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A screen for compounds with antigiardial activity in the Compounds Australia Scaffolds library identified SN00797640 (supplied structure being 8-acylaminodibenzoxazepinone 1) as a hit compound with potent anti-parasitic activity (concentration for 50% growth inhibition of Giardia duodenalis, IC50 0.18 μM). To further explore the structure–activity relationships in this series, compound 1 and analogues, including its 7-acylaminodibenzoxazepinone regioisomer (2), were synthesized and assessed for anti-Giardia activity. While regioisomer 2 demonstrated antigiardial activity, resynthesized 1 and other 8-acylaminodibenzoxazepinone analogues were inactive. Comparison of spectroscopic and physical properties demonstrated the correct structure of SN00797640 to be 7-acylamino regioisomer 2. These results highlight the importance of independent synthesis in verifying the structure and activity of screening hits.

Background: Depression as it were having been defined as a common and serious medical illness that negatively affects how you feel, the way you think and how you. The WHO in a fact sheet report has stated that depression is a common mental disorder and one of the main causes of disability worldwide. They added that globally, an estimated 264 million people are affected by depression. In 2020, an estimated 21.0 million adults in the United States had at least one major depressive episode. The pressure to perform well in school against all odds induces elements of depression when the results are not proportional to the efforts put into the study. Hence, this study was done to assess the level depression and suicidality amongst college students in the University of Port Harcourt, Rivers State, Nigeria. Materials and Methods: The study was descriptive cross-sectional with a total of 104 students who were recruited conveniently from the College of Health Sciences, University of Port Harcourt, Rivers State, Nigeria. The research instrument was a close-ended questionnaire structured in four parts: socio-demography, depression, coping, and suicidality adapted from the Beck-depression-inventory, COPE inventory tool, and Ask Suicide-Screening Questions (ASQ) tool. The statistical analysis was done using statistical package for social sciences (SPSS) version 23. The descriptive statistics was done using simple descriptive tool, chi square test was used to test for association between variables with the confidence interval 95%, p at 0.05 and power of 80. Results and Discussions: Age group (yrs) was the only significant socio-demographic characteristic that was significantly associated (X2 39.102, P=0.001) with depression status. The depression status of the participants showed that those who had Mild mood disturbance were 5(4.8%), Borderline clinical depression 4(3.8%), Moderate depression 10(9.6%), Severe depression 3(2.9%), and Extreme depression 6(5.8%). The study showed ...

Background Huntington disease (HD) is a neurodegenerative disease where a genetic mutation leads to excessive polyglutamine (Q) repeats in the huntingtin protein. The polyglutamine repeats create toxic plaques when the protein is cleaved, leading to neuron death. The glycolipid GM1 ganglioside (GM1) has been shown to be neuroprotective in HD models, as it prevents the cleavage of the mutant huntingtin protein by phosphorylation of serine 13 and 16. Previous studies have tested GM1 in both adult-onset and juvenile-onset HD models, but this study set out to investigate whether GM1 mediated cytoprotection is influenced by the length of polyglutamine repeats. Method and result This study utilized cell culture to analyze the effect of GM1 on cell viability, directly comparing the response between cells with adult-onset HD and juvenile-onset HD. HEK293 cells expressing either wild-type huntingtin (Htt) (19Q) exon 1, adult-onset HD mutant Htt exon 1 (55Q), or Juvenile HD mutant Htt exon 1 (94Q) were assessed for cell viability using the WST-1 assay. Our results suggested moderate doses of GM1 increased cell viability for all cell lines when compared to untreated cells. When comparing HEK293 55Q and 94Q cells, there was no difference in cell viability within each dose of GM1. Conclusion These data suggest cellular responses to GM1 are independent of polyglutamine repeats in HD cells and provide insight on GM1’s application as a therapeutic agent for HD and other diseases.

The Green Weaver ants, Oecophylla smaragdina are iconic animals known for their extreme cooperative behaviour where they bridge gaps by linking to each other to build living chains. They are visually oriented animals, build chains towards closer targets, use celestial compass cues for navigation and are visual predators. Here, we describe their visual sensory capacity. The major workers of O. smaragdina have more ommatidia (804) in each eye compared to minor workers (508), but the facet diameters are comparable between both castes. We measured the impulse responses of the compound eye and found their response duration (42 ms) was similar to that seen in other slow-moving ants. We determined the flicker fusion frequency of the compound eye at the brightest light intensity to be 132 Hz, which is relatively fast for a walking insect suggesting the visual system is well suited for a diurnal lifestyle. Using pattern-electroretinography we identified the compound eye has a spatial resolving power of 0.5 cycles deg−1 and reached peak contrast sensitivity of 2.9 (35% Michelson contrast threshold) at 0.05 cycles deg−1. We discuss the relationship of spatial resolution and contrast sensitivity, with number of ommatidia and size of the lens.

Supplementary Figure 6 - PDF file 75K, Statistical analysis of in vivo growth suppression. (A) Growth rates of BE2C, 1643, and EBC1 xenografts treated with 200 mg/kg LEE011 or vehicle, as determined by linear mixed effects analysis. (B) Summary table of statistics

Table S1. Specific mutations of genes listed in Table 1. Table S2. Foundation Medicine sequencing calls of cancer-specific gene panel. Table S3. Gene lists corresponding to microarray analysis described in Figures 1A and 1B: (A) binimetinib and (B) ribociclib. Significant genes (in bold type) are defined as having an adjusted p-value of 0.25 or less.

This document contains Supplementary information, including materials and methods as well as Figure Legends for the Supplementary Figures.

Supplementary Table 2 - PDF file 48KB, Copy number variations within the Cyclin D/CDK4/CDK6/RB pathway occur in high-risk neuroblastoma patients

Supplementary Figure 2 - PDF file 55K, Neuroblastoma tissue microarray. A tissue microarray demonstrates expression of RB in neuroblastoma that is higher in high-risk and MYCN amplified samples compared to low-risk or non-amplified samples (p = 0.03)

Statistical analysis of in vivo tumor growth delay for dose reduction studies in SH-SY5Y xenografts and Felix-PDX.

Neuroblastoma cell line characteristics and Combination Index values in validation panel.

Supplementary Figure 5 - PDF file 138K, CDK4/6 inhibition does not induce cytotoxicity in neuroblastoma. (A) Caspase 3/7 activation and (B) PARP cleavage were not observed in cell lines with demonstrated sensitivity to LEE011. SN38, a known cytotoxic agent, was used as a positive control

Supplementary Table 1 - PDF file 78K, Genomic aberrations in the Cyclin D/CDK4/CDK6/RB pathway occur frequently in neuroblastoma cell lines

Supplementary Figure 4 - PDF file 88K, Protein level expression of FOXM1 in neuroblastoma

1.Western blot analysis of the cleaved caspase-3 and p53 pathways in Ceritinib and Ribociclib treated cells. 2.Combination ALK and CDK 4/6 inhibition leads to enhanced G0/G1 arrest.

Supplementary Figure 1 - PDF file 56K, Expression of CDK4, CDK6, CCND1, and RB1 in neuroblastoma patients. Expression analysis of neuroblastoma primary tumors demonstrates that CDK4 expression, and to a lesser extent RB1 expression, is higher in high-risk neuroblastoma patients than in low risk patients

Supplementary Figure S1. Neuroblastoma cell lines are sensitive to binimetinib. Supplementary Figure S2. Gene expression profiling of human neuroblastoma cell lines with regards to relative sensitivity to MEK1/2 and CDK4/6 inhibition Supplementary Figure S3. Combined MEK and CDK4/6 inhibition does not induce significant levels of apoptosis or senescence. Supplementary Figure S4. G1 arrest induced by MEK1/2 and CDK4/6 inhibition is reversible. Supplementary Figure S5. Gene expression profiling of human neuroblastoma cell lines with regards to the synergy observed from combined binimetinib-ribociclib treatment. Figure S6. Neuroblastoma xenografts are sensitive to combined binimetinib-ribociclib treatment.

Purpose: Neuroblastoma is a pediatric cancer that continues to exact significant morbidity and mortality. Recently, a number of cell-cycle proteins, particularly those within the Cyclin D/CDK4/CDK6/RB network, have been shown to exert oncogenic roles in neuroblastoma, suggesting that their therapeutic exploitation might improve patient outcomes.Experimental Procedures: We evaluated the effect of dual CDK4/CDK6 inhibition on neuroblastoma viability using LEE011 (Novartis Oncology), a highly specific CDK4/6 inhibitor.Results: Treatment with LEE011 significantly reduced proliferation in 12 of 17 human neuroblastoma-derived cell lines by inducing cytostasis at nanomolar concentrations (mean IC50 = 307 ± 68 nmol/L in sensitive lines). LEE011 caused cell-cycle arrest and cellular senescence that was attributed to dose-dependent decreases in phosphorylated RB and FOXM1, respectively. In addition, responsiveness of neuroblastoma xenografts to LEE011 translated to the in vivo setting in that there was a direct correlation of in vitro IC50 values with degree of subcutaneous xenograft growth delay. Although our data indicate that neuroblastomas sensitive to LEE011 were more likely to contain genomic amplification of MYCN (P = 0.01), the identification of additional clinically accessible biomarkers is of high importance.Conclusions: Taken together, our data show that LEE011 is active in a large subset of neuroblastoma cell line and xenograft models, and supports the clinical development of this CDK4/6 inhibitor as a therapy for patients with this disease. Clin Cancer Res; 19(22); 6173–82. ©2013 AACR.

Complete dataset for synergy screen.

Impact of ALK and CDK4 knockdown in NB-1691.

Overview of compound activity by cell line.

Purpose: Anaplastic lymphoma kinase (ALK) is the most frequently mutated oncogene in the pediatric cancer neuroblastoma. We performed an in vitro screen for synergistic drug combinations that target neuroblastomas with mutations in ALK to determine whether drug combinations could enhance antitumor efficacy.Experimental Design: We screened combinations of eight molecularly targeted agents against 17 comprehensively characterized human neuroblastoma-derived cell lines. We investigated the combination of ceritinib and ribociclib on in vitro proliferation, cell cycle, viability, caspase activation, and the cyclin D/CDK4/CDK6/RB and pALK signaling networks in cell lines with representative ALK status. We performed in vivo trials in CB17 SCID mice bearing conventional and patient-derived xenograft models comparing ceritinib alone, ribociclib alone, and the combination, with plasma pharmacokinetics to evaluate for drug–drug interactions.Results: The combination of ribociclib, a dual inhibitor of cyclin-dependent kinase (CDK) 4 and 6, and the ALK inhibitor ceritinib demonstrated higher cytotoxicity (P = 0.008) and synergy scores (P = 0.006) in cell lines with ALK mutations as compared with cell lines lacking mutations or alterations in ALK. Compared with either drug alone, combination therapy enhanced growth inhibition, cell-cycle arrest, and caspase-independent cell death. Combination therapy achieved complete regressions in neuroblastoma xenografts with ALK-F1174L and F1245C de novo resistance mutations and prevented the emergence of resistance. Murine ribociclib and ceritinib plasma concentrations were unaltered by combination therapy.Conclusions: This preclinical combination drug screen with in vivo validation has provided the rationale for a first-in-children trial of combination ceritinib and ribociclib in a molecularly selected pediatric population. Clin Cancer Res; 23(11); 2856–68. ©2016 AACR.

Purpose: Neuroblastoma is treated with aggressive multimodal therapy, yet more than 50% of patients experience relapse. We recently showed that relapsed neuroblastomas frequently harbor mutations leading to hyperactivated ERK signaling and sensitivity to MEK inhibition therapy. Here we sought to define a synergistic therapeutic partner to potentiate MEK inhibition.Experimental Design: We first surveyed 22 genetically annotated human neuroblastoma-derived cell lines (from 20 unique patients) for sensitivity to the MEK inhibitor binimetinib. After noting an inverse correlation with sensitivity to ribociclib (CDK4/6 inhibitor), we studied the combinatorial effect of these two agents using proliferation assays, cell-cycle analysis, Ki67 immunostaining, time-lapse microscopy, and xenograft studies.Results: Sensitivity to binimetinib and ribociclib was inversely related (r = −0.58, P = 0.009). MYCN amplification status and expression were associated with ribociclib sensitivity and binimetinib resistance, whereas increased MAPK signaling was the main determinant of binimetinib sensitivity and ribociclib resistance. Treatment with both compounds resulted in synergistic or additive cellular growth inhibition in all lines tested and significant inhibition of tumor growth in three of four xenograft models of neuroblastoma. The augmented growth inhibition was attributed to diminished cell-cycle progression that was reversible upon removal of drugs.Conclusions: Here we demonstrate that combined binimetinib and ribociclib treatment shows therapeutic synergy across a broad panel of high-risk neuroblastoma preclinical models. These data support testing this combination therapy in relapsed high-risk neuroblastoma patients, with focus on cases with hyperactivated RAS–MAPK signaling. Clin Cancer Res; 23(7); 1785–96. ©2016 AACR.

Supplementary Figure Legend

Supplementary Figure 3 - PDF file 127K, MYCN expression is inversely correlated with LEE011 sensitivity. (A) High mRNA expression of MYCN correlates with low LEE011 IC50s (r = -0.55, p = 0.02). This correlation is further strengthened (r = -0.7, p = 0.003) by the removal of two outliers, SKNSH (IC50 = 148 nM) and its subclone, SY5Y (IC50 = 154 nM). (B) Sensitive cell lines also tend to express higher levels of MYCN protein than resistant cell lines

Statistical analysis of in vivo tumor growth delay and event-free survival in SH-SY5Y and NB-1691 xenografts.

Supplementary Figures 1-7, Table 1 from Overcoming Hypoxia-Induced Apoptotic Resistance through Combinatorial Inhibition of GSK-3β and CDK1

In the era of living with COVID-19, the risk of localised SARS-CoV-2 outbreaks remains. Here, we develop a multi-scale modelling framework for estimating the local outbreak risk for a viral disease (the probability that a major outbreak results from a single case introduced into the population), accounting for within-host viral dynamics. Compared to population-level models previously used to estimate outbreak risks, our approach enables more detailed analysis of how the risk can be mitigated through pre-emptive interventions such as antigen testing. Considering SARS-CoV-2 as a case study, we quantify the within-host dynamics using data from individuals with omicron variant infections. We demonstrate that regular antigen testing reduces, but may not eliminate, the outbreak risk, depending on characteristics of local transmission. In our baseline analysis, daily antigen testing reduces the outbreak risk by 45% compared to a scenario without antigen testing. Additionally, we show that accounting for heterogeneity in within-host dynamics between individuals affects outbreak risk estimates and assessments of the impact of antigen testing. Our results therefore highlight important factors to consider when using multi-scale models to design pre-emptive interventions against SARS-CoV-2 and other viruses.

During the COVID-19 pandemic, human behavior change as a result of nonpharmaceutical interventions such as isolation may have induced directional selection for viral evolution. By combining previously published empirical clinical data analysis and multi-level mathematical modeling, we found that the SARS-CoV-2 variants selected for as the virus evolved from the pre-Alpha to the Delta variant had earlier and higher infectious periods but a shorter duration of infection. Selection for increased transmissibility shapes the viral load dynamics, and the isolation measure is likely to be a driver of these evolutionary transitions. In addition, we showed that a decreased incubation period and an increased proportion of asymptomatic infection were also positively selected for as SARS-CoV-2 mutated to the extent that people did not isolate. We demonstrated that the Omicron variants evolved in these ways to adapt to human behavior. The quantitative information and predictions we present here can guide future responses in the potential arms race between pandemic interventions and viral evolution.

Fufu is a popular food in West Africa made from fresh or fermented cassava. As a product of cassava, when not properly processed may lead to some neurological impairment. This study investigated the physical and neurological effects of fufu in male wistar rats. Two groups of animals were used for this study. Group 1 (control group N=10) received the normal rat feed while group 2 (n=10) received the fufu produce. Both were administered for about 5 weeks after which a reach-to-grasp experiment was carried out using the reaching apparatus. Their physical appearances were observed and it was seen that the group fed with fufu experienced some hair loss and other physical changes. Qualitative assessment of their reaching movements showed that the group fed with fufu performed poorly in the reach-to-grasp experiment than the control group. In the observation of the movement pattern of both groups, it was clearly seen that the group fed with fufu had difficulties aiming and grasping as well as withdrawing of food pellets during the experiment and they also showed signs of weakness due to the fact that they were not able to lift their limbs properly in order to reach the pellets on the pedestal, therefore showing under reaching movements. Conclusion: the prolonged consumption of not properly processed fufu has both physical and neurological effects on the albino wistar rat.

Dementia cases are expected to grow for African Americans and surrogate decision makers (SDMs) will have a significant role at the end of life (EOL). This qualitative exploratory case study used Cognitive Task Analysis and an integrated conceptual framework to understand the EOL decision experience of African American SDMs for patients with advanced dementia. Using a holistic multiple-case design, 8 African American SDMs were interviewed about their experiences with the decision-making process, including role acceptance, role enactment, and emotional outcomes of decision making. Thirteen themes germane to understanding the EOL decision experience of African American SDMs were identified. Findings suggest African American SDMs often lack sufficient knowledge of disease prognosis and intervention options to make informed treatment choices at EOL. In particular, African Americans extend the caregiver role to SDM for patients with dementia at EOL without being fully aware of the role and decision-making responsibilities. Surrogates lacked a general understanding of EOL options resulting in underutilization of hospice and palliative care and subsequent regret, and few interventions exist to improve the uptake of EOL care services. There is a need to develop culturally appropriate role preparation, education, and decision support to improve EOL treatment decisions and emotional adjustment of surrogates of patients with advanced dementia, which should be rendered early and throughout the illness trajectory.

Viruses evolve in infected host populations, and host population dynamics affect viral evolution. RNA viruses with a short duration of infection and a high peak viral load, such as and SARS-CoV-2, are maintained in human populations. By contrast, RNA viruses characterized by a long infection duration and a low peak viral load (e.g., borna disease virus) can be maintained in nonhuman populations, and why the persistent viruses evolved has been rarely explored. Here, using a multi-level modeling approach including both individual-level virus infection dynamics and population-scale transmission, we consider virus evolution based on the host environment, specifically, the effect of the contact history of infected hosts. We found that, with a highly dense contact history, viruses with a high virus production rate but low accuracy are likely to be optimal, resulting in a short infectious period with a high peak viral load. In contrast, with a low-density contact history, viral evolution is toward low virus production but high accuracy, resulting in long infection durations with low peak viral load. Our study sheds light on the origin of persistent viruses and why acute viral infections but not persistent virus infection tends to prevail in human society.

On an annual basis the flagellate protozoan, Giardia duodenalis, is responsible for an estimated one billion human infections of which approximately two hundred million cause disease. However, the treatment of Giardia infections is reliant on a small group of chemotherapeutic classes that have a broad spectrum of antimicrobial activity and increasing treatment failure rates. To improve this situation, we need new drugs. In this study we screened the Compounds Australia Scaffolds Library for compounds with potent and selective activity against these parasites. Unlike previous drug discovery efforts that have focused on drug repurposing, this library is comprised of commercially available synthetic compounds arranged into lead-like scaffolds to facilitate structure activity relationship assessments and de novo drug discovery. A screen of 2451 compounds in this library identified 40 hits (>50% inhibitory activity at 10 µM, over 48 h). Secondary testing identified three compounds with IC50 values 50-fold selectivity for parasites over mammalian cells and a hit series, CL9406, comprising compounds with potent (lowest IC50 180 nM) and selective activity for Giardia parasites. The most promising compound in this series, SN00797640, displayed selective activity against assemblage A, B, and metronidazole resistant parasites which was parasiticidal (minimum lethal concentration 625 nM) and synergistic with albendazole. SN00797640 was well-tolerated when administered to mice at doses of 50 mg/kg daily for three days paving the way for pre-clinical in vivo activity assessment.

Introduction: Advanced mobile technology especially mobile phones provide useful and convenient means for individuals to communicate and access the internet anytime and anywhere. However, electromagnetic field (EMF) energy from the mobile phones has been mentioned to hamper neuronal activity and cognitive function in humans. Aim: This research was therefore undertaken to determine the relationship between age, gender, mobile phone usage and some cognitive functions among the Nigerian students. Methodology: This study used datafrom500 students randomly selected from populations in University of Port-Harcourt. Different ages specified by the respondents through structural. Questionnaires were used. Data obtained from the retrieved questionnaire were analyzed using multiple STATGRAPHICS for the descriptive statistics. While SPSS (IBM Amos V21.0.0, USA) was used for the inferential statistics. Results: The results revealed that, there was no significant association between age and smartphone ownership (P>0.05). However, for gender, there were significant distributional differences in males (38.5%) and females (29.4%) (P=0.022), as well as stress caused by phone usage (males=76.8%; females=89.7). Correlations of cognitive function variables revealed significant relationship between all the cognitive functional variables. Conclusion: Distraction was found to have a significant relationship with stress (P=0.033). Therefore attachment to use of smart phone among youths should be advisably minimized.

Common pharmacological treatments for attention-deficit hyperactivity disorder (ADHD) are central nervous system stimulants acting as norepinephrine-dopamine reuptake inhibitors. The noradrenergic and dopaminergic systems have been shown to impact performance on tasks assessing creativity. Some previous studies suggest higher performance on creativity tasks in ADHD. Stimulant medication has been shown to differentially impact creativity in those without ADHD. However, the full range of effects of stimulant medication on creativity in those with ADHD is not known. This study examined the effects of stimulants on convergent and divergent tasks associated with creativity in adults with ADHD. Seventeen adults diagnosed with ADHD who were prescribed stimulant medication attended two counterbalanced sessions: one after taking their prescribed stimulant dose and one after the dose was withheld. Participants completed convergent problem-solving (anagrams, Compound Remote Associates) and divergent generative (letter/semantic fluency, Torrance Test for Creative Thinking (TTCT)-Verbal) tasks. There was a significant increase in words generated on the semantic fluency task for the stimulant session. Additionally, significant increases were found in the stimulant session for originality, flexibility, and fluency scores on the TTCT. Stimulant medication did not have an effect on any of the problem-solving tasks. Stimulant medication enhanced verbal fluency in adults with ADHD but had no effect on convergent abilities. Furthermore, stimulants enhanced fluency, flexibility, and originality scores on the TTCT. Therefore, stimulants appear to have positive effects on divergent task performance in adults with ADHD, but not convergent tasks. This finding warrants further studies into the specific roles of norepinephrine and dopamine in this effect.

Here, we show that hypoxia drives especially long-lasting epithelial-mesenchymal transition (EMT) in pancreatic ductal adenocarcinoma (PDAC) primarily through a positive-feedback histone methylation-MAPK signaling axis. We find that neoplastic PDAC cells preferentially undergo EMT in hypoxic tumor regions in multiple model systems and that hypoxia drives a cell-autonomous EMT in PDAC cells which, unlike EMT in response to growth factors, can last for weeks. We further demonstrate that hypoxia reduces histone demethylase KDM2A activity, suppresses PP2 family phosphatase expression, and activates MAPKs to post-translationally stabilize histone methyltransferase NSD2, leading to an H3K36me2-dependent EMT in which hypoxia-inducible factors play only a supporting role. This mechanism can be antagonizedin vivoby combinations of MAPK inhibitors that may be effective in multi-drug therapies designed to target EMT.

We characterize relationships between stratigraphy and natural fractures in outcrops of Mesozoic strata that rim the San Juan Basin in New Mexico and Colorado. These outcrops expose fluvial and shallow-marine siliciclastic deposits and calcareous mudstones deposited in a distal marine setting. We focus primarily on a regionally extensive fracture set formed during the Eocene to minimize localized tectonic effects on fracture development. Where possible, we supplement our observations with wireline log- or laboratory-derived measurements of rock properties. Our goals are twofold: 1) to illustrate how direct integration of data and concepts from stratigraphy and structural geology can lead to better fracture characterization, and 2) to develop thought processes that will stimulate new exploration and development strategies. Genetic beds form one scale of stratification in the outcrops we describe. For example, sandstone beds can be arranged into coarsening and thickening upward successions that are the depositional record of shoreline progradation. In fluvial settings, cm- to dm-scale sandstone beds can also be part of m-scale single-storey channel complexes that, themselves, can be arranged into amalgamated channel complexes 10s of m thick. In these and other settings, it is important to distinguish between beds and features that can be defined via wireline logs because it is the former (cm- to dm-scale) that are usually the primary control the distribution of natural fractures. The extension fractures we describe are typically bed-bound, with bedding being defined by lithology contrasts and the associated changes in elastic properties. Fracture spacing distributions are typically lognormal with average spacing being less than bed thickness. Although mechanical bedding and depositional bedding are commonly the same, diagenesis can cut across bed boundaries and complicate this relationship, especially where lithologic contrasts are small. Deposits from similar depositional environments which undergo different diagenetic histories can have substantially different mechanical properties and therefore deform differently in response to similar imposed stresses.

This paper examines the relationships between stratigraphy and hydrocarbon production from the San Juan Basin of New Mexico and Colorado. Abundant data and the long production history allow lessons to be learned, both from an exploration and development perspective, that can be applied in other basins. Conversely, as new play types and technologies are defined and developed elsewhere, the applicability of those tools in the San Juan Basin needs to be understood for well-informed exploration and development activities to continue. The San Juan Basin is a Latest Cretaceous – Tertiary (Paleogene) structure that contains rocks deposited from the Lower Paleozoic to the Tertiary, but only the Upper Cretaceous section has significant hydrocarbon, mostly gas, production. Herein I make the case for studying depositional systems, and the controls thereon (e.g., basin development, eustasy, sediment supply), because they are the first-order controls on whether a sedimentary basin can become a hydrocarbon province, or super basin as the San Juan Basin has recently been defined. Only in the Upper Cretaceous did a suitable combination of forcing mechanisms combine to form source and reservoir rocks, and repeated transgressive-regressive cycles of the Upper Cretaceous stacked multiple successions of source and reservoir rocks in a way that leads to stacked pay potential. Because of the types of depositional systems that could develop, the source rocks were primarily gas prone, like those of other Rocky Mountain basins. Oil-prone source rocks are present but primarily restricted to episodes of peak transgression. A lack of suitable trapping mechanisms helps to explain the relative dearth of conventional oil pools. Although gas production has dropped precipitously in the past decade, driven primarily by overabundance of gas supply associated with the shale-gas boom, the combination of horizontal drilling and multi-stage hydraulic fracturing is being applied to revive oil production from some unconventional stratigraphic targets with success.

Background Histological remission is an important target for Ulcerative Colitis (UC) treatment; however, scoring of histological images is time-consuming and prone to inter and intra-observer variability. Thus, a need exists for an accurate, reproducible, and reliable automated method. Previously, we demonstrated an Artificial Intelligence (AI) Tool using image processing and machine learning algorithms to measure histological disease activity using the Nancy index consistently and accurately.1 Here, we aim to enhance the capabilities of the AI Tool, by adding substantially more population-diversified training data while maintaining accuracy and robustness of results. Methods Eight global sites submitted 600 UC histological images. These were added to the 200 images previously used to train and validate the AI Tool. The 800-image dataset was divided into 2 groups: 90% used for training, 10% for testing. The novel AI algorithms were trained using state-of-the-art image processing and machine learning techniques based on deep learning and feature extraction. Cell and tissue regions of each training image were manually annotated, measured, and assigned a Nancy Index independently by 3 histopathologists, and used to further train the AI using over 43,000 characterisations. The AI Tool fully characterises histological images, identifying tissue types, cell types, cell numbers and locations, and automatically measures the Nancy Index for each image. Intra Class Correlation (ICC) and Confusion Matrix analyses were performed to evaluate the AI Tool and assess accuracy. Results The average ICC was 92.1% among the histopathologists and 91.1% between histopathologists and AI Tool, compared with 88.3% and 87.2% in the previous study.1 Confusion matrix analysis (Table 1) demonstrated the strongest correlation at the extremes of the Nancy Index, with 80% correlation between predicted and true labels for Nancy Scores of 0 or 4. When 2 adjacent scores were combined, correlations were stronger: 96% for a true Nancy score of 0 being predicted as 0 or 1, and 100% for a true Nancy score of 2 being predicted as 2 or 3. Conclusion By adding a larger number of images to the AI Tool training data, the robustness of the AI Tool was substantially improved while maintaining accuracy. The continued high correlation of AI Tool performance with the histopathologists reinforces the potential role for the AI Tool for IBD clinical applications. Fully characterising whole slides could standardise and validate an AI-driven scoring system for histology slides in IBD, eliminating the subjectivity of the human pathologist in assessment of disease activity. References: 1. Peyrin-Biroulet L, et al. J Crohn's and Colitis. 2022;16(Suppl 1):i105.