigated before and after high-frequency (15Hz) rTMS using 3-tesla proton magnetic resonance spectroscopy (1H-MRS). The results were compared with 28 age- and gender-matched healthy controls. Executive functioning was measured with the Wisconsin Card Sorting Test (WCST) among 34 subjects with TRD and 28 healthy subjects.Results:Significant reductions in N-acetylaspartate (NAA) and choline-containingCompound levels in the left ACC were found in subjects with TRD pre-rTMS when compared with healthy controls. After successful treatment, NAA levels increased significantly in the left ACC of subjects and were not different from those of age-matched controls. In the WCST, more perseverative errors and fewer correct numbers were observed in TRD subjects at baseline. Improvements in both perseverative errors and correct numbers occurred after active rTMS. In addition, improvement of perseverative errors was positively correlated with enhancement of NAA levels in the left ACC in the active rTMS group.Conclusions:Our results suggest that the NAA concentration in the left ACC is associated with an improvement in cognitive functioning among subjects with TRD response to active rTMS.

Objective Little is known about the brain systems that contribute to vulnerability to post-traumatic stress disorder (PTSD). Comparison of the resting-state patterns of intrinsic functional synchronization, as measured by functional magnetic resonance imaging (fMRI), between groups with and without PTSD following a traumatic event can help identify the neural mechanisms of the disorder and targets for intervention. Methods Fifty-four PTSD patients and 72 matched traumatized subjects who experienced the 2008 Sichuan earthquake were imaged with blood oxygen level-dependent (BOLD) fMRI and analyzed using the measure of regional homogeneity (ReHo) during the resting state. Results PTSD patients presented enhanced ReHo in the left inferior parietal lobule and right superior frontal gyrus, and reduced ReHo in the right middle temporal gyrus and lingual gyrus, relative to traumatized individuals without PTSD. Conclusion Our findings showed that abnormal brain activity exists under resting conditions in PTSD patients who had been exposed to a major earthquake. Alterations in the local functional connectivity of cortical regions are likely to contribute to the neural mechanisms underlying PTSD.

BackgroundWhite matter abnormalities can cause network dysfunction that underlies major depressive disorder (MDD). Diffusion tensor imaging (DTI) is used to examine the neural connectivity and integrity of the white matter. Previous studies have implicated frontolimbic neural networks in the pathophysiology of MDD. Approximately 30% of MDD patients demonstrate treatment-resistant depression (TRD). However, the neurobiology of TRD remains unclear.MethodsWe used a voxel-based analysis method to analyze DTI data in young patients with TRD (n = 30; 19 males, 11 females) compared with right-handed, age- and sex-matched healthy volunteers (n = 25; 14 males, 11 females).ResultsWe found a significant decrease in fractional anisotropy (FA) (corrected, cluster size >50) in the left middle frontal gyrus (peak coordinates [−18 46–14]), left limbic lobe uncus (peak coordinates [−18 2–22]), and right cerebellum posterior lobe (peak coordinates [26–34 -40]). There was no increase in FA in any brain region in patients. We also found a significant negative correlation between mean regional FA values in the three areas and Beck Depression Inventory symptom scores.ConclusionsWe found significant differences in white matter FA in the frontal lobe, limbic lobe and cerebellum between TRD patients and controls. These data suggest that abnormalities of cortical-limbic-cerebellar white matter networks may contribute to TRD in young patients.