Weakened APC/C activity at mitotic exit drives cancer vulnerability to KIF18A inhibition.

The efficacy of current antimitotic cancer drugs is limited by toxicity in highly proliferative healthy tissues. A cancer-specific dependency on the microtubule motor protein KIF18A therefore makes it an attractive therapeutic target. Not all cancers require KIF18A, however, and the determinants underlying this distinction remain unclear. Here, we show that KIF18A inhibition drives a modest and widespread increase in spindle assembly checkpoint (SAC) signaling from kinetochores which can result in lethal mitotic delays. Whether cells arrest in mitosis depends on the robustness of the metaphase-to-anaphase transition, and cells predisposed with weak basal anaphase-promoting complex/cyclosome (APC/C) activity and/or persistent SAC signaling through metaphase are uniquely sensitive to KIF18A inhibition. KIF18A-dependent cancer cells exhibit hallmarks of this SAC:APC/C imbalance, including a long metaphase-to-anaphase transition, and slow mitosis overall. Together, our data reveal vulnerabilities in the cell division apparatus of cancer cells that can be exploited for therapeutic benefit.

Nuclear accumulation of host transcripts during Zika Virus Infection.

Zika virus (ZIKV) infects fetal neural progenitor cells (NPCs) causing severe neurodevelopmental disorders in utero. Multiple pathways involved in normal brain development are dysfunctional in infected NPCs but how ZIKV centrally reprograms these pathways remains unknown. Here we show that ZIKV infection disrupts subcellular partitioning of host transcripts critical for neurodevelopment in NPCs and functionally link this process to the up-frameshift protein 1 (UPF1). UPF1 is an RNA-binding protein known to regulate decay of cellular and viral RNAs and is less expressed in ZIKV-infected cells. Using infrared crosslinking immunoprecipitation and RNA sequencing (irCLIP-Seq), we show that a subset of mRNAs loses UPF1 binding in ZIKV-infected NPCs, consistent with UPF1's diminished expression. UPF1 target transcripts, however, are not altered in abundance but in subcellular localization, with mRNAs accumulating in the nucleus of infected or UPF1 knockdown cells. This leads to diminished protein expression of FREM2, a protein required for maintenance of NPC identity. Our results newly link UPF1 to the regulation of mRNA transport in NPCs, a process perturbed during ZIKV infection.

Longitudinal symptom network structure in first-episode psychosis: a possible marker for remission.

BACKGROUND: Network approach has been applied to a wide variety of psychiatric disorders. The aim of the present study was to identify network structures of remitters and non-remitters in patients with first-episode psychosis (FEP) at baseline and the 6-month follow-up. METHODS: Participants (n = 252) from the Korean Early Psychosis Study (KEPS) were enrolled. They were classified as remitters or non-remitters using Andreasen's criteria. We estimated network structure with 10 symptoms (three symptoms from the Positive and Negative Syndrome Scale, one depressive symptom, and six symptoms related to schema and rumination) as nodes using a Gaussian graphical model. Global and local network metrics were compared within and between the networks over time. RESULTS: Global network metrics did not differ between the remitters and non-remitters at baseline or 6 months. However, the network structure and nodal strengths associated with positive-self and positive-others scores changed significantly in the remitters over time. Unique central symptoms for remitters and non-remitters were cognitive brooding and negative-self, respectively. The correlation stability coefficients for nodal strength were within the acceptable range. CONCLUSION: Our findings indicate that network structure and some nodal strengths were more flexible in remitters. Negative-self could be an important target for therapeutic intervention.

Intelligent Evaluation of Global Spinal Alignment by a Decentralized Convolutional Neural Network.

Degenerative changes of the spine can cause spinal misalignment, with part of the spine arching beyond normal limits or moving in an incorrect direction, potentially resulting in back pain and significantly limiting a person's mobility. The most important parameters related to spinal misalignment include pelvic incidence, pelvic tilt, lumbar lordosis, thoracic kyphosis, and cervical lordosis. As a general rule, alignment of the spine for diagnosis and surgical treatment is estimated based on geometrical parameters measured manually by experienced doctors. However, these measurements consume the time and effort of experts to perform repetitive tasks that could be automated, especially with the powerful support of current artificial intelligence techniques. This paper focuses on creation of a decentralized convolutional neural network to precisely measure 12 spinal alignment parameters. Specifically, this method is based on detecting regions of interest with its dimensions that decrease by three orders of magnitude to focus on the necessary region to provide the output as key points. Using these key points, parameters representing spinal alignment are calculated. The quality of the method's performance, which is the consistency of the measurement results with manual measurement, is validated by 30 test cases and shows 10 of 12 parameters with a correlation coefficient > 0.8, with pelvic tilt having the smallest absolute deviation of 1.156°.

Pedestrian Crossing Decisions in Virtual Environments: Behavioral Validity in CAVEs and Head-Mounted Displays.

OBJECTIVE: To contribute to the validation of virtual reality (VR) as a tool for analyzing pedestrian behavior, we compared two types of high-fidelity pedestrian simulators to a test track. BACKGROUND: While VR has become a popular tool in pedestrian research, it is uncertain to what extent simulator studies evoke the same behavior as nonvirtual environments. METHOD: An identical experimental procedure was replicated in a CAVE automatic virtual environment (CAVE), a head-mounted display (HMD), and on a test track. In each group, 30 participants were instructed to step forward whenever they felt the gap between two approaching vehicles was adequate for crossing. RESULTS: Our analyses revealed distinct effects for the three environments. Overall acceptance was highest on the test track. In both simulators, crossings were initiated later, but a relationship between gap size and crossing initiation was apparent only in the CAVE. In contrast to the test track, vehicle speed significantly affected acceptance rates and safety margins in both simulators. CONCLUSION: For a common decision task, the results obtained in virtual environments deviate from those in a nonvirtual test bed. The consistency of differences indicates that restrictions apply when predicting real-world behavior based on VR studies. In particular, the higher susceptibility to speed effects warrants further investigation, since it implies that differences in perceptual processing alter experimental outcomes. APPLICATION: Our observations should inform the conclusions drawn from future research in pedestrian simulators, for example by accounting for a higher sensitivity to speed variations and a greater uncertainty associated with crossing decisions.

The first cohort of the COVID-19 patients in Vietnam and the national response to the pandemic.

The COVID-19 pandemic is a novel infectious disease pandemic with the agent SARS-CoV-2 virus which is currently affecting and causing damage globally. The outbreak has been crossing over 200 countries in the world. In the situation of the outbreak of COVID-19, Vietnam has first sixteen typical cases confirmed positive updated to Feb 28th, 2020. After completely applying the medical prevention and active control, Vietnam has the ability to take control of the outbreak of COVID-19 as a recent of WHO assessment. Vietnam has been reported as an effective country for prevention and control the outbreak of COVID-19. We retroactive reviewed our experience with 16 positive cases isolation. This article aims to present the first cohort of COVID-19 patients updated to Feb 28th, 2020 in Vietnam and sharing the national response to the pandemic.

Role of information and communication technologies and innovation in driving carbon emissions and economic growth in selected G-20 countries.

This paper contributes to the growing literature regarding the role of Information and Communication Technologies as well as Innovation on driving the level of carbon dioxide emissions and economic growth in context of the 21st conference of the Parties to the Climate convention (COP21). Drawing the data from 13 selected G-20 countries (including Argentina, Canada, China, France, Germany, Italy, Japan, Mexico, Republic of Korea, Russian Federation, Turkey, United Kingdom, United States) during the period of 15 years, our study achieves significant results. First, only five factors impede the carbon emissions namely energy price, foreign direct investment, technology, spending on innovation and trade openness while the remainder of determinants contribute to contamination of environment, including financial development. Second, when it comes to economic growth, information and communication technological and financial development are positive driving factors. Our results do reject the absence of Environmental Kuznets Curve (EKC) from our sample. Finally, our study empirically suggests that the work of controlling consumption of oil and environmentally friendly process including manufacture-trading in these economies will limit the amount of pollution.

S100a4 upregulation in Pik3caH1047R;Trp53R270H;MMTV-Cre-driven mammary tumors promotes metastasis.

BACKGROUND: PIK3CA mutations are frequent in human breast cancer. Pik3caH1047R mutant expression in mouse mammary gland promotes tumorigenesis. TP53 mutations co-occur with PIK3CA mutations in human breast cancers. We previously generated a conditionally activatable Pik3caH1047R;MMTV-Cre mouse model and found a few malignant sarcomatoid (spindle cell) carcinomas that had acquired spontaneous dominant-negative Trp53 mutations. METHODS: A Pik3caH1047R;Trp53R270H;MMTV-Cre double mutant mouse breast cancer model was generated. Tumors were characterized by histology, marker analysis, transcriptional profiling, single-cell RNA-seq, and bioinformatics. Cell lines were developed from mutant tumors and used to identify and confirm genes involved in metastasis. RESULTS: We found Pik3caH1047R and Trp53R270H cooperate in driving oncogenesis in mammary glands leading to a shorter latency than either alone. Double mutant mice develop multiple histologically distinct mammary tumors, including adenocarcinoma and sarcomatoid (spindle cell) carcinoma. We found some tumors to be invasive and a few metastasized to the lung and/or the lymph node. Single-cell RNA-seq analysis of the tumors identified epithelial, stromal, myeloid, and T cell groups. Expression analysis of the metastatic tumors identified S100a4 as a top candidate gene associated with metastasis. Metastatic tumors contained a much higher percentage of epithelial-mesenchymal transition (EMT)-signature positive and S100a4-expressing cells. CRISPR/CAS9-mediated knockout of S100a4 in a metastatic tumor-derived cell line disrupted its metastatic potential indicating a role for S100a4 in metastasis. CONCLUSIONS: Pik3caH1047R;Trp53R270H;MMTV-Cre mouse provides a preclinical model to mimic a subtype of human breast cancers that carry both PIK3CA and TP53 mutations. It also allows for understanding the cooperation between the two mutant genes in tumorigenesis. Our model also provides a system to study metastasis and develop therapeutic strategies for PIK3CA/TP53 double-positive cancers. S100a4 found involved in metastasis in this model can be a potential diagnostic and therapeutic target.

Comprehensive genomic analysis identifies pathogenic variants in maturity-onset diabetes of the young (MODY) patients in South India.

BACKGROUND: Maturity-onset diabetes of the young (MODY) is an early-onset, autosomal dominant form of non-insulin dependent diabetes. Genetic diagnosis of MODY can transform patient management. Earlier data on the genetic predisposition to MODY have come primarily from familial studies in populations of European origin. METHODS: In this study, we carried out a comprehensive genomic analysis of 289 individuals from India that included 152 clinically diagnosed MODY cases to identify variants in known MODY genes. Further, we have analyzed exome data to identify putative MODY relevant variants in genes previously not implicated in MODY. Functional validation of MODY relevant variants was also performed. RESULTS: We found MODY 3 (HNF1A; 7.2%) to be most frequently mutated followed by MODY 12 (ABCC8; 3.3%). They together account for ~ 11% of the cases. In addition to known MODY genes, we report the identification of variants in RFX6, WFS1, AKT2, NKX6-1 that may contribute to development of MODY. Functional assessment of the NKX6-1 variants showed that they are functionally impaired. CONCLUSIONS: Our findings showed HNF1A and ABCC8 to be the most frequently mutated MODY genes in south India. Further we provide evidence for additional MODY relevant genes, such as NKX6-1, and these require further validation.

Effects of social defeat stress on dopamine D2 receptor isoforms and proteins involved in intracellular trafficking.

BACKGROUND: Chronic social defeat stress induces depression and anxiety-like behaviors in rodents and also responsible for differentiating defeated animals into stress susceptible and resilient groups. The present study investigated the effects of social defeat stress on a variety of behavioral parameters like social behavior, spatial learning and memory and anxiety like behaviors. Additionally, the levels of various dopaminergic markers, including the long and short form of the D2 receptor, and total and phosphorylated dopamine and cyclic adenosine 3',5'-monophosphate regulated phosphoprotein-32, and proteins involved in intracellular trafficking were assessed in several key brain regions in young adult mice. METHODS: Mouse model of chronic social defeat was established by resident-intruder paradigm, and to evaluate the effect of chronic social defeat, mice were subjected to behavioral tests like spontaneous locomotor activity, elevated plus maze (EPM), social interaction and Morris water maze tests. RESULTS: Mice were divided into susceptible and unsusceptible groups after 10 days of social defeat stress. The susceptible group exhibited greater decreases in time spent in the open and closed arms compared to the control group on the EPM. In the social interaction test, the susceptible group showed greater increases in submissive and neutral behaviors and greater decreases in social behaviors relative to baseline compared to the control group. Furthermore, increased expression of D2L, D2S, Rab4, and G protein-coupled receptor associated sorting protein-1 was observed in the amygdala of the susceptible group compared to the control group. CONCLUSION: These findings suggest that social defeat stress induce anxiety-like and altered social interacting behaviors, and changes in dopaminergic markers and intracellular trafficking-related proteins.

Binding of carboxylate and trimethylammonium salts to octa-acid and TEMOA deep-cavity cavitands.

In participation of the fifth statistical assessment of modeling of proteins and ligands (SAMPL5), the strength of association of six guests (3-8) to two hosts (1 and 2) were measured by 1H NMR and ITC. Each host possessed a unique and well-defined binding pocket, whilst the wide array of amphiphilic guests possessed binding moieties that included: a terminal alkyne, nitro-arene, alkyl halide and cyano-arene groups. Solubilizing head groups for the guests included both positively charged trimethylammonium and negatively charged carboxylate functionality. Measured association constants (K a ) covered five orders of magnitude, ranging from 56 M-1 for guest 6 binding with host 2 up to 7.43 × 106 M-1 for guest 6 binding to host 1.

The shared genomic architecture of human nucleolar organizer regions.

The short arms of the five acrocentric human chromosomes harbor sequences that direct the assembly and function of the nucleolus, one of the key functional domains of the nucleus, yet they are absent from the current human genome assembly. Here we describe the genomic architecture of these human nucleolar organizers. Sequences distal and proximal to ribosomal gene arrays are conserved among the acrocentric chromosomes, suggesting they are sites of frequent recombination. Although previously believed to be heterochromatic, characterization of these two flanking regions reveals that they share a complex genomic architecture similar to other euchromatic regions of the genome, but they have distinct genomic characteristics. Proximal sequences are almost entirely segmentally duplicated, similar to the regions bordering centromeres. In contrast, the distal sequence is predominantly unique to the acrocentric short arms and is dominated by a very large inverted repeat. We show that the distal element is localized to the periphery of the nucleolus, where it appears to anchor the ribosomal gene repeats. This, combined with its complex chromatin structure and transcriptional activity, suggests that this region is involved in nucleolar organization. Our results provide a platform for investigating the role of NORs in nucleolar formation and function, and open the door for determining the role of these regions in the well-known empirical association of nucleoli with pathology.

The mRNA Expression Status of Dopamine Receptor D2, Dopamine Receptor D3 and DARPP-32 in T Lymphocytes of Patients with Early Psychosis.

Peripheral blood lymphocytes are an attractive tool because there is accumulating evidence indicating that lymphocytes may be utilized as a biomarker in the field of psychiatric study as they could reveal the condition of cells distributed in the brain. Here, we measured the mRNA expression status of dopamine receptor D2 (DRD2), DRD3, and dopamine and cyclic adenosine 3',5'-monophosphate regulated phosphoprotein-32 (DARPP-32) in T lymphocytes of patients with early psychosis by quantitative real-time polymerase chain reaction (q-PCR) and explored the relationships between their mRNA levels and the psychopathological status of patients. The present study demonstrated that the mRNA expression levels of DRD3 in T lymphocytes were significantly different among controls, and in patients with psychotic disorder not otherwise specified (NOS) and schizophrenia/schizophreniform disorder. However, no significant differences in mRNA expression levels of DRD2 and DARPP-32 were found among the three groups. We found a significant positive correlation between the DRD2 mRNA level and the score of the excited factor of the Positive and Negative Syndrome Scale (PANSS) in patients with schizophrenia/schizophreniform disorder. These findings suggest that DRD3 mRNA levels may serve as a potential diagnostic biomarker differentiating patients with early psychosis from controls.

3-Ketone-4,6-diene ceramide analogs exclusively induce apoptosis in chemo-resistant cancer cells.

Multidrug-resistance is a major cause of cancer chemotherapy failure in clinical treatment. Evidence shows that multidrug-resistant cancer cells are as sensitive as corresponding regular cancer cells under the exposure to anticancer ceramide analogs. In this work we designed five new ceramide analogs with different backbones, in order to test the hypothesis that extending the conjugated system in ceramide analogs would lead to an increase of their anticancer activity and selectivity towards resistant cancer cells. The analogs with the 3-ketone-4,6-diene backbone show the highest apoptosis-inducing efficacy. The most potent compound, analog 406, possesses higher pro-apoptotic activity in chemo-resistant cell lines MCF-7TN-R and NCI/ADR-RES than the corresponding chemo-sensitive cell lines MCF-7 and OVCAR-8, respectively. However, this compound shows the same potency in inhibiting the growth of another pair of chemo-sensitive and chemo-resistant cancer cells, MCF-7 and MCF-7/Dox. Mechanism investigations indicate that analog 406 can induce apoptosis in chemo-resistant cancer cells through the mitochondrial pathway. Cellular glucosylceramide synthase assay shows that analog 406 does not interrupt glucosylceramide synthase in chemo-resistant cancer cell NCI/ADR-RES. These findings suggest that due to certain intrinsic properties, ceramide analogs' pro-apoptotic activity is not disrupted by the normal drug-resistance mechanisms, leading to their potential use for overcoming cancer multidrug-resistance.

Features of the built environment related to physical activity friendliness and children's obesity and other risk factors.

OBJECTIVES: We investigated the relationships among environmental features of physical activity friendliness, socioeconomic indicators, and prevalence of obesity (BMI status), central adiposity (waist circumference, waist-height ratio), and hypertension. DESIGN AND SAMPLE: The design was cross-sectional; the study was correlational. The sample was 911 kindergarteners through sixth graders from three schools in an urban school district residing in 13 designated neighborhoods. MEASURES: Data from walking environmental community audits, census data for socioeconomic indicators, body mass index, waist circumference, waist-height ratio, and blood pressure were analyzed. A modified Alfonzo's Hierarchy of Walking Needs model was the conceptual framework for environmental features (i.e., accessibility, safety, comfort, and pleasurability) related to physical activity. RESULTS: Accessibility was significantly and negatively correlated with prevalence of obesity and with prevalence of a waist-height ratio >0.50. When neighborhood education was controlled, and when both neighborhood education and poverty were controlled with partial correlational analysis, comfort features of a walking environment were significantly and positively related to prevalence of obesity. When poverty was controlled with partial correlation, accessibility was significantly and negatively correlated with prevalence of waist-height ratio >0.50. CONCLUSIONS: The built environment merits further research to promote physical activity and stem the obesity epidemic in children. Our approach can be a useful framework for future research.

Liver-specific mitochondrial amidoxime-reducing component 1 (Mtarc1) knockdown protects the liver from diet-induced MASH in multiple mouse models.

BACKGROUND: Human genetic studies have identified several mitochondrial amidoxime-reducing component 1 (MTARC1) variants as protective against metabolic dysfunction-associated steatotic liver disease. The MTARC1 variants are associated with decreased plasma lipids and liver enzymes and reduced liver-related mortality. However, the role of mARC1 in fatty liver disease is still unclear. METHODS: Given that mARC1 is mainly expressed in hepatocytes, we developed an N-acetylgalactosamine-conjugated mouse Mtarc1 siRNA, applying it in multiple in vivo models to investigate the role of mARC1 using multiomic techniques. RESULTS: In ob/ob mice, knockdown of Mtarc1 in mouse hepatocytes resulted in decreased serum liver enzymes, LDL-cholesterol, and liver triglycerides. Reduction of mARC1 also reduced liver weight, improved lipid profiles, and attenuated liver pathological changes in 2 diet-induced metabolic dysfunction-associated steatohepatitis mouse models. A comprehensive analysis of mARC1-deficient liver from a metabolic dysfunction-associated steatohepatitis mouse model by metabolomics, proteomics, and lipidomics showed that Mtarc1 knockdown partially restored metabolites and lipids altered by diet. CONCLUSIONS: Taken together, reducing mARC1 expression in hepatocytes protects against metabolic dysfunction-associated steatohepatitis in multiple murine models, suggesting a potential therapeutic approach for this chronic liver disease.

Anesthetic Management for a Child With a Newly Identified Mitochondrial Disease SLC25A46 Mutation: A Case Report.

SLC25A46 mutation is a newly recognized mitochondrial mutation causing neurological and muscular abnormalities. We describe a first-ever report of the anesthetic management of a seven-year-old boy with an SLC25A46 mutation during a major orthopedic procedure. The patient was nonverbal and presented with cerebral visual impairment, torticollis, and lower extremity contractures. Because of his new diagnosis of mitochondrial disease and history of delayed awakening after anesthesia, we performed general anesthesia with sevoflurane, a low-dose ketamine infusion, and small doses of fentanyl while avoiding propofol and maintaining normoglycemia and normothermia. No postoperative complications were noted during the recovery period.

Enhancement of Hip X-ray with Convolutional Autoencoder for Increasing Prediction Accuracy of Bone Mineral Density.

It is very important to keep track of decreases in the bone mineral density (BMD) of elderly people since it can be correlated with the risk of incidence of major osteoporotic fractures leading to fatal injuries. Even though dual-energy X-ray absorptiometry (DXA) is the one of the most precise measuring techniques used to quantify BMD, most patients have restricted access to this machine due to high cost of DXA equipment, which is also rarely distributed to local clinics. Meanwhile, the conventional X-rays, which are commonly used for visualizing conditions and injuries due to their low cost, combine the absorption of both soft and bone tissues, consequently limiting its ability to measure BMD. Therefore, we have proposed a specialized automated smart system to quantitatively predict BMD based on a conventional X-ray image only by reducing the soft tissue effect supported by the implementation of a convolutional autoencoder, which is trained using proposed synthesized data to generate grayscale values of bone tissue alone. From the enhanced image, multiple features are calculated from the hip X-ray to predict the BMD values. The performance of the proposed method has been validated through comparison with the DXA value, which shows high consistency with correlation coefficient of 0.81 and mean absolute error of 0.069 g/cm2.

Machine Learning-Based Measurement of Regional and Global Spinal Parameters Using the Concept of Incidence Angle of Inflection Points.

This study delves into the application of convolutional neural networks (CNNs) in evaluating spinal sagittal alignment, introducing the innovative concept of incidence angles of inflection points (IAIPs) as intuitive parameters to capture the interplay between pelvic and spinal alignment. Pioneering the fusion of IAIPs with machine learning for sagittal alignment analysis, this research scrutinized whole-spine lateral radiographs from hundreds of patients who visited a single institution, utilizing high-quality images for parameter assessments. Noteworthy findings revealed robust success rates for certain parameters, including pelvic and C2 incidence angles, but comparatively lower rates for sacral slope and L1 incidence. The proposed CNN-based machine learning method demonstrated remarkable efficiency, achieving an impressive 80 percent detection rate for various spinal angles, such as lumbar lordosis and thoracic kyphosis, with a precise error threshold of 3.5°. Further bolstering the study's credibility, measurements derived from the novel formula closely aligned with those directly extracted from the CNN model. In conclusion, this research underscores the utility of the CNN-based deep learning algorithm in delivering precise measurements of spinal sagittal parameters, and highlights the potential for integrating machine learning with the IAIP concept for comprehensive data accumulation in the domain of sagittal spinal alignment analysis, thus advancing our understanding of spinal health.