CDK9 inhibition inhibits multiple oncogenic transcriptional and epigenetic pathways in prostate cancer.

BACKGROUND: Cyclin-dependent kinase 9 (CDK9) stimulates oncogenic transcriptional pathways in cancer and CDK9 inhibitors have emerged as promising therapeutic candidates. METHODS: The activity of an orally bioavailable CDK9 inhibitor, CDKI-73, was evaluated in prostate cancer cell lines, a xenograft mouse model, and patient-derived tumor explants and organoids. Expression of CDK9 was evaluated in clinical specimens by mining public datasets and immunohistochemistry. Effects of CDKI-73 on prostate cancer cells were determined by cell-based assays, molecular profiling and transcriptomic/epigenomic approaches. RESULTS: CDKI-73 inhibited proliferation and enhanced cell death in diverse in vitro and in vivo models of androgen receptor (AR)-driven and AR-independent models. Mechanistically, CDKI-73-mediated inhibition of RNA polymerase II serine 2 phosphorylation resulted in reduced expression of BCL-2 anti-apoptotic factors and transcriptional defects. Transcriptomic and epigenomic approaches revealed that CDKI-73 suppressed signaling pathways regulated by AR, MYC, and BRD4, key drivers of dysregulated transcription in prostate cancer, and reprogrammed cancer-associated super-enhancers. These latter findings prompted the evaluation of CDKI-73 with the BRD4 inhibitor AZD5153, a combination that was synergistic in patient-derived organoids and in vivo. CONCLUSION: Our work demonstrates that CDK9 inhibition disrupts multiple oncogenic pathways and positions CDKI-73 as a promising therapeutic agent for prostate cancer, particularly aggressive, therapy-resistant subtypes.

The role of hypoxia on prostate cancer progression and metastasis.

Prostate cancer is the second most common cancer diagnosed in men and the fifth-leading cause of cancer death in men worldwide. Like any solid tumor, the hypoxic microenvironment of prostatic cancer drives hypoxia-inducible factors (HIFs) to mediate cell adaptions to hypoxic conditions. HIFs direct different signaling pathways such as PI3K/Akt/mTOR, NOX, and Wnt/ß-Catenin to tumor progression depending on the degree of hypoxia. HIFs regulate cytoskeleton protein expression, promoting epithelial-mesenchymal transition (EMT), which occurs when cancer cells lose cell-to-cell adhesions and start invasion and metastasis. Through activating pathways, the hypoxic microenvironment maintains the self-renewal, potency, and anti-apoptotic function of prostate cancer cells and induces tumor metastasis and transformation. These pathways could serve as a potential target for prostate cancer therapy. HIFs increase the expression of androgen receptors on cancer cells maintaining the growth and survival of prostate cancer and the development of its castration resistance. In this review, we elaborate on the role of hypoxia in prostatic cancer pathogenesis and different hypoxia-induced mechanisms.

Nanomedicine as a putative approach for active targeting of hepatocellular carcinoma.

The effectiveness of chemotherapy in hepatocellular carcinoma (HCC) is restricted by chemo-resistance and systemic side effects. To improve the efficacy and safety of chemotherapeutics in HCC management, scientists have attempted to deliver these drugs to malignant tissues using targeted carriers as nanoparticles (NPs). Among the three types of NPs targeting (active, passive, and stimuli-responsive), active targeting is the most commonly investigated in HCC treatment. Despite the observed promising results so far, clinical research on nanomedicine targeting for HCC treatment still faces many challenges.These include batch-to-batch physicochemical properties' variations, limiting large scale production and insufficient data on human and environmental toxicities. This review summarized the characteristics of different nanocarriers, ligands, targeted receptors on HCC cells and provided recommendations to overcome the challenges, facing this novel line of treatment for HCC.

Novel therapeutic strategies for spinal osteosarcomas.

At the dawn of the third millennium, cancer has become the bane of twenty-first century man, and remains a predominant public health burden, affecting welfare and life expectancy globally. Spinal osteogenic sarcoma, a primary spinal malignant tumor, is a rare and challenging neoplastic disease to treat. After the conventional therapeutic modalities of chemotherapy, radiation and surgery have been exhausted, there is currently no available alternative therapy in managing cases of spinal osteosarcoma. The defining signatures of tumor survival are characterised by cancer cell ability to stonewall immunogenic attrition and apoptosis by various means. Some of these biomarkers, namely immune-checkpoints, have recently been exploited as druggable targets in osteosarcoma and many other different cancers. These promising strides made by the use of reinvigorated immunotherapeutic approaches may lead to significant reduction in spinal osteosarcoma disease burden and corresponding reciprocity in increase of survival rates. In this review, we provide the background to spinal osteosarcoma, and proceed to elaborate on contribution of the complex ecology within tumor microenvironment giving arise to cancerous immune escape, which is currently receiving considerable attention. We follow this section on the tumor microenvironment by a brief history of cancer immunity. Also, we draw on the current knowledge of treatment gained from incidences of osteosarcoma at other locations of the skeleton (long bones of the extremities in close proximity to the metaphyseal growth plates) to make a case for application of immunity-based tools, such as immune-checkpoint inhibitors and vaccines, and draw attention to adverse upshots of immune-checkpoint blockers as well. Finally, we describe the novel biotechnique of CRISPR/Cas9 that will assist in treatment approaches for personalized medication.

CDKI-73: an orally bioavailable and highly efficacious CDK9 inhibitor against acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common form of acute leukemia with dismal long-term prognosis with age. The most aggressive subtype of AML is MLL-AML that is characterized by translocations of the mixed-lineage leukemia gene (MLL) and resistance to conventional chemotherapy. Cyclin dependent kinase 9 (CDK9) plays a crucial role in the MLL-driven oncogenic transcription, and hence, inhibiting activity of CDK9 has been proposed as a promising strategy for treatment of AML. We investigated the therapeutic potential of CDKI-73, one of the most potent CDK9 inhibitors, against a panel of AML cell lines and samples derived from 97 patients. CDKI-73 induced cancer cells undergoing apoptosis through transcriptional downregulation of anti-apoptotic proteins Bcl-2, Mcl-1 and XIAP by majorly targeting CDK9. Contrastively, it was relatively low toxic to the bone marrow cells of healthy donors. In MV4-11 xenograft mouse models, oral administration of CDKI-73 resulted in a marked inhibition of tumor growth (p < 0.0001) and prolongation of animal life span (P < 0.001) without causing body weight loss and other overt toxicities. The study suggests that CDKI-73 can be developed as a highly efficacious and orally deliverable therapeutic agent for treatment of AML.

Neuropsychiatric manifestations are not uncommon in Indian lupus patients and negatively affect quality of life.

Objectives The objectives of this paper are to look at the prevalence of neuropsychiatric manifestations and assess their impact on quality of life in North Indian lupus patients. Methods The study included consecutive patients with systemic lupus erythematosus (SLE) who were older than 18 years and met the SLICC 2012 criteria. A diagnosis of a neuropsychiatric syndrome was made as per ACR 1999 definitions. Manifestations occurring at any point in time after the diagnosis of SLE were considered if a reliable history and medical records were available. Quality of life was assessed by EuroQol-5D questionnaire. Means were compared by student t test for normally distributed data. Comparison of quality of life between groups was performed by the Kruskal-Wallis test and Mann-Whitney U test. Results This study included 101 patients of SLE with mean (±SD) age of 32.3 ± 10.0 years and a majority ( n = 92) were females. Mean (±SD) age of diagnosis of SLE was 27.8 ± 9.2 years and disease duration (after diagnosis) was 4.6 ± 4.5 years. Thirty-three patients had neuropsychiatric manifestations with a total of 42 events. The most common manifestation was headache (10%) followed by anxiety disorder (5%) and peripheral neuropathy (9%). Other NPSLE syndromes observed in the study are seizure (4%), cognitive dysfunction (4%), depression (4%), acute confusional state (2%), autonomic neuropathy (2%), movement disorder (1%), and mononeuritis multiplex (1%). On comparing the groups of NPSLE, nephritis, and neither, there was a significant difference in mobility, self-care, pain, and worry. On post hoc test, there was a significant difference between the NPSLE and neither group. Conclusion Neuropsychiatric manifestations significantly affect quality of life in North Indian SLE patients.

Meta-analysis of patient survival and rate of alcohol relapse in liver-transplanted patients for acute alcoholic hepatitis.

PURPOSE: This review investigated survival and alcoholic relapse following liver transplantation (LT) in patients with severe acute alcoholic hepatitis (AH) without 6 months of alcohol abstinence. METHODS: All studies comparing acute AH patients undergoing LT with a control group were included. CENTRAL, MEDLINE, and Web of Science databases were searched. Survival benefits or odds ratios (OR) and 95% confidence intervals (CI) were assessed by meta-analyses using a random effects model. The study was registered in PROSPERO (CRD42017057971). According to the search results, two separate meta-analyses were performed: meta-analysis A compared early LT with medical therapy alone in patients with severe AH that were not responding to medical therapy and meta-analysis B compared LT outcome in patients with AH and chronic alcoholic cirrhosis (AC). RESULTS: The search yielded 2232 articles. Eight studies were included in the two meta-analyses-two studies in meta-analysis A and six studies in meta-analysis B. The two studies (n = 70) included in meta-analysis A revealed that 1-year patient survival was significantly higher in the LT group compared with the medical therapy-alone group (survival benefit, 15.88; 95% CI, 3.98-63.35; p < 0.0001). The six studies in meta-analysis B (including 1091 patients) showed that 1-year (survival benefit, 1.65; 95% CI, 0.95-2.89; p = 0.08), 3-year (survival benefit, 1.31; 95% CI, 0.79-2.18; p = 0.30), and 5-year survival (survival benefit, 1.54; 95% CI, 0.92-2.56; p = 0.10) were not significantly different between AH and AC groups. There was no significant difference in the rate of alcohol relapse between the groups (OR, 1.26; 95% CI, 0.53-2.96; p = 0.60). CONCLUSIONS: Early LT is a life-saving treatment for AH patients that do not respond to medical therapy. The chance of alcohol relapse after LT is not increased in selected patients.

A comparative study of conventional and liquid-based cervical cytology.

OBJECTIVES: The aim of our study is the comparison of the results of conventional smear (CC) technique and liquidbased cytology (LBC) technique used as cervical cancer screening methods. MATERIAL AND METHODS: The results of 47954 patients submitted to smear screening in our gynecology clinic between January 2008 and December 2014 have been studied. The smear results have been divided into two groups CC and LBC according to the technique used. RESULTS: When considering the distribution within CC group, the results were as follows: intraepithelial cell abnormalities 2,0% (n=619), insufficient sample for analysis 2,1% (n=660), Atypical squamous cells of undetermined significance (ASC-US) 1.8% (n=554), Low grade squamous intraepithelial lesion (LGSIL) 0.1% (n=35), High grade squamous intraepithelial lesion (HGSIL) 0.1% (n=16), Atypical squamous cells - cannot exclude HGSIL (ASC-H) 0.029% (n=9), Atypical glandular cells- not other wise specified (AGC-NOS) 0.012% (n=4), squamous carcinoma 0.003% (n=1). When considering the distribution in LBC group, the results were as follows: intraepithelial cell abnormalities2.1% (n=357), insufficient sample for analysis 0.9% (n=144), ASC-US 1.8% (n=296), LGSIL 0.2% (n=38), HGSIL 0.1% (n=8), ASC-H 0.1% (n=10), AGC-NOS 0.017% (n=3), squamous carcinoma 0.011% (n=2). CONCLUSIONS: Although the rates of epithelial cell abnormalities are similar for both tests, LSIL results are more frequently observed in LBC technique. In LBC technique, the number of insufficient sample for analysis is quite low compared to CC group and thus constitutes an advantage.

Le Fort III distraction osteogenesis versus conventional Le Fort III osteotomy in correction of syndromic midfacial hypoplasia: a systematic review.

PURPOSE: It has been debated whether the Le Fort III procedure using distraction osteogenesis (LFIII-DO) reduces the risk of postintervention relapse compared with conventional Le Fort III (LFIII) osteotomy in the correction of syndromic midfacial hypoplasia. Our objective was to evaluate the short- and long-term stability of the bony structures after midfacial advancement using conventional LFIII osteotomy versus LFIII-DO in patients with syndromic midfacial hypoplasia. MATERIALS AND METHODS: We performed a systematic review of the published data. An electronic search of 10 databases was performed from their inception through June 2012. The reference lists of the relevant publications were also reviewed. Studies were considered for inclusion if they were longitudinal clinical studies with follow-up periods of at least 1 year after surgery (LFIII group) or at the end of the consolidation period (LFIII-DO group). Study selection, risk of bias assessment, and data extraction were performed in duplicate. The methodologic and clinical heterogeneity across the studies precluded combining the findings using meta-analyses. RESULTS: A total of 57 reports met the initial search criteria, and 12 reports were finally selected. The studies demonstrated a mean midfacial advancement of 8 to 12 mm in the LFIII group and 9 to 16 mm in the LFIII-DO group. For the LFIII group, horizontal short-term follow-up showed a maximal rate of relapse of 8.7 to 11.9% in 2 studies, with 1 study demonstrating a far more severe rate of maximal relapse of 50%. For the LFIII-DO procedure, the horizontal short-term relapse rate was 14.4% in 1 study, with the remainder demonstrating a rate of relapse of less than 10%. Moreover, 3 studies even showed additional advancement without any rate of relapse. CONCLUSIONS: Current evidence suggests that conventional LFIII and LFIII-DO techniques can effectively advance the midface forward in patients with syndromic midfacial hypoplasia and have good to excellent stability, with a mild rate of relapse. However, the LFIII-DO technique appears to achieve a greater amount of advancement with a lower rate of relapse compared with the conventional LFIII technique.

Investigating the Impact of Drone Transport on the Stability of Monoclonal Antibodies for Inter-Hospital Transportation.

In the field of healthcare logistics, the reliance on conventional transport methods such as cars for the delivery of monoclonal antibodies (mAbs) is susceptible to challenges posed by traffic and infrastructure, leading to increased and unpredictable transport times. Recognizing the potential role of drones in mitigating these challenges, we aimed to investigate the impact of medical drone transport on the stability of mAbs. Compromised stability could lead to aggregation and immunogenicity, thereby jeopardizing the efficacy and safety of mAbs. We studied the transportation of vials as well as ready-to-administer infusion bags with blinatumomab, tocilizumab, and daratumumab. The methodology involved the measurement of both temperature and mechanical shock during drone transport. Moreover, the analytical techniques High Performance Size-Exclusion Chromatography (HP-SEC), Dynamic Light Scattering (DLS), Light Obscuration (LO), Micro-Flow Imaging (MFI), and Nanoparticle Tracking Analysis (NTA) were employed to comprehensively assess the presence of aggregates and particle formation. The key findings revealed no significant differences between car and drone transport, indicating that the stability of mAbs in both vials and infusion bags was adequately maintained during drone transport. This suggests that medical drones are a viable and reliable means for the inter-hospital transport of mAbs, paving the way for more efficient and predictable logistics in healthcare delivery.

Reduction of polystyrene/polyurethane plastic wastes from the environment into binders for water-resistant emulsion paints.

Waste management is fundamental to resource and environmental sustainability. Expanded polystyrene (EPS) and polyurethane (PU) waste plastics were recycled and applied as binder in emulsion paint formulation. The recycled polystyrene (rPS) and polyurethane (rPU) were blended into composite resins, where toluene was used as the solvent. The blends of rPS and rPU were optimized, while some physicochemical properties of the composite blends (rPS/PU) were evaluated. The results showed that the incorporation of rPU into rPS increased the viscosity (1818 mPa-3924 mPa), rate of gelation (dry-to-touch time: 15 min-0.25 min), moisture content (2.7%-8.1%), moisture uptake (3.2%-5.0%), solid content (48%-53.4%) and density (0.82 g/cm3 to 1.050.82 g/cm3) of the rPS/PU composite resins. Characterization was carried out using Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), thermogravimetric analysis (TGA), scanning electron microscope (SEM), and atomic force microscopy (AFM). The results summarily showed that there are interactions among the rPS and rPU molecules in the composite, where complimentary structural and morphological characteristics were also achieved. The composite resin also exhibited superior bond strength (0.5-4.24 Mpa) on wood, cast mortar, ceramic, and steel surfaces due to its stronger intra- and inter-surface interactions compared to the neat rPS resin. The composite resin was used as a binder in the formulation of emulsion paint. The paint exhibited stronger resistance to water, among other superior properties, when compared to the paints formulated using neat rPS and conventional polyvinyl acetate (PVA) resins. The reduction of plastic waste in this study holds potential for the production of highly water-resistant emulsion paint for outdoor and indoor applications.

Evaluation of the possible effects of the COVID-19 period on the clinical outcomes of acute mesenteric ischemia.

Objective: The objective of the study was to investigate the possible effects of the coronavirus disease 2019 (COVID-19) period on the frequency and clinical course of acute mesenteric ischemia (AMI) cases. Material and methods: A total of 35 patients who were treated and followed up with a diagnosis of AMI over 44 months were included. Results: The mean age of the patients was 69 ± 12 years. Of these patients, 22 were male (63%). The most common cause of AMI in the patients was arterial embolism/thrombosis (68.6%). Thirty-three (94%) of the patients underwent surgical intervention. The duration of the pre-COVID-19 and COVID-19 periods was equal as 22 months, and 18 (51%) of the patients were admitted during the pandemic period. The mortality rate of the patients admitted during the COVID-19 period was also significantly higher than that of the patients admitted during the pre-COVID-19 period (61% and 29%) (p = 0.05). Conclusions: Although the COVID-19 period did not cause a significant increase in the number of AMI cases when compared to the pre-COVID-19 period, the mortality rate was higher in this period. It is thought that further studies are required to investigate the cause of this increased mortality rate during the pandemic period.

Objetivo: Investigar los posibles efectos del período COVID-19 en la frecuencia y el curso clínico de los casos de isquemia mesentérica aguda (IAM). Material y métodos: Se incluyeron un total de 35 pacientes tratados y seguidos con diagnóstico de IAM durante 44 meses. Resultados: La edad media de los pacientes fue de 69 ± 12 años. De estos pacientes, 22 eran hombres (63%). La causa más frecuente de IAM en los pacientes fue la embolia/trombosis arterial (68.6%). Treinta y tres (94%) de los pacientes fueron intervenidos quirúrgicamente. La duración de los períodos pre-COVID-19 y COVID-19 fue igual a 22 meses, y 18 (51%) de los pacientes ingresaron durante el período pandémico. La tasa de mortalidad de los pacientes ingresados durante el periodo COVID-19 también fue significativamente mayor que la de los pacientes ingresados durante el periodo pre-COVID-19 (61% y 29%) (p = 0.05). Conclusiones: Si bien el período COVID-19 no provocó un aumento significativo en el número de casos de IAM en comparación con el período pre-COVID-19, la tasa de mortalidad fue mayor en este período. Se cree que se requieren más estudios para investigar la causa de este aumento en la tasa de mortalidad durante el período pandémico.

Anti-Leukaemic Activity of Rilpivirine Is Mediated by Aurora A Kinase Inhibition.

Acute myeloid leukaemia (AML) affects predominantly elderly people and has an incidence of 1% of all cancers and 2% of all cancer deaths. Despite using intensive chemotherapy and allogeneic stem cell transplantation, the treatment options for AML remain open for innovation. Thus, there is a need to explore alternative therapies such as less toxic targeted therapies in AML. Aurora A kinase is a well-established target for the treatment of various cancers, including AML. This kinase plays a pivotal role in the cell-division cycle, particularly in different stages of mitosis, and is also involved in many other cellular regulatory processes. In a previous study, we demonstrated that the anti-viral drug rilpivirine is an Aurora A kinase inhibitor. In the current study, we have further explored the selectivity of rilpivirine for Aurora A kinase inhibition by testing this drug against a panel of 429 kinases. Concurrently, we demonstrated that rilpivirine significantly inhibited the proliferation of AML cells in a time- and concentration-dependent manner that was preceded by G2/M cell-cycle arrest leading to the induction of apoptosis. Consistent with its kinase inhibitory role, rilpivirine modulated the expression of critical proteins in the Aurora A kinase-signalling pathway. Importantly, orally administered rilpivirine significantly inhibited tumour growth in an HL-60 xenograft model without showing body weight changes or other clinical signs of toxicity. Furthermore, rilpivirine enhanced the anti-proliferative efficacy of the conventional anti-leukaemic chemotherapeutic agent cytarabine. Collectively, these findings provide the stimulus to explore further the anti-leukaemic activity of the anti-viral drug rilpivirine.

Aberrant splicing prediction across human tissues.

Aberrant splicing is a major cause of genetic disorders but its direct detection in transcriptomes is limited to clinically accessible tissues such as skin or body fluids. While DNA-based machine learning models can prioritize rare variants for affecting splicing, their performance in predicting tissue-specific aberrant splicing remains unassessed. Here we generated an aberrant splicing benchmark dataset, spanning over 8.8 million rare variants in 49 human tissues from the Genotype-Tissue Expression (GTEx) dataset. At 20% recall, state-of-the-art DNA-based models achieve maximum 12% precision. By mapping and quantifying tissue-specific splice site usage transcriptome-wide and modeling isoform competition, we increased precision by threefold at the same recall. Integrating RNA-sequencing data of clinically accessible tissues into our model, AbSplice, brought precision to 60%. These results, replicated in two independent cohorts, substantially contribute to noncoding loss-of-function variant identification and to genetic diagnostics design and analytics.

A Systematic Characterization Approach for Vacuum Bag Only Prepregs towards an Accurate Process Design.

Aerospace-grade composite parts can be manufactured using Vacuum Bag Only prepregs through an accurate process design. Quality in the desired part can be realized by following process modeling, process optimization, and validation, which strongly depend on a primary and systematic material characterization methodology of the prepreg system and material constitutive behavior. The present study introduces a systematic characterization approach of a Vacuum Bag Only prepreg by covering the relevant material properties in an integrated manner with the process mechanisms of fluid flow, consolidation, and heat transfer. The characterization recipe is practiced under the categories of (i) resin system, (ii) fiber architecture, and (iii) thermal behavior. First, empirical models are successively developed for the cure-kinetics, glass transition temperature, and viscosity for the resin system. Then, the fiber architecture of the uncured prepreg system is identified with X-ray tomography to obtain the air permeability. Finally, the thermal characteristics of the prepreg and its constituents are experimentally characterized by adopting a novel specimen preparation technique for the specific heat capacity and thermal conductivity. Thus, this systematic approach is designed to provide the material data to process modeling with the motivation of a robust and integrated Vacuum Bag Only process design.

Synthesis and antibacterial properties of new N4-acetylated hexahydro-2,7-dioxopyrido[2,3-f]quinoxaline-8-carboxylic acids.

Direct interaction between 7-chloro-1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and primary α-amino acids (exemplified by glycine, alanine, and l-valine) in aqueous ethanolic NaHCO(3) at 70-80°C for 24-72 h produced the respective N-(4-oxoquinolin-7-yl)-α-amino acids (6a-c). The latter derivatives underwent reductive lactamization upon treatment with Na(2)S(2)O(4) in aqueous ethanol to afford moderate yields of the corresponding pyrido[2,3-f]quinoxaline-8-carboxylic acids (8a-c). Acetylation of 8a-c using acetyl chloride afforded N(4)-acetylated hexahydro-2,7-dioxopyrido[2,3-f]quinoxaline-8-carboxylic acids (9a-c). The structures, assigned to these new heterocyclic products, are supported by analytical and spectral data. The synthesized compounds (6a-c/9a-c) showed appreciable antibacterial activity as compared with ciprofloxacin.

Hydroxytyrosol alleviate intestinal inflammation, oxidative stress and apoptosis resulted in ulcerative colitis.

Hydroxytyrosol (HYT) is one of the main alcoholic compounds of the olive leaves extract (OLE), which is known for its beneficial effects. This study aimed to investigate the effectiveness of olive leaves extract standardized with 25% hydroxytyrosol (OLES-25%HYT) in treatment of induced ulcerative colitis. Three groups of albino rats, were divided as following, group 1 (normal control), group 2 (induced ulcerative colitis and untreated) and group 3 (induced ulcerative colitis and treated with OLES-25%HYT). Colonic tissue samples were collected from all studied groups, the antioxidant activity for malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX), myeloperoxidase (MPO) and nitric oxide (NO) were performed. The expression of pro-inflammatory cytokines, the apoptotic gene Bax and the anti-apoptotic gene Bcl2 was obtained in colon tissue to evaluate the OLES-25%HYT effect on ulcerative colitis. OLES-25%HYT showed effectiveness on reduction of mortality rate and disease activity index (DAI). Also, reduced oxidative stress and inflammation in colon tissue, OLES-25%HYT showed a significant reduction in colon MDA, MPO and NO levels and a significant elevation in SOD, CAT and GPX levels and cause down regulation of pro-inflammatory cytokines. Also, the apoptotic gene Bax downregulated and the anti-apoptotic gene Bcl2 upregulated as a result of the treatment compared to untreated induced ulcerative colitis group. OLES-25%HYT showed intestinal anti-inflammatory, antioxidants and anti-apoptotic effects in experimental models of ulcerative colitis.

Detection of aberrant splicing events in RNA-seq data using FRASER.

Aberrant splicing is a major cause of rare diseases.  However, its prediction from genome sequence alone remains in most cases inconclusive. Recently, RNA sequencing has proven to be an effective complementary avenue to detect aberrant splicing. Here, we develop FRASER, an algorithm to detect aberrant splicing from RNA sequencing data. Unlike existing methods, FRASER captures not only alternative splicing but also intron retention events. This typically doubles the number of detected aberrant events and identified a pathogenic intron retention in MCOLN1 causing mucolipidosis. FRASER automatically controls for latent confounders, which are widespread and affect sensitivity substantially. Moreover, FRASER is based on a count distribution and multiple testing correction, thus reducing the number of calls by two orders of magnitude over commonly applied z score cutoffs, with a minor loss of sensitivity. Applying FRASER to rare disease diagnostics is demonstrated by reprioritizing a pathogenic aberrant exon truncation in TAZ from a published dataset. FRASER is easy to use and freely available.

Dynamic evolution of hyperuniformity in a driven dissipative colloidal system.

Hyperuniformity is evolving to become a unifying concept that can help classify and characterize equilibrium and nonequilibrium states of matter. Therefore, understanding the extent of hyperuniformity in dissipative systems is critical. Here, we study the dynamic evolution of hyperuniformity in a driven dissipative colloidal system. We experimentally show and numerically verify that the hyperuniformity of a colloidal crystal is robust against various lattice imperfections and environmental perturbations. This robustness even manifests during crystal disassembly as the system switches between strong (class I), logarithmic (class II), weak (class III), and non-hyperuniform states. To aid analyses, we developed a comprehensive computational toolbox, enabling real-time characterization of hyperuniformity in real- and reciprocal-spaces together with the evolution of several order metric features, and measurements showing the effect of external perturbations on the spatiotemporal distribution of the particles. Our findings provide a new framework to understand the basic principles that drive a dissipative system to a hyperuniform state.