Identification of conserved skeletal enhancers associated with craniosynostosis risk genes.

Craniosynostosis, defined by premature fusion of one or multiple cranial sutures, is a common congenital defect affecting more than 1/2000 infants and results in restricted brain expansion. Single gene mutations account for 15-20% of cases, largely as part of a syndrome, but the majority are nonsyndromic with complex underlying genetics. We hypothesized that the two noncoding genomic regions identified by a GWAS for craniosynostosis contain distal regulatory elements for the risk genes BMPER and BMP2. To identify such regulatory elements, we surveyed conserved noncoding sequences from both risk loci for enhancer activity in transgenic Danio rerio. We identified enhancers from both regions that direct expression to skeletal tissues, consistent with the endogenous expression of bmper and bmp2. For each locus, we also found a skeletal enhancer that also contains a sequence variant associated with craniosynostosis risk. We examined the activity of each enhancer during craniofacial development and found that the BMPER-associated enhancer is active in the restricted region of cartilage closely associated with frontal bone initiation. The same enhancer is active in mouse skeletal tissues, demonstrating evolutionarily conserved activity. Using enhanced yeast one-hybrid assays, we identified transcription factors that bind each enhancer and observed differential binding between alleles, implicating multiple signaling pathways. Our findings help unveil the genetic mechanism of the two craniosynostosis risk loci. More broadly, our combined in vivo approach is applicable to many complex genetic diseases to build a link between association studies and specific genetic mechanisms.

Nivolumab plus ipilimumab combination therapy in patients with advanced hepatocellular carcinoma previously treated with sorafenib: 5-year results from CheckMate 040.

BACKGROUND: Nivolumab plus ipilimumab demonstrated promising clinical activity and durable responses in sorafenib-treated patients with advanced hepatocellular carcinoma (HCC) in the CheckMate 040 study at 30.7-month median follow-up. Here, we present 5-year results from this cohort. PATIENTS AND METHODS: Patients were randomized 1 : 1 : 1 to arm A [nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W (four doses)] or arm B [nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W (four doses)], each followed by nivolumab 240 mg Q2W, or arm C (nivolumab 3 mg/kg Q2W plus ipilimumab 1 mg/kg Q6W). The primary objectives were safety, tolerability, investigator-assessed objective response rate (ORR), and duration of response (DOR) per RECIST version 1.1. RESULTS: A total of 148 patients were randomized across treatment arms. At 60-month minimum follow-up (62.6-month median follow-up), the ORR was 34% (n = 17), 27% (n = 13), and 29% (n = 14) in arms A, B, and C, respectively. The median DOR was 51.2 months [95% confidence interval (CI) 12.6 months-not estimable (NE)], 15.2 months (95% CI 7.1 months-NE), and 21.7 months (95% CI 4.2 months-NE), respectively. The median overall survival (OS) was 22.2 months (34/50; 95% CI 9.4-54.8 months) in arm A, 12.5 months (38/49; 95% CI 7.6-16.4 months) in arm B, and 12.7 months (40/49; 95% CI 7.4-30.5 months) in arm C; 60-month OS rates were 29%, 19%, and 21%, respectively. In an exploratory analysis of OS by response (6-month landmark), the median OS was meaningfully longer for responders versus nonresponders for all arms. No new safety signals were identified with longer follow-up. There were no new discontinuations due to immune-mediated adverse events since the primary analysis. CONCLUSIONS: Consistent with the primary analysis, the arm A regimen of nivolumab plus ipilimumab continued to demonstrate clinically meaningful responses and long-term survival benefit, with no new safety signals in patients with advanced HCC following sorafenib treatment, further supporting its use as a second-line treatment in these patients.

Autoimmune blistering diseases treated with glucocorticoids: An international study of steroid-induced myopathy.

BACKGROUND: Patients with autoimmune blistering diseases (AIBDs) are often exposed to chronic glucocorticoid (GC) treatment with many side effects. Glucocorticoid-induced myopathy (GIM) is a well-established side effect, which particularly affects the proximal muscles. The Glucocorticoid Toxicity Index (GTI) is a validated global assessment tool which quantifies GC toxicity over time. OBJECTIVES: This study marks the first study which analyses GIM in patients with AIBDs. The objectives of this study were to utilize the GTI to investigate the nature and prevalence of GIM in AIBD patients and explore potential risk factors. METHODS: This international cohort study was conducted in blistering disease clinics across Australia, China, Greece, Iran, Japan, the Philippines, Turkey and the United States of America between February 2019 and July 2023. The GTI tool was completed by a medical practitioner at each patient visit. Data related to glucocorticoid toxicity were entered into the Steritas GTI 2.0 to generate an aggregate improvement and cumulative worsening score at each visit. RESULTS: The study included 139 patients. There were 132 episodes of myopathy, and 47.5% of patients developed muscle weakness at some point during the study period. Cumulative GC dose correlated positively with myopathy risk, while average dose and treatment duration were not significant. Older age, male gender and obesity more than doubled the likelihood of developing GIM. CONCLUSIONS: GIM is a common side effect experienced by AIBD patients on GC treatment. Muscle weakness is less likely to occur if cumulative GC dose is less than 0.75 mg/kg/day. Studies of exercise programs to mitigate myopathy and newer alternative treatments to reduce cumulative GC dose should be considered.

CREB inactivation by HDAC1/PP1γ contributes to dopaminergic neurodegeneration in Parkinson's disease.

Understanding the pathogenesis of nigral dopaminergic neurodegeneration is critical for developing mechanism-based treatments for Parkinson's disease (PD). In the nigral dopaminergic neurons of postmortem human PD brains, we found that CREB, a well-recognized pro-survival transcription factor in neurons, was inactivated by dephosphorylation at Ser133. CREB dephosphorylation correlated with decreased expression of NURR1, one of its target genes crucial for dopaminergic neuron survival, confirming that CREB function was impaired in nigral dopaminergic neurons in PD. An MPTP mouse model was used to further elucidate the mechanism underlying CREB dephosphorylation. Protein phosphatase 1γ (PP1γ), which dephosphorylates CREB, was constitutively associated with histone deacetylase 1 (HDAC1). HDAC1 promotes CREB Ser133 dephosphorylation via a stable interaction with PP1γ. We found that CREB interacted with the HDAC1/PP1γ complex during dopaminergic neurodegeneration. Importantly, increased CREB/HDAC1 interaction occurred in the nigral dopaminergic neurons of PD patients as demonstrated using a proximity ligation assay. Disrupting CREB/HDAC1 interaction via either overexpression of GAL4 M1, a CREB mutant, or administration of trichostatin A, a pan-HDAC inhibitor, restored the expression levels of phospho-CREB (Ser133) and NURR1, and protected nigral dopaminergic neurons in the MPTP-treated mice brain. Collectively, our results demonstrated that HDAC1/PP1γ-mediated CREB inactivation contributed to dopaminergic neuronal degeneration. Disruption of CREB/HDAC1 interaction has the potential as a new approach for PD therapy.Significance StatementPD is the most common movement disorder attributed to the progressive loss of dopaminergic neurons in the substantia nigra. Understanding the pathogenesis of nigral dopaminergic neurodegeneration is critical for developing mechanism-based treatments for PD. We found in nigral dopaminergic neurons of postmortem human PD brains that CREB, a well-recognized pro-survival transcription factor in neurons, was inactivated by dephosphorylation at Ser133. HDAC1, constitutively associated with PP1γ, interacted with CREB to mediate its dephosphorylation during dopaminergic degeneration. Disrupting CREB/HDAC1 interaction restored CREB activity and protected nigral dopaminergic neurons in the MPTP mouse brains. This work suggests that disruption of the CREB/HDAC1 interaction to restore CREB activity may be a potential therapeutic approach in PD.

Novelty is not surprise: Human exploratory and adaptive behavior in sequential decision-making.

Classic reinforcement learning (RL) theories cannot explain human behavior in the absence of external reward or when the environment changes. Here, we employ a deep sequential decision-making paradigm with sparse reward and abrupt environmental changes. To explain the behavior of human participants in these environments, we show that RL theories need to include surprise and novelty, each with a distinct role. While novelty drives exploration before the first encounter of a reward, surprise increases the rate of learning of a world-model as well as of model-free action-values. Even though the world-model is available for model-based RL, we find that human decisions are dominated by model-free action choices. The world-model is only marginally used for planning, but it is important to detect surprising events. Our theory predicts human action choices with high probability and allows us to dissociate surprise, novelty, and reward in EEG signals.

MiR-744 mediates the Oxaliplatin chemoresistance in colorectal cancer through inhibiting BIN1.

Colorectal cancer (CRC) is one of the most common malignant cancers worldwide. However, lacking of novel and sensitive chemotherapy revealed the major challenge to improve the survival of CRC patients. The aim of this study was to explore the effect and mechanism of miR-744 on the oxaliplatin chemoresistance in CRC. Firstly, the levels of miR-744 were elevated significantly in CRC tissues from patients with oxaliplatin administration before surgery and in oxaliplatin-resistant HCT116 cells. Then, the oxaliplatin chemoresistance was enhanced by miR-744 overexpression, while was attenuated by miR-744 inhibition in HCT116 and T84 cells. Additionally, the level of BIN1 protein was found to be regulated negatively by miR-744, and BIN1 overexpression blocked the oxaliplatin chemoresistance induced by miR-744. Furthermore, BIN1 was proved to be a direct target of miR-744 by luciferase reporter assay. Taken together, these findings demonstrated that miR-744 might positively mediate the oxaliplatin chemoresistance through suppressing BIN1 expression in CRC cells, thus suggested a rationale target for the developing more effective strategies to reverse oxaliplatin resistance in CRC treatment.

Cryptoanalysis on optical image encryption systems based on the vector decomposition technique in the Fourier domain.

In this paper, the security of optical cryptosystems based on the vector decomposition technique in the Fourier domain is analyzed. Compared to the conventional cryptosystem based on the equal modulus decomposition (EMD) technique, an additional EMD structure is introduced in the cascaded EMD-based cryptosystem; hence, the mask including the phase information of the Fourier spectrum is further encoded in the second EMD structure to enhance the security level. However, it is shown that the number of the private keys has not been increased in the cascaded EMD-based cryptosystem, which makes it possible to crack the cascaded EMD-based cryptosystem. Therefore, a chosen-plaintext attack (CPA) and a special attack with an arbitrarily given private key are proposed to retrieve information from encoded images obtained by the cascaded EMD-based cryptosystem. In addition, the security of the cryptosystem based on the random modulus decomposition (RMD) technique is also analyzed. Compared to the EMD-based cryptosystem in which the Fourier spectrum is decomposed into two vectors with equal moduli, the security level of the cryptosystem has been improved by using the RMD technique to decompose the spectrum into vectors with unequal moduli to decrease the number of the amplitude constraints. However, it is found that the arbitrarily given ciphertext provides the attackers enough information to retrieve the precise information of the plaintext without any knowledge of the private keys. A special attack is proposed to crack the RMD-based cryptosystem. This is the first time to report that these two cryptosystems based on the vector decomposition technique are attacked successfully. Numerical simulation is conducted to validate the feasibility and effectiveness of the proposed attacks.

Security analysis and enhancement of a cryptosystem based on phase truncation and a designed amplitude modulator.

In this paper, the security of a cryptosystem based on phase truncation and a designed amplitude modulator (AM) is evaluated. In the cryptosystem, an undercover AM used as an additional key is added to modulate the amplitude information of the spectrum in the Fourier plane. Compared to the conventional phase-truncated Fourier transform (PTFT)-based cryptosystem, the security of the cryptosystem is improved by increasing the number of unknown keys. However, it is found that the designed AM is irrelative to the plaintext, and one of the parameters in the designed AM contributes less to the security enhancement of the cryptosystem due to low key sensitivity. Based on the analysis, a special attack containing two iterative processes is proposed to crack the cryptosystem, in which the known-plaintext-attack-based iterative process I with a specific normalization operator is used to retrieve the designed AM and the amplitude-phase-retrieval-technique-based iterative process II is used to retrieve the corresponding plaintext from the arbitrarily given ciphertext with the help of the retrieved AM. In addition, an inherent drawback widely existing in PTFT-based cryptosystems is reported for the first time: most information of the original image could be retrieved using two correct phase keys (or only the first phase key) generated in the encryption process, even without the corresponding ciphertext in PTFT-based cryptosystems. To address this issue, a security-enhanced cryptosystem is proposed in this paper. Numerical simulation is carried out to demonstrate the effectiveness and feasibility of the proposed attack and cryptosystem.

A phase 2 study of the PARP inhibitor veliparib plus temozolomide in patients with heavily pretreated metastatic colorectal cancer.

BACKGROUND: Poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors such as veliparib are potent sensitizing agents and have been safely combined with DNA-damaging agents such as temozolomide. The sensitizing effects of PARP inhibitors are magnified when cells harbor DNA repair defects. METHODS: A single-arm, open-label, phase 2 study was performed to investigate the disease control rate (DCR) after 2 cycles of veliparib plus temozolomide in patients with metastatic colorectal cancer (mCRC) refractory to all standard therapies. Fifty patients received temozolomide (150 mg/m2 /d) on days 1 to 5 and veliparib (40 mg twice daily) on days 1 to 7 of each 28-day cycle. Another 5 patients with mismatch repair-deficient (dMMR) tumors were also enrolled. Twenty additional patients were then treated with temozolomide at 200 mg/m2 /d. Archived tumor specimens were used for immunohistochemistry to assess mismatch repair, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), and O(6)-methylguanine-DNA methyltransferase (MGMT) protein expression levels. RESULTS: The combination was well tolerated, although some patients required dose reductions for myelosuppression. The primary endpoint was successfully met with a DCR of 24% and 2 confirmed partial responses. The median progression-free survival was 1.8 months, and the median overall survival was 6.6 months. PTEN protein expression and MGMT protein expression were not predictors of DCR. There was also a suggestion of worse outcomes for patients with dMMR tumors. CONCLUSIONS: In this heavily pretreated mCRC population, a combination of veliparib and temozolomide was well tolerated with temozolomide doses up to 200 mg/m2 /d, and it was clinically active. PARP inhibitor-based therapy merits further exploration in patients with mCRC. Cancer 2018;124:2337-46. © 2018 American Cancer Society.

Security analysis of a double-image encryption technique based on an asymmetric algorithm.

In this paper, we evaluate the security of a double-image encryption technique based on an asymmetric algorithm. Compared with traditional cryptosystems based on a phase-truncated Fourier transform, the technique is able to improve the security of the encryption by combining a joint transform correlator; consequently, the encryption scheme is immune to some common attacks. We propose a special attack based on a phase retrieval algorithm with median filtering and normalization operation to break the cryptosystem. Low key sensitivity of a position parameter set has been found and an additional constraint is utilized to improve the attack to simplify the process and further decrease the computational time. Numerical simulation results show that the cryptosystem is vulnerable to the proposed special attack.

Hybrid attack on an optical cryptosystem based on phase-truncated Fourier transforms and a random amplitude mask.

In this paper, the security of a cryptosystem based on phase-truncated Fourier transforms (PTFTs) and a random amplitude mask (RAM) is evaluated. In the cryptosystem, fake keys used as encryption keys in the second PTFT-based structure are generated by the first PTFT-based structure in which the RAM is encoded by random phase masks (RPMs) used as public keys. Compared to the classical PTFT-based encryption scheme, the security level of the cryptosystem is improved by using cascaded PTFTs to encode the encryption keys and the plaintext simultaneously. However, it is found that a known plaintext-ciphertext pair can provide enough constraints in the iterative process to retrieve the fake keys, which then can be used to retrieve unknown arbitrary plaintext from the corresponding ciphertext. Based on the analysis, we propose a specific attack based on hybrid iterative processes to break the cryptosystem. Two iterative processes with different constraints are involved in the proposed attack. The first known-plaintext-attack (KPA)-based iterative process is used to retrieve two fake keys with the help of two public keys and a known plaintext-ciphertext pair, while the second amplitude-phase retrieval algorithm-based iterative process with a median filter is employed to retrieve the plaintext from the corresponding ciphertext using two retrieval fake keys. To the best of our knowledge, it is the first time that the cryptosystem is attacked by the KPA-based iterative algorithm successfully. Numerical simulation results validate the feasibility and effectiveness of the proposed attack.

Genome-wide DNA methylation profiling of articular cartilage reveals significant epigenetic alterations in Kashin-Beck disease and osteoarthritis.

OBJECTIVE: To determine genome-wide DNA methylation profiles of knee cartilage from patients with Kashin-Beck disease (KBD) and osteoarthritis (OA). METHOD: Knee cartilage was collected from 14 grade III KBD patients, 5 primary OA patients and 13 healthy subjects. The genome-wide methylation profiles of 5 KBD cartilage, 5 OA cartilage and 5 normal cartilage were determined by Illumina HumanMethylation450 array. Illumina Methylation Analyzer package was employed for identifying differentially methylated CpG sites. Functional annotation and enrichment analysis of differentially methylated genes (DMG) were conducted using GeneRIF database, Ingenuity Pathway Analysis (IPA) and The Database for Annotation, Visualization and Integrated Discovery (DAVID). Mass spectrometry (MS) and immunohistochemistry (IHC) were conducted to validate the functional relevance of identified KBD associated gene. RESULTS: We identified a total of 1212 differentially methylated CpG sites in KBD vs Normal, annotated to 264 hypermethylated and 368 hypomethylated genes. Comparing the DNA methylation profiles of KBD vs Normal and OA vs Normal detected overlap of 367 differentially methylated CpG sites (annotated to 182 genes) as well as 845 KBD-specific differentially methylated CpG sites (annotated to 471 unique genes). MS and IHC confirmed the hypermethylation status and decreased protein expression of HAPLN1 gene in KBD cartilage. CONCLUSION: Our data implicate epigenetic dysregulation of a host of genes in KBD and OA. Furthermore, we observed common causal epigenetic changes shared by KBD and OA.

Simplified paraboloid phase model-based phase tracker for demodulation of a single complex fringe.

A regularized phase tracker (RPT) is an effective method for demodulation of single closed-fringe patterns. However, lengthy calculation time, specially designed scanning strategy, and sign-ambiguity problems caused by noise and saddle points reduce its effectiveness, especially for demodulating large and complex fringe patterns. In this paper, a simplified paraboloid phase model-based regularized phase tracker (SPRPT) is proposed. In SPRPT, first and second phase derivatives are pre-determined by the density-direction-combined method and discrete higher-order demodulation algorithm, respectively. Hence, cost function is effectively simplified to reduce the computation time significantly. Moreover, pre-determined phase derivatives improve the robustness of the demodulation of closed, complex fringe patterns. Thus, no specifically designed scanning strategy is needed; nevertheless, it is robust against the sign-ambiguity problem. The paraboloid phase model also assures better accuracy and robustness against noise. Both the simulated and experimental fringe patterns (obtained using electronic speckle pattern interferometry) are used to validate the proposed method, and a comparison of the proposed method with existing RPT methods is carried out. The simulation results show that the proposed method has achieved the highest accuracy with less computational time. The experimental result proves the robustness and the accuracy of the proposed method for demodulation of noisy fringe patterns and its feasibility for static and dynamic applications.

MicroRNA-320 regulates matrix metalloproteinase-13 expression in chondrogenesis and interleukin-1ß-induced chondrocyte responses.

OBJECTIVE: Metalloproteinases (MMPs) are key regulators of osteoarthritis (OA) and collagen degradation and have been shown to participate in endochondral ossification. The aim of this study was to determine whether microRNA-320 (miR-320) regulates the expression of MMP-13 in chondrogenesis and inflammation. EXPERIMENTAL DESIGN: miR-320 expression was assessed in vitro, in the ATDC5 cell model of chondrogenesis and in interleukin-1ß (IL-1ß)-treated primary mouse chondrocytes (PMCs), and in vivo, in normal and OA human cartilage by in situ hybridization. ATDC5 and PMCs were transfected with miR-320 or its antisense inhibitor (anti-miR-320), respectively. The roles of activated MAP kinases (MAPK) and NF-κB were evaluated by using specific inhibitors. Direct interaction between miR-320 and its putative binding site in the 3'-untranslated region (3'-UTR) of Mmp-13 mRNA was confirmed by the luciferase reporter assay. RESULTS: miR-320 expression was elevated in chondrogenic and hypertrophic ATDC5, while significantly reduced in OA cartilage compared with normal cartilage. Stimulation with IL-1ß led to a significant reduction in miR-320 expression in PMCs. Upregulation of MMP-13 expression was correlated with downregulation of miR-320 expression in both PMCs and ATDC5. Overexpression of miR-320 suppressed the activity of a reporter construct containing the 3'-UTR and inhibited MMP-13 expression in both ATDC5 and IL-1ß-treated PMCs, while treatment with anti-miR-320 enhanced MMP-13 expression. NF-κB and MAPK activation downregulated miR-320 expression. CONCLUSION: Cartilage development and homeostasis are influenced by miR-320, which directly targets MMP-13 and regulates chondrogenesis and the IL-1ß-stimulated catabolic effect in mouse chondrocytes.

Chondrogenesis of mesenchymal stem cells in a novel hyaluronate-collagen-tricalcium phosphate scaffolds for knee repair.

Scaffolds are expected to play a key role in the induction of chondrogenesis of mesenchymal stem cells (MSCs) for cartilage tissue regeneration. Here, we report the development of a novel tricalcium phosphate-collagen-hyaluronate (TCP-COL-HA) scaffold that can function as a stem cell carrier to induce chondrogenesis and promote cartilage repair, and the investigation of chondroinductive properties of scaffolds containing varying amounts of TCP, COL and HA. TCP-COL-HA scaffolds, as well as TCP-COL scaffolds at two different TCP/COL ratios (50:50 and 25:75), were evaluated for their ability to induce cartilage regeneration from rabbit mesenchymal stem cells (rMSCs) in vitro and in vivo. Chondrogenic differentiation was evaluated by sulphated glycosaminoglycan quantification, collagen type II immunohistochemistry, and qRT-PCR. Mechanical strength was evaluated by the compression test. The results showed that the TCP-COL-HA scaffolds enhanced rMSC chondrogenesis to a greater degree than did the TCP-COL scaffolds; for the latter, the scaffold with the lower TCP/COL ratio (25:75) was superior in terms of promoting rMSC chondrogenesis. Similar results were obtained in an ectopic implantation model in nude mice. In a critical-size rabbit osteochondral defect-repair model, rMSCs seeded on TCP-COL-HA scaffolds showed greater cartilage regeneration and integration into surrounding tissue than the TCP-COL groups, in which cartilage repair was more efficient at the 25:75 than at the 50:50 ratio. These results indicate that the addition of HA and different TCP/COL ratios can affect the chondroinductive capacity of scaffolds, and suggest that the TCP-COL-HA scaffold can serve as an effective cell carrier for cartilage regeneration.

Distinctive transcriptome alterations of prefrontal pyramidal neurons in schizophrenia and schizoaffective disorder.

Schizophrenia is associated with alterations in working memory that reflect dysfunction of dorsolateral prefrontal cortex (DLPFC) circuitry. Working memory depends on the activity of excitatory pyramidal cells in DLPFC layer 3 and, to a lesser extent, in layer 5. Although many studies have profiled gene expression in DLPFC gray matter in schizophrenia, little is known about cell-type-specific transcript expression in these two populations of pyramidal cells. We hypothesized that interrogating gene expression, specifically in DLPFC layer 3 or 5 pyramidal cells, would reveal new and/or more robust schizophrenia-associated differences that would provide new insights into the nature of pyramidal cell dysfunction in the illness. We also sought to determine the impact of other variables, such as a diagnosis of schizoaffective disorder or medication use at the time of death, on the patterns of gene expression in pyramidal neurons. Individual pyramidal cells in DLPFC layers 3 or 5 were captured by laser microdissection from 36 subjects with schizophrenia or schizoaffective disorder and matched normal comparison subjects. The mRNA from cell collections was subjected to transcriptome profiling by microarray followed by quantitative PCR validation. Expression of genes involved in mitochondrial (MT) or ubiquitin-proteasome system (UPS) functions were markedly downregulated in the patient group (P-values for MT-related and UPS-related pathways were <10(-7) and <10(-5), respectively). MT-related gene alterations were more prominent in layer 3 pyramidal cells, whereas UPS-related gene alterations were more prominent in layer 5 pyramidal cells. Many of these alterations were not present, or found to a lesser degree, in samples of DLPFC gray matter from the same subjects, suggesting that they are pyramidal cell specific. Furthermore, these findings principally reflected alterations in the schizophrenia subjects were not present or present to a lesser degree in the schizoaffective disorder subjects (diagnosis of schizoaffective disorder was the most significant covariate, P<10(-6)) and were not attributable to factors frequently comorbid with schizophrenia. In summary, our findings reveal expression deficits in MT- and UPS-related genes specific to layer 3 and/or layer 5 pyramidal cells in the DLPFC of schizophrenia subjects. These cell type-specific transcriptome signatures are not characteristic of schizoaffective disorder, providing a potential molecular-cellular basis of differences in clinical phenotypes.

GATA4 represses an ileal program of gene expression in the proximal small intestine by inhibiting the acetylation of histone H3, lysine 27.

GATA4 is expressed in the proximal 85% of small intestine where it promotes a proximal intestinal ('jejunal') identity while repressing a distal intestinal ('ileal') identity, but its molecular mechanisms are unclear. Here, we tested the hypothesis that GATA4 promotes a jejunal versus ileal identity in mouse intestine by directly activating and repressing specific subsets of absorptive enterocyte genes by modulating the acetylation of histone H3, lysine 27 (H3K27), a mark of active chromatin, at sites of GATA4 occupancy. Global analysis of mouse jejunal epithelium showed a statistically significant association of GATA4 occupancy with GATA4-regulated genes. Occupancy was equally distributed between down- and up-regulated targets, and occupancy sites showed a dichotomy of unique motif over-representation at down- versus up-regulated genes. H3K27ac enrichment at GATA4-binding loci that mapped to down-regulated genes (activation targets) was elevated, changed little upon conditional Gata4 deletion, and was similar to control ileum, whereas H3K27ac enrichment at GATA4-binding loci that mapped to up-regulated genes (repression targets) was depleted, increased upon conditional Gata4 deletion, and approached H3K27ac enrichment in wild-type control ileum. These data support the hypothesis that GATA4 both activates and represses intestinal genes, and show that GATA4 represses an ileal program of gene expression in the proximal small intestine by inhibiting the acetylation of H3K27.

Dimple Grinding Coupled with Optical Microscopy for Porosity Analysis of Metallic Coatings.

Dimple grinding is one of the steps used in a common method of preparing samples for transmission electron microscopy (TEM); the TEM sample preparation process also involves ion beam sputtering after the dimpling stage. During dimpling, a spherical depression is machined into the sample, leaving a thicker rim to support and facilitate sample handling. In this paper, an alternative application for dimple grinding is developed; dimple grinding combined with optical microscopy is utilized to quantify internal porosity present within coatings. This technique essentially permits three dimensional porosity quantification across the coating thickness using a simple polishing method which provides analysis of areas larger than those observed during standard cross sectional microscopy. The application of this technique to nine electroless nickel-phosphorus (Ni-P) coatings deposited on Mg substrates is demonstrated. An analysis linking medium P content in the Ni-P coatings and high coating thickness to lower porosity is also performed. The lowest porosity was observed for medium P content coatings (5.2 wt% P), while the largest porosity occurred for the high P content coatings (10.0 wt% P). Porosity levels decreased continuously with increasing coating thickness (from 28 µm to 57 µm).

Accelerating Clinical Text Annotation in Underrepresented Languages: A Case Study on Text De-Identification.

Clinical notes contain valuable information for research and monitoring quality of care. Named Entity Recognition (NER) is the process for identifying relevant pieces of information such as diagnoses, treatments, side effects, etc., and bring them to a more structured form. Although recent advancements in deep learning have facilitated automated recognition, particularly in English, NER can still be challenging due to limited specialized training data. This exacerbated in hospital settings where annotations are costly to obtain without appropriate incentives and often dependent on local specificities. In this work, we study whether this annotation process can be effectively accelerated by combining two practical strategies. First, we convert usually passive annotation tasks into a proactive contest to motivate human annotators in performing a task often considered tedious and time-consuming. Second, we provide pre-annotations for the participants to evaluate how recall and precision of the pre-annotations can boost or deteriorate annotation performance. We applied both strategies to a text de-identification task on French clinical notes and discharge summaries at a large Swiss university hospital. Our results show that proactive contest and average quality pre-annotations can significantly speed up annotation time and increase annotation quality, enabling us to develop a text de-identification model for French clinical notes with high performance (F1 score 0.94).

Incidence and risk of hemorrhagic events with vascular endothelial growth factor receptor tyrosine-kinase inhibitors: an up-to-date meta-analysis of 27 randomized controlled trials.

BACKGROUND: We aimed at determining the overall incidence and risk of hemorrhagic events associated with vascular endothelial growth factor receptor-tyrosine-kinase inhibitors (VEGFR-TKIs). METHODS: We searched PubMed, EMBASE and Cochrane library databases for relevant prospective, randomized controlled trials (RCTs). Statistical analyses were conducted to calculate the summary incidence, relative risks (RRs) and 95% confidence intervals (CIs) by using either random-effects or fixed-effects models according to the heterogeneity of included studies. RESULTS: The overall incidence of all-grade and high-grade hemorrhagic events was 9.1% (95% CI: 6.8-12.1%) and 1.3% (95% CI 0.8% to 2.1%), respectively. And the use of VEGFR-TKIs was associated with an increased risk of hemorrhagic events, with a relative risk (RR) of 1.67 (95% CI 1.19-2.33, P = 0.003), but not for high-grade hemorrhagic events (RR 1.23, 95% CI 0.86-1.77, P = 0.25). The risk of developing all-grade hemorrhagic events varied significantly with tumor types (P < 0.001) and different VEGFR-TKIs (P < 0.001). Additionally, the most common causes of all-grade hemorrhagic events were hemoptysis (48.6%) and epistaxis (20.7%), while hemoptysis (41.8%) and CNS hemorrhage (13.4%) was the most common cause of high-grade hemorrhagic events. CONCLUSIONS: While the use of VEGFR-TKIs is associated with a significantly increased risk of developing hemorrhagic events in cancer patients, this is primarily for lower grade events.