Changes in cognitive function after a 12-week POWER rehabilitation in older adults with schizophrenia and frailty.

BACKGROUND: The effectiveness of isolated resistance training (RT) on cognitive function among older adults with schizophrenia is insufficiently investigated. This study investigated the effectiveness of 12-weeks POWER rehabilitation, a novel RT regimen, on cognitive function among older patients with schizophrenia and frailty. METHODS: Thirty-two older adults with schizophrenia and frailty were enrolled and randomized to receive either a 12-week, twice weekly POWER rehabilitation, or without add-on training. Cognitive functioning was assessed using mini-mental state examination (MMSE), digit symbol substitution test, color trail task (CTT), and digit span task (DST). Physical performance was assessed by walking speed and hand grip strength. The generalized estimating equations was used to compare pre- and post-training outcome measure between groups. RESULTS: Between-group analysis revealed significant improvement in CTT1 and hand grip strength in the intervention group compared to the controls. Subgroup analyses showed CTT1 performance significantly improved after 12 weeks of POWER rehabilitation in the intervention group (time, p < .001), independent of age, educational level, global cognition, depressive symptoms, and psychotropic medication use. Increased hand grip strength was significantly associated with improved performance in MMSE, CTT1, and DST forward at study endpoint. CONCLUSION: A 12-week POWER rehabilitation for older patients with schizophrenia and frailty is safe and feasible, and may benefit physical and some domains of cognitive functioning.

Effect of Community Treatment Orders on Mental Health Service Usage, Emergency Visits, and Violence: a Systematic Review and Meta-Analysis.

INTRODUCTION: Community treatment orders (CTOs) enable patients to actively engage in mental health services while being supervised in the community outside the hospital setting. However, the efficacy of CTOs remains controversial in terms of mental health services usage or service contacts, emergency visits, and violence. METHODS: The databases PsychINFO, Embase, and Medline were searched on 11 March 2022 by 2 independent reviewers through the Covidence website (www.covidence.org). Randomised or non-randomised case-control studies and pre-post studies were included if they examine the effect of CTOs on service contacts, emergency visits, and violence in individuals with mental illnesses by comparing with control groups or pre-CTO conditions. Conflicts were resolved by consultation of the third independent reviewer. RESULTS: Sixteen studies provided sufficient data in the target outcome measures and were included in analysis. Variability in the risk of bias was high among studies. Meta-analyses were conducted separately for case-control studies and pre-post studies. For service contacts, a total of 11 studies with 66,192 patients reported changes in the number of service contacts under CTOs. In 6 case-control studies, a small non-significant increase in service contacts was observed in those under CTOs (Hedge's g = 0.241, z = 1.535, p = 0.13). In 5 pre-post studies, a large and significant increase in service contacts was noted after CTOs (Hedge's g = 0.830, z = 5.056, p < 0.001). For emergency visits, a total of 6 studies with 930 patients reported changes in the number of emergency visits under CTOs. In 2 case-control studies, a small non-significant increase in emergency visits was noted in those under CTOs (Hedge's g = -0.196, z = -1.567, p = 0.117). In 4 pre-post studies, a small significant decrease in emergency visits was noted after CTOs (Hedge's g = 0.553, z = 3.101, p = 0.002). For violence, a total of 2 pre-post studies reported a moderate significant reduction in violence after CTOs (Hedge's g = 0.482, z = 5.173, p < 0.001). CONCLUSION: Case-control studies showed inconclusive evidence, but pre-post studies showed significant effects of CTOs in promoting service contacts and reducing emergency visits and violence. Future studies on cost-effectiveness analysis and qualitative analysis for specific populations with various cultures and backgrounds are warranted.

Awareness, perceptions, and acceptance of human papillomavirus vaccination among parents in Hong Kong.

INTRODUCTION: This study investigated the awareness, perceptions, and acceptance of human papillomavirus (HPV) vaccination for children among parents in Hong Kong. It also explored factors associated with, and differences in, vaccine acceptance and hesitancy between parents of girls and boys. METHODS: Parents of boys or girls in Primary 5 to 6 were invited to participate in an online survey through an established health and lifestyle e-platform. RESULTS: Overall, 851 parents completed the survey: 419 (49.2%) had daughters, 348 (40.9%) had sons, and 84 (9.9%) had children of both genders. Parents who enrolled their children into the Childhood Immunisation Programme were more likely to accept HPV vaccination (79.7% vs 33.7%, odds ratio [OR]=7.70; 95% confidence interval [CI]=5.39-11.01; P<0.001); parents of girls were more likely to accept than parents of boys (86.0% vs 71.8%, OR=2.40; 95% CI=1.67-3.46; P<0.001). Among parents of girls and boys, the main reasons for HPV vaccination acceptance were prevention of cancers (girls: 68.8% and boys: 68.7%), prevention of sexually transmitted diseases (girls: 67.3% and boys: 68.3%), and optimal timing before initiation of sexual activity (girls: 62.8% and boys: 59.8%). Vaccine hesitancy was mainly associated with concerns about serious side-effects (girls: 66.7% and boys: 68.0%) and the belief that their children were too young (girls: 60.0% and boys: 54.0%). CONCLUSION: Parents in Hong Kong are hesitant about HPV vaccination for their sons. This barrier could be removed by providing information to correct vaccine safety misconceptions and offering a gender-neutral vaccination programme through the school-based Childhood Immunisation Programme.

Brain structural abnormalities and trait impulsivity in suicidal and non-suicidal patients with bipolar disorder.

BACKGROUND: Impulsivity is a characteristic of patients with bipolar disorder (BD) and may result in a higher risk of suicide attempt (SA). Although brain structural abnormalities have been suggested in the pathophysiology of BD, the relationship to impulsivity and suicide in BD is still not clear. METHODS: 52 euthymic patients with BD (26 of them had a history of SA) and 56 age- and sex-matched healthy controls were recruited. All participants received clinical assessment, including Barratt impulsiveness scale (BIS), and underwent structural magnetic resonance imaging examination. An automated surface-based method (FreeSurfer) was used to measure brain volume and cortical surface area. A general linear model was applied to analyze the association between brain-wise greater gray matter volume (GMV), surface area and BIS scores separately for BD patients with and without SA history. RESULTS: BD patients with SA history scored higher in BIS total score and subscores in attention, motor, cognitive complexity and cognitive instability than those without SA history and controls (all p < 0.01). In patients with SA history, higher BIS scores were associated with greater GMV in the left pars triangularis and greater surface area in left pars opercularis (all p < 0.01). BD patients with SA history showed a greater GMV in inferior frontal gyrus than patients without SA history (p < 0.05). LIMITATION: The cross-sectional design precluded examination of chronological relationships of SA, brain structural abnormalities, and trait impulsivity among BD. CONCLUSIONS: The findings indicate that the prefrontal cortex, especially the left inferior frontal gyrus, plays a vital role in trait impulsivity and suicidal behavior among patients with BD.

A longitudinal study of the association between pro-inflammatory cytokines and mood symptoms in bipolar disorder.

BACKGROUND: Because of a relative dearth of longitudinal studies, the directionality of the relationship between mood and inflammation among patients with bipolar disorder (BD) is still unclear. We aimed to investigate the longitudinal associations of pro-inflammatory markers with mood symptom severity in BD. METHODS: Hundred and thirty-two adult patients with BD were enrolled. At the baseline and 1-year follow-up visit, all participants received mood assessment with Montgomery Åsberg depression rating scale (MADRS) and Young mania rating scale, and underwent blood draws to quantify metabolic profile and serum levels of the pro-inflammatory markers, including soluble interleukin-6 receptor, soluble tumor necrosis factor-α receptor type 1 (sTNF-αR1), monocyte chemoattractant protein-1, and C-reactive protein. A four-factor model of MADRS, consisting of sadness, negative thoughts, detachment, and neurovegetative symptoms, were applied. RESULTS: At baseline, 65 patients with BD were in depressed state, and 67 patients with BD were in euthymic state. Among patients in depressed state, baseline MADRS total score positively correlated with sTNF-αR1 level at follow-up. While baseline sTNF-αR1 level positively predicted sadness symptom in euthymic patients with BD who later developed depression (n = 22), sadness in patients with bipolar depression predicted later increase in serum sTNF-αR1 level even after remission (n = 17). Moreover, lithium had a stronger effect of lowering peripheral sTNF-αR1 level as compared with other mood stabilizers. CONCLUSION: Our results indicate the bidirectional inflammation-depression relationship in BD.

Exploring the role of hub and network dysfunction in brain connectomes of schizophrenia using functional magnetic resonance imaging.

Introduction: Pathophysiological etiology of schizophrenia remains unclear due to the heterogeneous nature of its biological and clinical manifestations. Dysfunctional communication among large-scale brain networks and hub nodes have been reported. In this study, an exploratory approach was adopted to evaluate the dysfunctional connectome of brain in schizophrenia. Methods: Two hundred adult individuals with schizophrenia and 200 healthy controls were recruited from Taipei Veterans General Hospital. All subjects received functional magnetic resonance imaging (fMRI) scanning. Functional connectivity (FC) between parcellated brain regions were obtained. Pair-wise brain regions with significantly different functional connectivity among the two groups were identified and further analyzed for their concurrent ratio of connectomic differences with another solitary brain region (single-FC dysfunction) or dynamically interconnected brain network (network-FC dysfunction). Results: The right thalamus had the highest number of significantly different pair-wise functional connectivity between schizophrenia and control groups, followed by the left thalamus and the right middle frontal gyrus. For individual brain regions, dysfunctional single-FCs and network-FCs could be found concurrently. Dysfunctional single-FCs distributed extensively in the whole brain of schizophrenia patients, but overlapped in similar groups of brain nodes. A dysfunctional module could be formed, with thalamus being the key dysfunctional hub. Discussion: The thalamus can be a critical hub in the brain that its dysfunctional connectome with other brain regions is significant in schizophrenia patients. Interconnections between dysfunctional FCs for individual brain regions may provide future guide to identify critical brain pathology associated with schizophrenia.

Pro-inflammatory cytokines and cognitive dysfunction among patients with bipolar disorder and major depression.

AIM: Bipolar disorder and major depressive disorder (MDD) have been demonstrated to be associated with proinflammatory states and cognitive function deficits. We aimed to investigate the differences of cognitive function and proinflammatory cytokines between patients with bipolar I disorder (BDI), bipolar II disorder (BDII), and MDD. METHODS: Thirty-seven patients with BDI, 33 with BDII, 25 with MDD, and 54 age-, sex-matched controls were enrolled. All patients had a clinical global impression-severity scale ≤2. Serum levels of proinflammatory markers, including soluble interleukin-6 receptor, C-reactive protein, and soluble tumor necrosis factor receptor 1 (sTNF-αR1) were measured. Performance in the Word List Memory Task (WLMT), Wisconsin Card Sorting Task (WCST), 2-back task, Go/No-Go task, and divided attention task was assessed. RESULTS: Patients with BDI had higher levels of sTNF-αR1 than patients with MDD and controls (P < 0.001). Patients with BDI performed worse on WLMT, WCST, 2-back task, divided attention_visual and divided attention_auditory tasks than the other three groups (all P < 0.05). Furthermore, sTNF-αR1 levels were negatively correlated with cognitive function measured using the WLMT and divided attention_auditory (all P < 0.05). CONCLUSIONS: Patients with BDI had higher levels of sTNF-αR1 and cognitive function impairments than the remaining groups. Future studies are needed to explore the pathophysiology of sTNF-αR1 in the contribution of cognitive alterations.

Predictors of emergency department visit among people with dementia in Taiwan.

BACKGROUND: We aimed to identify predictors of emergency department (ED) visit by people with dementia (PWDs) and their caregivers with a one-year follow-up in a country with public health system. METHODS: Data were collected from a national dementia registration survey. Andersen's Behavioral Model of Health Services Use was used. Variables such as demographic data of PWDs and their caregivers, caregivers' monthly income, the relationship between PWD and caregivers, the severity of dementia (clinical dementia rating, CDR), physical comorbidities, cognitive function (mini-mental state examination, MMSE), and activities of daily living of PWDs, the caregiver burden, and neuropsychiatric symptoms (assessed by the Neuropsychiatric Inventory Questionnaire) were included in the analyses. RESULTS: A total of 1,227 PWDs-caregiver dyads completed the survey, and 405 (33%) of PWDs visited ED during the one-year follow-up. Multivariable logistic analyses revealed that older age of PWDs (odds ratio [OR] = 1.03, 95% confidence interval [CI] = 1.01-1.05), more severe dementia (CDR; OR = 1.42, 95% CI = 1.09-1.86), higher cognitive function (MMSE; OR = 1.04, 95% CI = 1.01-1.07), and having a female family caregiver (OR = 1.50, 95% CI = 1.13-2.01) were predictors of ED visit. CONCLUSION: Our study results provided information for healthcare providers and policy makers to target models of care that support PWD and their caregivers and reduce the need for ED visits.

RETRACTED - Risk factors for mild behavioral impairment in non-demented geriatrics: a population-based survey in Taiwan.

OBJECTIVES: To investigate potential risk factors for mild behavioral impairment (MBI) among non-demented geriatrics. DESIGN: Population-based, cross-sectional survey. SETTING: Taiwan Alzheimer Disease Association (TADA) Database. PARTICIPANTS: Participants were selected by multistage random sampling of all Taiwan counties. They received in-person interviews between December 2011 and March 2013. MEASUREMENTS: Demographic data, lifestyle and habits, medical comorbidities, cognitive status measured by the Taiwanese Mini-Mental Status Examination (TMSE) and presence of MCI of the participants were collected. Subjects were distributed to the MBI and non-MBI groups. These factors had been evaluated for their effects on MBI in the univariate and multivariable logistic regression models. RESULTS: In total, 6,196 non-demented participants aged 65 years or older, including 409 MBI and 5,787 non-MBI participants, were recruited. After adjustment for age, sex, education, body mass index, lifestyle and habits, medical comorbidities, and MCI, good sleep was associated with lower risk of MBI (OR 0.09, 95% CI 0.07 - 0.12). Low body weight (OR 2.01, 95% CI 1.21-3.33), low-to-medium education (OR 1.40, 95%CI 1.06-1.85; OR 2.32, 95% CI 1.67-3.21), medical comorbidities of hypertension (OR 1.56, 95% CI 1.25-1.95), hyperlipidemia (OR 1.29, 95% CI 1.00-1.67), cancer (OR 2.05, 95% CI 1.37-3.06) were significantly associated with increased MBI risk. MCI neither increased nor decreased risk of MBI (OR 1.00, 95% CI 0.76-1.32). CONCLUSIONS: Good sleep was associated with lower MBI risk. Underweight, lower education, medical comorbidities of cancer, hypertension, hyperlipidemia were predictive of MBI.

Pro-inflammatory cytokines and suicidal behavior among patients with bipolar I disorder.

OBJECTIVE: Suicidal behavior and different mood states of bipolar I disorder (BD) have been shown to be associated with dysregulated proinflammatory cytokines. Only a few studies have examined the association between inflammation and SB in BD, and the association between proinflammatory cytokines, SB, and cognitive deficits in patients with BD remains unclear. METHODS: 77 patients with BD and 61 age-/sex-matched healthy controls were recruited. Patients were divided into two groups: with suicidal ideation (SI; n = 21) and no SI (n = 56). SI was defined by a score of ≥1 in item 10 of Montgomery Åsberg Depression Rating Scale. Levels of proinflammatory cytokines, including soluble interleukin-6 receptor (sIL-6R), soluble tumor necrosis factor-α receptor type 1 (sTNF-αR1), and C-reactive protein (CRP), were measured, and cognitive function was assessed using 2-back task and Go/No-Go task. RESULTS: Patients with SI had higher levels of sTNF-αR1 than those without SI and the controls (p = .004). BD patients with or without a history of suicide attempt had higher levels of CRP than the controls. SI was associated with serum levels of sTNF-αR1 and IL-6sR, even after additionally controlling for working memory and inhibitory control (p < .05). CONCLUSION: This study indicates that serum levels of sTNF-αR1 have distinct differences between BD patients with or without SI, and our findings strengthen the hypothesis of a link between suicidal behavior and neuro-inflammation pathophysiology in BD.

Treatment response and age of onset as risk indicators for parkinson disease in patients with major depressive disorder: A nationwide longitudinal study.

BACKGROUND: Individuals with major depressive disorder (MDD) have a higher risk of developing Parkinson disease (PD). This study investigated whether response to treatment with antidepressants for MDD can determine patients at risk of developing PD later in life. METHODS: We enrolled 3303 patients with newly-diagnosed MDD and 13,212 controls between 2002 and 2004 using Taiwan's Nationwide Health Insurance Research Database. We stratified patients with MDD according to the number of antidepressant regimens prescribed to them and the age at MDD onset and followed all participants until the end of 2013. During follow-up, we evaluated patients for the possibility of developing PD. RESULTS: Patients with MDD had a greater likelihood of developing PD than controls. Patients with difficult-to-treat (DTT) MDD had a higher risk of developing PD than the other MDD subgroups (hazard ratio [HR] = 3.44, 95% confidence interval [95% CI]: = 1.99-5.95). When stratified by age (<50, 50-65, >65 years), DTT patients with middle-age or late-onset MDD exhibited elevated risks of developing PD (50-65 years: HR: 7.03, 95% CI: 2.95-16.76; >65 years: HR: 2.89, 95% CI: 1.26-6.65). DISCUSSION: Patients with MDD and an onset age of >50 years who responded poorly to antidepressant treatment have an associated higher risk of subsequently developing PD. Therefore, when treating patients with MDD, clinicians should provide intensive antidepressant treatment and evaluations for PD so that risk-prevention measures can be implemented upon MDD diagnosis.

Enhanced retinoid response by a combination of the vitamin A ester retinyl propionate with niacinamide and a flavonoid containing Ceratonia siliqua extract in retinoid responsive in vitro models.

OBJECTIVES: Retinoids have been used for decades as efficacious topical agents to treat photoaged skin. The purpose of our present research is to evaluate whether the activity of the vitamin A ester retinyl propionate (RP) can be enhanced by niacinamide (Nam) and a flavonoid containing Ceratonia siliqua (CS) fruit extract in retinoid responsive in vitro models. METHODS: Retinyl propionate was tested alone and in combination with Nam and CS in an RARα reporter cell line for promoter activation and compared to trans-retinoic acid (tRA) activation. These treatments were also tested in keratinocytes for gene expression profiling by qPCR using a panel of 40 retinoid responsive genes. RESULTS: tRA or RP elicited RARα reporter activation in a dose-dependent manner. The combination of 0.5 µM or 2 µM RP with 10 mM Nam had a 56% and 95% signal increase compared to RP, respectively. The addition of 1% CS to 0.5 µM or 2 µM RP with 10 mM Nam elicited a further increase of 114% and 156%, respectively, over RP and Nam combinations. All retinoids elicited an increase in expression of 40 retinoid sensitive genes over control levels. Of the 40 genes, 27 were enhanced by either 0.1 µM RP or 0.5 µM RP with 10 mM Nam and 1% CS. Nam or CS had very modest activity in both models. CONCLUSION: The combination of RP with Nam and CS showed a higher retinoid response than RP in two separate retinoid responsive in vitro models. We hypothesize Nam and CS enhances RP activity by modulating metabolism to tRA via increasing NAD+ pools and inhibiting reduction of retinal (RAL) back to retinol, respectively. The findings provide evidence that this combination may have enhanced efficacy for treating the appearance of photoaged skin.

OBJECTIFS: Les rétinoïdes sont utilisés depuis des décennies comme agents topiques efficaces pour traiter la peau photo-âgée. Le but de notre recherche actuelle est d'évaluer si l'activité du propionate rétinyl ester de vitamine A (RP) peut être augmentée par le niacinamide (Nam) et un flavonoïde contenant un extrait de fruit de Ceratonia Siliqua (CS) dans les modèles in vitro sensibles aux rétinoïdes. MÉTHODES: RP a été testé seul et en combinaison avec Nam et CS dans une ligne de cellule rapporteur de RARα pour l'activation du promoteur et par rapport à l'activation de l'acide transrétinoïque(tRA). Ces traitements ont également été testés dans les kératinocytes pour le profilage d'expression génique par qPCR à l'aide d'un panel de 40 gènes rétinoïdes sensibles. RÉSULTATS: tRA ou RP ont provoqué l'activation du promoteur RARα d'une manière dépendante de la dose. La combinaison de 0,5 µM ou 2 µM de RP avec 10 mM de Nam a permis une augmentation respectivement de 56% et 95% du signal par rapport à RP. L'ajout de 1 % de CS à 0,5 µM ou 2 µM de RP avec 10 mM de Nam a permis une nouvelle augmentation de 114 % et 156 %, respectivement, qu'avec la combinaison RP et Nam. Tous les rétinoïdes ont provoqué une augmentation de l'expression de 40 gènes sensibles aux rétinoïdes sur les niveaux de contrôle. Sur les 40 gènes, 27 ont été améliorés soit par 0,1 µM de RP ou 0.5 µM de RP avec 10 mM de Nam et 1% de CS. Nam ou CS avaient une activité très modeste dans les deux modèles. CONCLUSION: La combinaison de RP avec Nam et CS a montré une réponse rétinoïde plus élevée que RP dans deux modèles in vitro séparés sensibles aux rétinoïdes. Nous émettons l'hypothèse que Nam et CS améliorent l'activité RP en modulant le métabolisme de tRA par l'augmentation des groupement NAD+ et en inhibant la réduction du rétinal (RAL) en rétinol, respectivement. Les résultats fournissent la preuve que cette combinaison peut améliorer l'efficacité du traitement de l'aspect de la peau photo-âgée.

Association between gastrointestinal symptoms and depression among older adults in Taiwan: A cross-sectional study.

BACKGROUND: Older adults with depression more frequently experience somatic and gastrointestinal (GI) problems compared with people without depression and younger adults with depression. However, whether GI symptoms are predictive of elevated rates of depression among older adults is unclear. METHODS: We enrolled 106 older adults (>60 years old); 69 had late-life depression (LLD), and 37 were controls. All participants gave ratings on the Gastrointestinal Symptom Rating Scale (GSRS) and Hamilton Depression Rating Scale. Food consumption was assessed using a food frequency questionnaire, and a Mediterranean diet score was used as a covariate. RESULTS: Compared with the controls, patients with LLD reported higher levels of depressive and GI symptoms and reported more reflux, abdominal pain, and dyspepsia symptoms, and these symptoms were correlated with Hamilton Depression Rating Scale scores (GSRS total: ß = 0.47; reflux: ß = 1.47; abdominal pain: ß = 1.98; dyspepsia: ß = 1.02; all p < 0.01). After demographic variables and Mediterranean diet score were controlled for, a logistic regression analysis indicated that total GSRS score was an independent determinant of LLD (odds ratio: 1.20, 95% CI: 1.04-1.38). Moreover, a stratified analysis by depression severity indicated that higher total GSRS score may contribute to greater depression severity (odds ratio: 1.25, 95% CI: 1.04-1.52). CONCLUSION: We provide evidence that GI symptoms are associated with depressive symptoms among patients with LLD. Older people with more specific GI symptoms, such as reflux, abdominal pain, and dyspepsia, are potentially at greater risk of having LLD.

Treatment-Resistant depression enhances risks of dementia and alzheimer's disease: A nationwide longitudinal study.

BACKGROUND: Previous evidence indicates late-onset depression or depression with greater severity are associated with subsequent risk of dementia or Alzheimer's disease (AD). However, whether treatment-resistant depression is associated with such risks remain elusive. METHODS: Using the Taiwan Nationwide Health Insurance Research Database, 3,345 patients with newly-diagnosed major depressive disorder (MDD) and 13,380 well-matched controls were enrolled between 2002 and 2004. MDD patients were stratified according to their treatment response to adequate antidepressant trials, and all participants were followed up until the end of 2013. Those who developed dementia and AD were identified. RESULTS: MDD patients were more likely to develop dementia and AD than controls. Difficult-to-treat patients (i.e., DTT; those who failed to respond to at least two adequate antidepressant trials) had the highest risk of developing dementia (hazard ratio [HR] = 5.19) and AD (HR 4.44), whereas easy-to-treat patients (i.e., ETT-1; those who had no prescription of antidepressants) had the lowest risk of developing dementia (HR 2.37) and AD (HR 2.59) compared with controls. Subsequent analysis demonstrated that only among patients with late-onset depression (age > 65 years), DTT patients consistently showed higher risks and faster development of dementia (HR 6.64, mean: 1.45 yr) and AD (HR 4.97, mean: 1.67 yr) than did ETT-1 patients and controls. LIMITATIONS: Subjects who have not received medical examination were not included as diagnosis were determined by ICD codes. Also, longer follow-up period might be needed for the younger group. CONCLUSIONS: Late-onset treatment-resistant depression is associated with an elevated risk of dementia and AD.

Single-cell reconstruction of follicular remodeling in the human adult ovary.

The ovary is perhaps the most dynamic organ in the human body, only rivaled by the uterus. The molecular mechanisms that regulate follicular growth and regression, ensuring ovarian tissue homeostasis, remain elusive. We have performed single-cell RNA-sequencing using human adult ovaries to provide a map of the molecular signature of growing and regressing follicular populations. We have identified different types of granulosa and theca cells and detected local production of components of the complement system by (atretic) theca cells and stromal cells. We also have detected a mixture of adaptive and innate immune cells, as well as several types of endothelial and smooth muscle cells to aid the remodeling process. Our results highlight the relevance of mapping whole adult organs at the single-cell level and reflect ongoing efforts to map the human body. The association between complement system and follicular remodeling may provide key insights in reproductive biology and (in)fertility.

BRD4 bimodal binding at promoters and drug-induced displacement at Pol II pause sites associates with I-BET sensitivity.

BACKGROUND: Deregulated transcription is a major driver of diseases such as cancer. Bromodomain and extra-terminal (BET) proteins (BRD2, BRD3, BRD4 and BRDT) are chromatin readers essential for maintaining proper gene transcription by specifically binding acetylated lysine residues. Targeted displacement of BET proteins from chromatin, using BET inhibitors (I-BETs), is a promising therapy, especially for acute myeloid leukemia (AML), and evaluation of resistance mechanisms is necessary to optimize the clinical efficacy of these drugs. RESULTS: To uncover mechanisms of intrinsic I-BET resistance, we quantified chromatin binding and displacement for BRD2, BRD3 and BRD4 after dose response treatment with I-BET151, in sensitive and resistant in vitro models of leukemia, and mapped BET proteins/I-BET interactions genome wide using antibody- and compound-affinity capture methods followed by deep sequencing. The genome-wide map of BET proteins sensitivity to I-BET revealed a bimodal pattern of binding flanking transcription start sites (TSSs), in which drug-mediated displacement from chromatin primarily affects BRD4 downstream of the TSS and prolongs the pausing of RNA Pol II. Correlation of BRD4 binding and drug-mediated displacement at RNA Pol II pause sites with gene expression revealed a differential behavior of sensitive and resistant tumor cells to I-BET and identified a BRD4 signature at promoters of sensitive coding and non-coding genes. CONCLUSIONS: We provide evidence that I-BET-induced shift of Pol II pausing at promoters via displacement of BRD4 is a determinant of intrinsic I-BET sensitivity. This finding may guide pharmacological treatment to enhance the clinical utility of such targeted therapies in AML and potentially other BET proteins-driven diseases.

Correction: FOXO3a represses VEGF expression through FOXM1-dependent and -independent mechanisms in breast cancer.

In the published version of this article, the images for cytoplasmic and nuclear FGF7 in MDA-MB-231 cells were duplicated and mistaken for total FGF7 in SKBR-3 and MDA-MB-231 cells.