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In an ever-increasingly diverse workforce, cross-cultural communication skills are essential for success regardless of job title or task. We present an engaging and customizable 30-minute activity designed to develop participants' cross-cultural communication skills by increasing awareness and sensitivity to interpersonal differences in collaborative group settings. Drawing from a multiculturalism approach to diversity, participants learn that acknowledging our differences facilitates more effective and strategic communication. We provide detailed instructions for running this exercise to meet instructors' and students' outlined learning objectives. The debriefing questions and post-lesson reflections support an environment where facilitators and participants grow. This experiential exercise suits any discipline's synchronous undergraduate, graduate, and professional classes.

In the search for mechanisms that contribute to dyslexia, the term "attention" has been invoked to explain performance in a variety of tasks, creating confusion since all tasks do, indeed, demand "attention." Many studies lack an experimental manipulation of attention that would be necessary to determine its influence on task performance. Nonetheless, an emerging view is that children with dyslexia have an impairment in the exogenous (automatic/reflexive) orienting of spatial attention. Here we investigated the link between exogenous attention and reading ability by presenting exogenous spatial cues in the multi-letter processing task--a task relevant for reading. The task was gamified and administered online to a large sample of children (N = 187) between 6 and 17 years. Children with dyslexia performed worse overall at rapidly recognizing and reporting strings of letters. However, we found no evidence for a difference in the utilization of exogenous spatial cues, resolving two decades of ambiguity in the field. Previous studies that claimed otherwise may have failed to distinguish attention effects from overall task performance or found spurious group differences in small samples.

Abstract Background Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). Method In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Results Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer’s disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10–3) in PSP. Conclusions Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.

Abstract Background Pancreatic fibrosis is an early diagnostic feature of the common inherited disorder cystic fibrosis (CF). Many people with CF (pwCF) are pancreatic insufficient from birth and the replacement of acinar tissue with cystic lesions and fibrosis is a progressive phenotype that may later lead to diabetes. Little is known about the initiating events in the fibrotic process though it may be a sequela of inflammation in the pancreatic ducts resulting from loss of CFTR impairing normal fluid secretion. Here we use a sheep model of CF (CFTR −/− ) to examine the evolution of pancreatic disease through gestation. Methods Fetal pancreas was collected at six time points from 50-days of gestation through to term, which is equivalent to ~ 13 weeks to term in human. RNA was extracted from tissue for bulk RNA-seq and single cells were prepared from 80-day, 120-day and term samples for scRNA-seq. Data were validated by immunochemistry. Results Transcriptomic evidence from bulk RNA-seq showed alterations in the CFTR −/− pancreas by 65-days of gestation, which are accompanied by marked pathological changes by 80-days of gestation. These include a fibrotic response, confirmed by immunostaining for COL1A1, αSMA and SPARC, together with acinar loss. Moreover, using scRNA-seq we identify a unique cell population that is significantly overrepresented in the CFTR −/− animals at 80- and 120-days gestation, as are stellate cells at term. Conclusion The transcriptomic changes and cellular imbalance that we observe likely have pivotal roles in the evolution of CF pancreatic disease and may provide therapeutic opportunities to delay or prevent pancreatic destruction in CF.

Background/Objectives: Azole resistance in Aspergillus fumigatus associated with the TR34/L98H mutations in the cyp51A gene have been increasingly reported. Determining the environmental resistance rate has been deemed important when considering front-line therapy for invasive aspergillosis. The aim of the study was to determine prevalence of azole resistance in environmental A. fumigatus isolates across South Wales.Methods: Over 5 months in 2015, 513 A. fumigatus isolates were cultured from 671 soil and 44 air samples and were screened for azole resistance using VIPcheck™ agar plates containing itraconazole, voriconazole and posaconazole. Resistance was confirmed by the CLSI M38-A2 methodology. The mechanism of resistance was investigated using the PathoNostics AsperGenius® Assay.Results: Screening by VIPcheck™ plate identified azole-resistance in 30 isolates, most of which (28/30) harbored the TR34/L98H mutation, generating a prevalence of 6.0%. Twenty-five isolates had a MIC of ≥2 mg/L with itraconazole, 23 isolates had a MIC of ≥2 mg/L with voriconazole and seven isolates had a MIC ≥0.25 mg/L with posaconazole. All isolates deemed resistant by VIPcheck™ plates were resistant to at least one azole by reference methodology.Conclusions: There is significant environmental azole resistance (6%) in South Wales, in close proximity to patients susceptible to aspergillosis. Given this environmental reservoir, azole resistance should be routinely screened for in clinical practice and environmental monitoring continued.

Organelle heterogeneity and inter-organelle contacts within a single cell contribute to the limited sensitivity of current organelle separation techniques, thus hindering organelle subpopulation characterization. Here, we use direct current insulator-based dielectrophoresis (DC-iDEP) as an unbiased separation method and demonstrate its capability by identifying distinct distribution patterns of insulin vesicles from INS-1E insulinoma cells. A multiple voltage DC-iDEP strategy with increased range and sensitivity has been applied, and a differentiation factor (ratio of electrokinetic to dielectrophoretic mobility) has been used to characterize features of insulin vesicle distribution patterns. We observed a significant difference in the distribution pattern of insulin vesicles isolated from glucose-stimulated cells relative to unstimulated cells, in accordance with maturation of vesicles upon glucose stimulation. We interpret the difference in distribution pattern to be indicative of high-resolution separation of vesicle subpopulations. DC-iDEP provides a path for future characterization of subtle biochemical differences of organelle subpopulations within any biological system.

Abstract A definitive diagnosis of Alzheimer’s disease (AD), even in the presence of co-morbid neuropathology (occurring in > 50% of AD cases), is a significant unmet medical need that has obstructed the discovery of effective AD therapeutics. An AD-biomarker, the Morphometric Imaging (MI) assay on cultured skin fibroblasts, was used in a double-blind, allcomers (ages 55–90) trial of 3 patient cohorts: AD dementia patients, N = 25, all autopsy confirmed, non-AD dementia patients, N = 21—all autopsy or genetically confirmed; and non-demented control (AHC) patients N = 27. Fibroblasts cells isolated from 3-mm skin punch biopsies were cultured on a 3-D Matrigel matrix with movement dynamics quantified by image analysis. From counts of all aggregates (N) in a pre-defined field image and measures of the average area (A) of aggregates per image, the number-to-area ratios in a natural logarithmic form Ln(A/N) were determined for all patient samples. AD cell lines formed fewer large aggregates (cells clustered together) than non-AD or AHC cell lines. The cut-off value of Ln(A/N) = 6.98 was determined from the biomarker values of non-demented apparently healthy control (AHC) cases. Unequivocal validation by autopsy, genetics, and/or dementia criteria was possible for all 73 patient samples. The samples were collected from multiple centers—four US centers and one center in Japan. The study found no effect of center-to-center variation in fibroblast isolation, cell growth, or cell aggregation values (Ln(A/N)). The autopsy-confirmed MI Biomarker distinguished AD from non-AD dementia (non-ADD) patients and correctly diagnosed AD even in the presence of other co-morbid pathologies at autopsy (True Positive = 25, False Negative = 0, False Positive = 0, True Negative = 21, and Accuracy = 100%. Sensitivity and specificity were calculated as 100% (95% CI = 84 to 100.00%). From these findings, the MI assay appears to detect AD with great accuracy—even with abundant co-morbidity.

Abstract Tauopathies are a category of neurodegenerative diseases characterized by the presence of abnormal tau protein-containing neurofibrillary tangles (NFTs). NFTs are universally observed in aging, occurring with or without the concomitant accumulation of amyloid-beta peptide (Aβ) in plaques that typifies Alzheimer disease (AD), the most common tauopathy. Primary age-related tauopathy (PART) is an Aβ-independent process that affects the medial temporal lobe in both cognitively normal and impaired subjects. Determinants of symptomology in subjects with PART are poorly understood and require clinicopathologic correlation; however, classical approaches to staging tau pathology have limited quantitative reproducibility. As such, there is a critical need for unbiased methods to quantitatively analyze tau pathology on the histological level. Artificial intelligence (AI)-based convolutional neural networks (CNNs) generate highly accurate and precise computer vision assessments of digitized pathology slides, yielding novel histology metrics at scale. Here, we performed a retrospective autopsy study of a large cohort (n = 706) of human post-mortem brain tissues from normal and cognitively impaired elderly individuals with mild or no Aβ plaques (average age of death of 83.1 yr, range 55–110). We utilized a CNN trained to segment NFTs on hippocampus sections immunohistochemically stained with antisera recognizing abnormal hyperphosphorylated tau (p-tau), which yielded metrics of regional NFT counts, NFT positive pixel density, as well as a novel graph-theory based metric measuring the spatial distribution of NFTs. We found that several AI-derived NFT metrics significantly predicted the presence of cognitive impairment in both the hippocampus proper and entorhinal cortex (p

Abstract Relapsing remitting multiple sclerosis (MS) is an inflammatory demyelinating disorder of the central nervous system that in many cases leads to progressive MS, a neurodegenerative disease. Progressive MS is untreatable and relentless, and its cause is unknown. Prior studies of MS have documented neuronal accumulation of phosphorylated tau protein, which characterizes another heterogeneous group of neurogenerative disorders, the tauopathies. Known causes of tauopathy are myriad, and include point mutations within the tau gene, amyloid beta accumulation, repeated head trauma, and viral infection. We and others have proposed that tau has essential features of a prion. It forms intracellular assemblies that can exit a cell, enter a secondary cell, and serve as templates for their own replication in a process termed “seeding.” We have previously developed specialized “biosensor” cell systems to detect and quantify tau seeds in brain tissues. We hypothesized that progressive MS is a tauopathy, potentially triggered by inflammation. We tested for and detected tau seeding in frozen brain tissue of 6/8 subjects with multiple sclerosis. We then evaluated multiple brain regions from a single subject for whom we had detailed clinical history. We observed seeding outside of MS plaques that was enriched by immunopurification with two anti-tau antibodies (HJ8.5 and MD3.1). Immunohistochemistry with AT8 and MD3.1 confirmed prior reports of tau accumulation in MS. Although larger studies are required, our data suggest that progressive MS may be considered a secondary tauopathy.

Abstract Age-related cognitive impairment is multifactorial, with numerous underlying and frequently co-morbid pathological correlates. Amyloid beta (Aβ) plays a major role in Alzheimer’s type age-related cognitive impairment, in addition to other etiopathologies such as Aβ-independent hyperphosphorylated tau, cerebrovascular disease, and myelin damage, which also warrant further investigation. Classical methods, even in the setting of the gold standard of postmortem brain assessment, involve semi-quantitative ordinal staging systems that often correlate poorly with clinical outcomes, due to imperfect cognitive measurements and preconceived notions regarding the neuropathologic features that should be chosen for study. Improved approaches are needed to identify histopathological changes correlated with cognition in an unbiased way. We used a weakly supervised multiple instance learning algorithm on whole slide images of human brain autopsy tissue sections from a group of elderly donors to predict the presence or absence of cognitive impairment (n = 367 with cognitive impairment, n = 349 without). Attention analysis allowed us to pinpoint the underlying subregional architecture and cellular features that the models used for the prediction in both brain regions studied, the medial temporal lobe and frontal cortex. Despite noisy labels of cognition, our trained models were able to predict the presence of cognitive impairment with a modest accuracy that was significantly greater than chance. Attention-based interpretation studies of the features most associated with cognitive impairment in the top performing models suggest that they identified myelin pallor in the white matter. Our results demonstrate a scalable platform with interpretable deep learning to identify unexpected aspects of pathology in cognitive impairment that can be translated to the study of other neurobiological disorders.

Abstract Background Polycyclic aromatic hydrocarbons (PAH), which are found in air pollution, have carcinogenic and endocrine disrupting properties that might increase breast cancer risk. PAH exposure might be particularly detrimental during pregnancy, as this is a time when the breast tissue of both the mother and daughter is undergoing structural and functional changes. In this study, we tested the hypothesis that ambient PAH exposure during pregnancy is associated with breast tissue composition, measured one to two decades later, in adolescent daughters and their mothers. Methods We conducted a prospective analysis using data from a New York City cohort of non-Hispanic Black and Hispanic mother–daughter dyads (recruited 1998–2006). During the third trimester of pregnancy, women wore backpacks containing a continuously operating air sampling pump for two consecutive days that measured ambient exposure to eight carcinogenic higher molecular weight nonvolatile PAH compounds (Σ8 PAH) and pyrene. When daughters (n = 186) and mothers (n = 175) reached ages 11–20 and 29–55 years, respectively, optical spectroscopy (OS) was used to evaluate measures of breast tissue composition (BTC) that positively (water content, collagen content, optical index) and negatively (lipid content) correlate with mammographic breast density, a recognized risk factor for breast cancer. Multivariable linear regression was used to evaluate associations between ambient PAH exposure and BTC, overall and by exposure to household tobacco smoke during pregnancy (yes/no). Models were adjusted for race/ethnicity, age, and percent body fat at OS. Results No overall associations were found between ambient PAH exposure (Σ8 PAH or pyrene) and BTC, but statistically significant additive interactions between Σ8 PAH and household tobacco smoke exposure were identified for water content and optical index in both daughters and mothers (interaction p values

Approximately 476,000 cases of Lyme disease are diagnosed in the United States annually, yet comprehensive economic evaluations are lacking. In a prospective study among reported cases in Lyme disease–endemic states, we estimated the total patient cost and total societal cost of the disease. In addition, we evaluated disease and demographic factors associated with total societal cost. Participants had a mean patient cost of ≈$1,200 (median $240) and a mean societal cost of ≈$2,000 (median $700). Patients with confirmed disseminated disease or probable disease had approximately double the societal cost of those with confirmed localized disease. The annual, aggregate cost of diagnosed Lyme disease could be $345–968 million (2016 US dollars) to US society. Our findings emphasize the importance of effective prevention and early diagnosis to reduce illness and associated costs. These results can be used in cost-effectiveness analyses of current and future prevention methods, such as a vaccine.

Abstract Pathologists can label pathologies differently, making it challenging to yield consistent assessments in the absence of one ground truth. To address this problem, we present a deep learning (DL) approach that draws on a cohort of experts, weighs each contribution, and is robust to noisy labels. We collected 100,495 annotations on 20,099 candidate amyloid beta neuropathologies (cerebral amyloid angiopathy (CAA), and cored and diffuse plaques) from three institutions, independently annotated by five experts. DL methods trained on a consensus-of-two strategy yielded 12.6–26% improvements by area under the precision recall curve (AUPRC) when compared to those that learned individualized annotations. This strategy surpassed individual-expert models, even when unfairly assessed on benchmarks favoring them. Moreover, ensembling over individual models was robust to hidden random annotators. In blind prospective tests of 52,555 subsequent expert-annotated images, the models labeled pathologies like their human counterparts (consensus model AUPRC = 0.74 cored; 0.69 CAA). This study demonstrates a means to combine multiple ground truths into a common-ground DL model that yields consistent diagnoses informed by multiple and potentially variable expert opinions.

Abstract Background The Colombian population, as well as those in other Latin American regions, arose from a recent tri-continental admixture among Native Americans, Spanish invaders, and enslaved Africans, all of whom passed through a population bottleneck due to widespread infectious diseases that left small isolated local settlements. As a result, the current population reflects multiple founder effects derived from diverse ancestries. Methods We characterized the role of admixture and founder effects on the origination of the mutational landscape that led to neurodegenerative disorders under these historical circumstances. Genomes from 900 Colombian individuals with Alzheimer’s disease (AD) [n = 376], frontotemporal lobar degeneration-motor neuron disease continuum (FTLD-MND) [n = 197], early-onset dementia not otherwise specified (EOD) [n = 73], and healthy participants [n = 254] were analyzed. We examined their global and local ancestry proportions and screened this cohort for deleterious variants in disease-causing and risk-conferring genes. Results We identified 21 pathogenic variants in AD-FTLD related genes, and PSEN1 harbored the majority (11 pathogenic variants). Variants were identified from all three continental ancestries. TREM2 heterozygous and homozygous variants were the most common among AD risk genes (102 carriers), a point of interest because the disease risk conferred by these variants differed according to ancestry. Several gene variants that have a known association with MND in European populations had FTLD phenotypes on a Native American haplotype. Consistent with founder effects, identity by descent among carriers of the same variant was frequent. Conclusions Colombian demography with multiple mini-bottlenecks probably enhanced the detection of founder events and left a proportionally higher frequency of rare variants derived from the ancestral populations. These findings demonstrate the role of genomically defined ancestry in phenotypic disease expression, a phenotypic range of different rare mutations in the same gene, and further emphasize the importance of inclusiveness in genetic studies.

West Nile virus (WNV) is the most common domestic arbovirus in the United States. During 2018, WNV was transmitted through solid organ transplantation to 2 recipients who had neuroinvasive disease develop. Because of increased illness and death in transplant recipients, organ procurement organizations should consider screening during region-specific WNV transmission months.

Abstract The diagnosis of Parkinson’s disease (PD) is challenging at all stages due to variable symptomatology, comorbidities, and mimicking conditions. Postmortem assessment remains the gold standard for a definitive diagnosis. While it is well recognized that PD manifests pathologically in the central nervous system with aggregation of α-synuclein as Lewy bodies and neurites, similar Lewy-type synucleinopathy (LTS) is additionally found in the peripheral nervous system that may be useful as an antemortem biomarker. We have previously found that detection of LTS in submandibular gland (SMG) biopsies is sensitive and specific for advanced PD; however, the sensitivity is suboptimal especially for early-stage disease. Further, visual microscopic assessment of biopsies by a neuropathologist to identify LTS is impractical for large-scale adoption. Here, we trained and validated a convolutional neural network (CNN) for detection of LTS on 283 digital whole slide images (WSI) from 95 unique SMG biopsies. A total of 8,450 LTS and 35,066 background objects were annotated following an inter-rater reliability study with Fleiss Kappa = 0.72. We used transfer learning to train a CNN model to classify image patches (151 × 151 pixels at 20× magnification) with and without the presence of LTS objects. The trained CNN model showed the following performance on image patches: sensitivity: 0.99, specificity: 0.99, precision: 0.81, accuracy: 0.99, and F-1 score: 0.89. We further tested the trained network on 1230 naïve WSI from the same cohort of research subjects comprising 42 PD patients and 14 controls. Logistic regression models trained on features engineered from the CNN predictions on the WSI resulted in sensitivity: 0.71, specificity: 0.65, precision: 0.86, accuracy: 0.69, and F-1 score: 0.76 in predicting clinical PD status, and 0.64 accuracy in predicting PD stage, outperforming expert neuropathologist LTS density scoring in terms of sensitivity but not specificity. These findings demonstrate the practical utility of a CNN detector in screening for LTS, which can translate into a computational tool to facilitate the antemortem tissue-based diagnosis of PD in clinical settings.

Theoretical source models of underwater explosions are often applied in studying tsunami hazards associated with subaqueous volcanism; however, their use in numerical codes based on the shallow water equations can neglect the significant dispersion of the generated wavefield. A non-hydrostatic multilayer method is validated against a laboratory-scale experiment of wave generation from instantaneous disturbances and at field-scale subaqueous explosions at Mono Lake, California, utilising the relevant theoretical models. The numerical method accurately reproduces the range of observed wave characteristics for positive disturbances and suggests a relationship of extended initial troughs for negative disturbances at low-dispersivity and high-non-linearity parameters. Satisfactory amplitudes and phase velocities within the initial wave group are found using underwater explosion models at Mono Lake. The scheme is then applied to modelling tsunamis generated by volcanic explosions at Lake Taupō, New Zealand, for a magnitude representing an ejecta volume of 0.1 km3. Waves reach all shores within 15 min with maximum incident crest amplitudes around 0.2 m at shores near the source. This work shows that the multilayer scheme used is computationally efficient and able to capture a wide range of wave characteristics, including dispersive effects, which is necessary when investigating subaqueous explosions. This research therefore provides the foundation for future studies involving a rigorous probabilistic hazard assessment to quantify the risks and relative significance of this tsunami source mechanism.

Abstract Background The Kaiser Permanente Research Bank (KPRB) is collecting biospecimens and surveys linked to electronic health records (EHR) from approximately 400,000 adult KP members. Within the KPRB, we developed a Cancer Cohort to address issues related to cancer survival, and to understand how genetic, lifestyle and environmental factors impact cancer treatment, treatment sequelae, and prognosis. We describe the Cancer Cohort design and implementation, describe cohort characteristics after 5 years of enrollment, and discuss future directions. Methods Cancer cases are identified using rapid case ascertainment algorithms, linkage to regional or central tumor registries, and direct outreach to KP members with a history of cancer. Enrollment is primarily through email invitation. Participants complete a consent form, survey, and donate a blood or saliva sample. All cancer types are included. Results As of December 31, 2020, the cohort included 65,225 cases (56% female, 44% male) verified in tumor registries. The largest group was diagnosed between 60 and 69 years of age (31%) and are non-Hispanic White (83%); however, 10,076 (16%) were diagnosed at ages 18–49 years, 4208 (7%) are Hispanic, 3393 (5%) are Asian, and 2389 (4%) are Black. The median survival time is 14 years. Biospecimens are available on 98% of the cohort. Conclusions The KPRB Cancer Cohort is designed to improve our understanding of treatment efficacy and factors that contribute to long-term cancer survival. The cohort’s diversity - with respect to age, race/ethnicity and geographic location - will facilitate research on factors that contribute to cancer survival disparities.

Abstract Maar-diatreme volcanoes are the second-most common type on land, occurring in volcanic fields within all major tectonic environments. Their deposits typically contain an abundance of lithic fragments quarried from the substrate, and many contain large, deep-sourced lithic fragments that were erupted to the surface. Primary volcaniclastic deposits fill the diatreme structure formed during eruption. There is negligible inelastic deformation of diatreme-adjacent country rock, indicating that country rock is removed to create the diatreme structures, either by being shifting downward below observable levels, ejected upward to contribute to surficial deposits, or dissolved and hidden in magma erupted or intruded at depth. No previous study has systematically reviewed and analysed the reported lithic fragments of maar-diatreme systems. We present a comprehensive compilation from published work of lithic characteristics in maar ejecta rings and in diatreme deposits of both common and kimberlite maar-diatremes. For maar-diatremes and their tephra ring deposits, we find no correlations among lithic clast sizes, shapes, depositional sites, and excavation depths. This is difficult to reconcile with models involving systematic diatreme deepening coupled with tephra-ring growth, but consistent with those involving chaotic explosions and mixing. Larger amounts of data are needed to further examine how these types of volcanoes operate.

Abstract Reading requires the correct identification of letters and letter positions within words. Selective attention is, therefore, required to select chunks of the text for sequential processing. Despite the extensive literature on visual attention, the well-known effects of spatial cues in simple perceptual tasks cannot inform us about the role of attention in a task as complex as reading. Here, we systematically manipulate spatial attention in a multi-letter processing task to understand the effects of spatial cues on letter encoding in typical adults. Overall, endogenous (voluntary) cue benefits were larger than exogenous (reflexive). We show that cue benefits are greater in the left than in the right visual field and larger for the most crowded letter positions. Endogenous valid cues reduced errors due to confusing letter positions more than misidentifications, specifically for the most crowded letter positions. Therefore, shifting endogenous attention along a line of text is likely an important mechanism to alleviate the effects of crowding on encoding letters within words. Our results help set the premise for constructing theories about how specific mechanisms of attention support reading development in children. Understanding the link between reading development and attention mechanisms has far-reaching implications for effectively addressing the needs of children with reading disabilities.

The success of CAR-T cells for treating acute myeloid leukaemia (AML) is hampered by toxicity to normal cells and low CAR-T cell persistence. Here, the authors show that the demethylating compound 5′-Azacitdine increases anti-CD123 CAR-T cell cytotoxicity against AML.

Abstract Although pathology of tauopathies is characterized by abnormal tau protein aggregation in both gray and white matter regions of the brain, neuropathological investigations have generally focused on abnormalities in the cerebral cortex because the canonical aggregates that form the diagnostic criteria for these disorders predominate there. This corticocentric focus tends to deemphasize the relevance of the more complex white matter pathologies, which remain less well characterized and understood. We took a data-driven machine-learning approach to identify novel disease-specific morphologic signatures of white matter aggregates in three tauopathies: Alzheimer disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). We developed automated approaches using whole slide images of tau immunostained sections from 49 human autopsy brains (16 AD,13 CBD, 20 PSP) to identify cortex/white matter regions and individual tau aggregates, and compared tau-aggregate morphology across these diseases. Tau burden in the gray and white matter for individual subjects strongly correlated in a highly disease-specific fashion. We discovered previously unrecognized tau morphologies for AD, CBD and PSP that may be of importance in disease classification. Intriguingly, our models classified diseases equally well based on either white or gray matter tau staining. Our results suggest that tau pathology in white matter is informative, disease-specific, and linked to gray matter pathology. Machine learning has the potential to reveal latent information in histologic images that may represent previously unrecognized patterns of neuropathology, and additional studies of tau pathology in white matter could improve diagnostic accuracy.

ABSTRACT: A study was aimed to investigate the effects of mixed Eimeria challenge on performance, gastrointestinal health, oxidative stress, inflammation, and expression of nutrient transporter genes of Hy-Line W-36 pullets. A total of 540, 16-d old pullets were randomly allocated into 5 treatment groups with 6 replicate cages, including a nonchallenged control group. A mixed Eimeria species solution containing 50,000 E. maxima, 50,000 E. tenella, and 250,000 E. acervulina oocysts per mL was prepared and challenged to one group as a high-dose treatment (High). The 2-fold serial dilution was done to prepare the medium-high (Med-High: 25,000 E. maxima; 25,000 E. tenella; and 125,000 E. acervulina), the medium-low (Med-Low: 12,500 E. maxima; 12,500 E. tenella; and 62,500 E. acervulina), and the low (Low: 6,250 E. maxima; 6,250 E. tenella; and 31,250 E. acervulina) dose treatments, and these dosages were challenged to 3 remaining groups, respectively. Growth performance, daily feed intake (FI), and mortality were calculated from 0-14 d postinfection (DPI). Gastrointestinal permeability (GP) was measured on 3, 5, 6, 7, and 9 DPI. The result indicated significant linear responses to the Eimeria challenge dosage in average body weight and body weight gain (P < 0.0001). An interaction between treatment and DPI was observed for FI (P < 0.0001). Feed intake significantly dropped from 4 DPI and did not recover until 12 DPI in the challenged groups. The lowest FI for each of the challenged groups was observed on 5 DPI. Gastrointestinal permeability increased linearly, peaking at 5 DPI, and was recovered back to normal by 9 DPI in the challenged groups. Furthermore, gene expression of tight junction proteins was linearly upregulated by increased Eimeria dosages. The oxidative status of the pullets was lowered in the challenged groups than the nonchallenged control group, whereas the expression of inflammatory and proinflammatory cytokines was upregulated by Eimeria challenge on 6 DPI (P < 0.05). The highest mortality was observed in pullets challenged with the High, followed by the Med-High (P < 0.0001) on 5 DPI. In summary, the mixed Eimeria challenge linearly reduced the growth performance of pullets with an increase in oxidative stress and inflammation. A severe effect of Eimeria on gastrointestinal health was observed on 5 or 6 DPI as suggested by GP, tight junction genes, and mortality results. This study indicates that Eimeria infection can be a threat to gastrointestinal health related issues in pullets.

Pancreatic β-cells respond to increased extracellular glucose levels by initiating a metabolic shift. That change in metabolism is part of the process of glucose-stimulated insulin secretion and is of particular interest in the context of diabetes. However, we do not fully understand how the coordinated changes in metabolic pathways and metabolite products influence insulin secretion. In this work, we apply systems biology approaches to develop a detailed kinetic model of the intracellular central carbon metabolic pathways in pancreatic β-cells upon stimulation with high levels of glucose. The model is calibrated to published metabolomics datasets for the INS1 823/13 cell line, accurately capturing the measured metabolite fold-changes. We first employed the calibrated mechanistic model to estimate the stimulated cell's fluxome. We then used the predicted network fluxes in a data-driven approach to build a partial least squares regression model. By developing the combined kinetic and data-driven modeling framework, we gain insights into the link between β-cell metabolism and glucose-stimulated insulin secretion. The combined modeling framework was used to predict the effects of common anti-diabetic pharmacological interventions on metabolite levels, flux through the metabolic network, and insulin secretion. Our simulations reveal targets that can be modulated to enhance insulin secretion. The model is a promising tool to contextualize and extend the usefulness of metabolomics data and to predict dynamics and metabolite levels that are difficult to measure in vitro. In addition, the modeling framework can be applied to identify, explain, and assess novel and clinically-relevant interventions that may be particularly valuable in diabetes treatment.

RNA-sequencing (RNA-seq) efforts in acute lymphoblastic leukaemia (ALL) have identified numerous prognostically significant genomic alterations which can guide diagnostic risk stratification and treatment choices when detected early. However, integrating RNA-seq in a clinical setting requires rapid detection and accurate reporting of clinically relevant alterations. Here we present RaScALL, an implementation of the k-mer based variant detection tool km, capable of identifying more than 100 prognostically significant lesions observed in ALL, including gene fusions, single nucleotide variants and focal gene deletions. We compared genomic alterations detected by RaScALL and those reported by alignment-based de novo variant detection tools in a study cohort of 180 Australian patient samples. Results were validated using 100 patient samples from a published North American cohort. RaScALL demonstrated a high degree of accuracy for reporting subtype defining genomic alterations. Gene fusions, including difficult to detect fusions involving EPOR and DUX4, were accurately identified in 98% of reported cases in the study cohort (n = 164) and 95% of samples (n = 63) in the validation cohort. Pathogenic sequence variants were correctly identified in 75% of tested samples, including all cases involving subtype defining variants PAX5 p.P80R (n = 12) and IKZF1 p.N159Y (n = 4). Intragenic IKZF1 deletions resulting in aberrant transcript isoforms were also detectable with 98% accuracy. Importantly, the median analysis time for detection of all targeted alterations averaged 22 minutes per sample, significantly shorter than standard alignment-based approaches. The application of RaScALL enables rapid identification and reporting of previously identified genomic alterations of known clinical relevance.

Abstract Background Focus groups and workshops can be used to gain insights into the persistence of and potential solutions for environmental health priorities in underserved areas. The objective of this study was to characterize focus group and workshop outcomes of a community-academic partnership focused on addressing environmental health priorities in an urban and a rural location in Alabama between 2012 and 2019. Methods Six focus groups were conducted in 2016 with 60 participants from the City of Birmingham (urban) and 51 participants from Wilcox County (rural), Alabama to discuss solutions for identified environmental health priorities based on previous focus group results in 2012. Recorded focus groups were transcribed and analyzed using the grounded theory approach. Four follow-up workshops that included written survey instruments were conducted to further explore identified priorities and determine whether the priorities change over time in the same urban (68 participants) and rural (72 participants) locations in 2018 and 2019. Results Consistent with focus groups in 2012, all six focus groups in 2016 in Birmingham identified abandoned houses as the primary environmental priority. Four groups listed attending city council meetings, contacting government agencies and reporting issues as individual-level solutions. Identified city-level solutions included city-led confiscation, tearing down and transferring of abandoned property ownership. In Wilcox County, all six groups agreed the top priority was drinking water quality, consistent with results in 2012. While the priority was different in Birmingham versus Wilcox County, the top identified reason for problem persistence was similar, namely unresponsive authorities. Additionally, individual-level solutions identified by Wilcox County focus groups were similar to Birmingham, including contacting and pressuring agencies and developing petitions and protesting to raise awareness, while local policy-level solutions identified in Wilcox County included government-led provision of grants to improve septic systems, and transparency in allocation of funds. Workshops in 2018 and 2019 further emphasized water quality as the top priority in Wilcox County, while participants in Birmingham transitioned from abandoned houses as a top priority in 2018 to drinking water quality as a new priority in 2019. Conclusions Applying a community-engaged approach in both urban and rural locations provided better understanding of the unique opportunities and challenges for identifying potential interventions for environmental health priorities in both locations. Results can help inform future efforts to address locally defined environmental health issues and solutions.

In all of the various sub-cases that comprise the case of what PIE tense of DO was employed to form the weak preterit, perfect origin falls somewhere in the range of “almost certain” to “quite possible”. By contrast, non-perfect origin is in most cases de- pendent on propositions that are either ad hoc or otherwise problematic. In the only case that at first appears to strongly favor non-perfect origin, 2SG /-dɛɛs/ can be seen as orig- inating by “opportunistic re-interpretation” of /-dɛd-t/ > /-dɛss/ as /-dɛɛs/, with 2SG /-s/. Obscure phonological changes of the traditional kind permit the 1SG, 3SG, and 3PL to be seen as having perfect origin. All forms can be seen as having perfect origin.

Abstract Primary age-related tauopathy (PART) is a form of Alzheimer-type neurofibrillary degeneration occurring in the absence of amyloid-beta (Aβ) plaques. While PART shares some features with Alzheimer disease (AD), such as progressive accumulation of neurofibrillary tangle pathology in the medial temporal lobe and other brain regions, it does not progress extensively to neocortical regions. Given this restricted pathoanatomical pattern and variable symptomatology, there is a need to reexamine and improve upon how PART is neuropathologically assessed and staged. We performed a retrospective autopsy study in a collection (n = 174) of post-mortem PART brains and used logistic regression to determine the extent to which a set of clinical and neuropathological features predict cognitive impairment. We compared Braak staging, which focuses on hierarchical neuroanatomical progression of AD tau and Aβ pathology, with quantitative assessments of neurofibrillary burden using computer-derived positive pixel counts on digitized whole slide images of sections stained immunohistochemically with antibodies targeting abnormal hyperphosphorylated tau (p-tau) in the entorhinal region and hippocampus. We also assessed other factors affecting cognition, including aging-related tau astrogliopathy (ARTAG) and atrophy. We found no association between Braak stage and cognitive impairment when controlling for age (p = 0.76). In contrast, p-tau burden was significantly correlated with cognitive impairment even when adjusting for age (p = 0.03). The strongest correlate of cognitive impairment was cerebrovascular disease, a well-known risk factor (p

Abstract Objective Flathead catfish are rapidly expanding into nonnative waterways throughout the United States. Once established, flathead catfish may cause disruptions to the local ecosystem through consumption and competition with native fishes, including species of conservation concern. Flathead catfish often become a popular sport fish in their introduced range, and so management strategies must frequently balance the need to protect native and naturalized fauna while meeting the desire to maintain or enhance fisheries. However, there are currently few tools available to inform management of invasive flathead catfish (Pylodictis olivaris). We describe a suite of microsatellite loci that can be used to characterize population structure, predict invasion history, and assess potential mitigation strategies for flathead catfish. Results Our panel of 13 microsatellite loci were polymorphic and appear to be informative for population genetic studies of flathead catfish. We found moderate levels of diversity in four nonnative collections of flathead catfish in the Pennsylvania and Maryland sections of the Susquehanna River and the Schuylkill River, Pennsylvania. Analyses suggested patterns of genetic differentiation within- and among-rivers, highlighting the utility of this marker panel for understanding the structure and assessing the degree of connectivity among flathead catfish populations.

Abstract Ruxolitinib (rux) Phase II clinical trials are underway for the treatment of high-risk JAK2-rearranged (JAK2r) B-cell acute lymphoblastic leukemia (B-ALL). Treatment resistance to targeted inhibitors in other settings is common; elucidating potential mechanisms of rux resistance in JAK2r B-ALL will enable development of therapeutic strategies to overcome or avert resistance. We generated a murine pro-B cell model of ATF7IP-JAK2 with acquired resistance to multiple type-I JAK inhibitors. Resistance was associated with mutations within the JAK2 ATP/rux binding site, including a JAK2 p.G993A mutation. Using in vitro models of JAK2r B-ALL, JAK2 p.G993A conferred resistance to six type-I JAK inhibitors and the type-II JAK inhibitor, CHZ-868. Using computational modeling, we postulate that JAK2 p.G993A enabled JAK2 activation in the presence of drug binding through a unique resistance mechanism that modulates the mobility of the conserved JAK2 activation loop. This study highlights the importance of monitoring mutation emergence and may inform future drug design and the development of therapeutic strategies for this high-risk patient cohort.

Abstract Background The incidence of anal squamous cell carcinoma has been increasing, particularly in people living with HIV (PLWH). There is concern that radiosensitizing drugs, such as protease inhibitors, commonly used in the management of HIV, may increase toxicities in patients undergoing chemoradiation. This study examines treatment outcomes and toxicities in PLWH managed with and without protease inhibitors who are receiving chemoradiation for anal cancer. Methods Patient demographic, HIV management, and cancer treatment information were extracted from multiple Veterans Affairs databases. Patients were also manually chart reviewed. Among PLWH undergoing chemoradiation for anal carcinoma, therapy outcomes and toxicities were compared between those treated with and without protease inhibitors at time of cancer treatment. Statistical analysis was performed using chi-square, Cox regression analysis, and logistic regression. Results A total of 219 PLWH taking anti-retroviral therapy undergoing chemoradiation for anal cancer were identified and included in the final analysis. The use of protease inhibitors was not associated with any survival outcome including colostomy-free survival, progression-free survival, or overall survival (all adjusted hazard ratio p-values> 0.05). Regarding toxicity, protease inhibitor use was not associated with an increased odds of hospitalizations or non-hematologic toxicities; however, protease inhibitor use was associated with increased hospitalizations for hematologic toxicities, including febrile neutropenia (p

Plain English summary Involving stakeholders in research about dementia care is recognized as an important approach to develop findings that are relevant to individuals living with dementia, family care partners, and health and social professionals in dementia care. Still, this approach is not often used and there is a need for more information about how researchers can engage stakeholders in the research process and the impact of engagement from the perspectives of stakeholders. In this paper, we describe how a mixed group of stakeholders was engaged for a project to identify priorities for dementia care research and their perspectives of the experience. A Stakeholder Advisory Council (SAC) worked together to develop their skills in research and connected with their communities to determine what is most important to be studied in the field of dementia care research. To understand the perspectives of the stakeholders involved in this project, we conducted individual interviews with members of the SAC. This study will help researchers understand how they can collaborate with stakeholders in dementia care and the benefits of including individuals living with dementia, family care partners, and professional stakeholders in the research process.

Abstract Background A woman’s health at the time of conception lays the foundation for a healthy pregnancy and the lifelong health of her child. We investigated the health behaviours of UK women planning pregnancy. Methods We analysed survey data from the ‘Planning for Pregnancy’ online tool (Tommy’s, UK). We described all women planning pregnancy and compared the frequency of non-adherence to preconception recommendations in women who had already stopped contraception (active planners) and those who had not (non-active planners). Results One hundred thirty-one thousand one hundred eighty-two women from across the UK were included, of whom 64.8% were actively planning pregnancy. Of the whole cohort, twenty percent were smokers and less than one third took folic acid supplements (31.5%). Forty two percent engaged in less than the recommended 150 min of weekly physical activity and only 53.3% consumed five portions of fruit or vegetables 4 days a week. Smokers were 1.87 times more likely to be active planners than non-smokers (95% CI 1.79–1.94), and women who took folic acid were 7 times more likely to be active planners (95% CI 6.97–7.59) compared to women who did not. Smoking, drug use and lack of folic acid supplementation were common in younger women and those who were underweight. Conclusions This unique survey of UK women has identified poor adherence to preconception recommendations in those planning pregnancies and supports the need for a greater public health focus on preconception health. This study provides a contemporary basis from which to inform preconception health advice and a benchmark to measure changes over time.

Objectives To assess smoking habits, nicotine use, exposure to passive smoking, awareness of associated harms, and experiences with and preferences for smoking cessation support among people with multiple sclerosis (MS).Design Online survey, convenience sampling.Setting Community setting, Australia.Participants Adults living in Australia with probable or diagnosed MS were recruited via social media and newsletters to participate in 2020.Results Of the 284 participants in our convenience sample, 25.7% were current smokers (n=73) and 38.0% were former smokers (n=108). Awareness of the harms of smoking on MS onset (n=68, 24.3%) and progression (n=116, 41.6%) was low. Almost a quarter (n=67, 23.8%) of participants were regularly exposed to passive smoke, and awareness of associated harm was also low (n=47, 16.8%). Among current smokers, 76.1% (n=54) had tried quitting and 73.2% considered quitting within 6 months (n=52). Many participants reported perceived short-term benefits of smoking, and long-term benefits of quitting, on MS symptoms and general well-being (short-term n=28, 40.0%; long-term n=28, 82.4%). While most participants reported that their neurologist (n=126, 75.4%) or other healthcare providers (n=125, 74.9%) had assessed smoking status, very few neurologists (n=3, 1.8%) or other healthcare providers (n=14, 8.4%) had provided help with quitting. Most current smokers preferred speaking about smoking to a neurologist (n=36, 52.2%) or general practitioner (n=41, 59.4%). Almost 60% of the current smokers wanted additional cessation information specific to MS (n=41, 59.4%), and 45.5% said this information would motivate them to quit smoking (n=30).Conclusions Our convenience sample, which may not be representative, indicated an urgent need for regular evidence-based smoking cessation supports for people with MS. Most participants felt they would benefit from smoking cessation advice. MS clinicians, in collaboration with patient organisations, smoking cessation services and general practitioners, should make smoking cessation promotion with people with MS a priority.

Abstract Objectives The purpose of this study was to partner with stakeholders to identify gaps in care for persons living with dementia and their family caregivers and from this list, identify priorities for dementia care research. Methods Using a community-engaged research approach, a Stakeholder Advisory Council (SAC) consisting of diverse membership including persons living with dementia and family caregivers was convened. Through our work with the SAC, along with input from the wider network through a symposium, webinars, and an online learning community, gaps in dementia care and a list of topics for dementia care research was generated. This list was reduced to 46 topics for dementia care research and sent to stakeholders (persons living with dementia, family caregivers, and health/social care professionals in dementia care) to be prioritized by rating each of the 46 topics as “Not so important,” “Important,” or “Very important.” Priorities for dementia care were summarized by frequencies and proportions. Results A total of 186 participants completed the survey from August through October 2020, including 23 (12.4%) persons living with dementia, 101 (54.3%) family caregivers, and 62 (33.3%) health/social care professionals. Consistent across stakeholder groups was the focus on research on how best to support families following a diagnosis of dementia. Among persons living with dementia, research focused on support for continuing to live in their own homes was ranked as the highest priority, rated by 91.3% as “Very Important”. High priority research areas for family caregivers included interventions to slow cognitive decline (76.3%) as well as non-pharmacological approaches to manage behavioral symptoms (74.7%). The highest priority research topics for health/social care professionals were focused on the diagnosis including benefits of an early diagnosis (71.4%), how best to deliver the diagnosis (70.9%), and supports needed following a diagnosis (78.6%). Conclusions This project draws on the strengths of its multi-stakeholder perspective to support patient-centered outcomes research. Findings are intended to inform those who conduct research and those who fund research about which research topics stakeholders believe are most important and thus have greatest potential to improve the quality of life among people living with dementia and their families.

Abstract Conservation research is dominated by vertebrate examples but the shorter generation times and high local population sizes of invertebrates may lead to very different management strategies, particularly for species with low movement rates. Here we investigate the genetic structure of an endangered flightless grasshopper, Keyacris scurra, which was used in classical evolutionary studies in the 1960s. It had a wide distribution across New South Wales (NSW) and Victoria in pre‐European times but has now become threatened because of land clearing for agriculture and other activities. We revisited remnant sites of K. scurra, with populations now restricted to only one area in Victoria and a few small patches in NSW and the Australian Capital Territory (ACT). Using DArtseq to generate SNP markers as well as mtDNA sequence data, we show that the remaining Victorian populations in an isolated valley are genetically distinct from the NSW populations and that all populations tend to be genetically unique, with large FST values up to 0.8 being detected for the SNP datasets. We also find that, with one notable exception, the NSW/ACT populations separate genetically into previously described chromosomal races (2n = 15 vs. 2n = 17). Isolation by distance was detected across both the SNP and mtDNA datasets, and there was substantial differentiation within chromosomal races. Genetic diversity as measured by heterozygosity was not correlated with the size of remaining habitat where the populations were found, with high variation present in some remnant cemetery sites. However, inbreeding correlated negatively with estimated habitat size at 25–500 m patch radius. These findings emphasize the importance of small habitat areas in conserving genetic variation in such species with low mobility, and they highlight populations suitable for future translocation efforts.

Using phasor-FLIM (Fluorescence Lifetime Imaging Microscopy), Wang et al. reveal differential usages of oxidative phosphorylation and glycolysis in living islet cells following glucose stimulation. This study suggests the applicability of FLIM as a drug discovery tool as it reports perturbations in glucose metabolism in living islet cells.

Children with neurofibromatosis have a higher risk of developing juvenile myelomonocytic leukemia and acute myeloid leukemia, but rarely develop B-cell acute lymphoblastic leukemia (B-ALL). Through in-vitro modeling, a novel NF1 p.L2467 frameshift (fs) mutation identified in a relapsed/refractory Ph-like B-ALL patient with neurofibromatosis demonstrated cytokine independence and increased RAS signaling, indicative of leukemic transformation. Furthermore, these cells were sensitive to the MEK inhibitors trametinib and mirdametinib. Bi-allelic NF1 loss of function may be a contributing factor to relapse and with sensitivity to MEK inhibitors, suggests a novel precision medicine target in the setting of neurofibromatosis patients with B-ALL.

Objectives We assessed the effect of gender, rank and research productivity on compensation for faculty at academic medical centres.Design A web-based retrospective review of salary for professors in 2016.Setting Faculty from six state-run, publicly funded academic medical centres in the Western USA.Participants 799 faculty members, 225 assistant (51% women), 200 associate (40% women) and 374 full professors (32% women) from general surgery (26% women), obstetrics and gynaecology (70% women) and radiology (34% women).Methods Archived online faculty profiles were reviewed for gender, rank and compensation (total, baseline and supplemental). Total compensation was defined as baseline compensation plus supplemental income. Baseline compensation was defined as base salary minus reductions due to participation in the voluntary Employee Reduction in Time and phased retirement programmes. Supplemental income was defined as additional salary for clinical care and research (eg, grants). Elsevier’s Scopus was used to collect data on h-index, a measure of research productivity. Linear regression models were estimated to determine the relationship between these factors and salary.Results Total compensation was significantly higher for men across all professorial ranks in both general surgery (R2=0.159,F(4,299)=14.123,p

Abstract Background The health of a woman before conception not only influences the outcome of her pregnancy but also the lifelong health of mother and child. Many women in the UK are inadequately prepared for pregnancy, with reports of a high prevalence of smoking, low folic acid supplement use, and suboptimal diet and physical activity. Get Ready! will link an online digital tool to identify women planning pregnancy most at risk of complications with a personalised intervention to improve health behaviours and biomarkers of metabolic health. Methods Women planning pregnancy will be identified from a free and widely used online preconception tool. A short online screening questionnaire will then be used to recruit women considered to be at high metabolic risk. Eligibility criteria include resident in the UK, age > 18–< 50 years, BMI ≥ 23 kg/m2 (South Asian) or ≥ 25 kg/m2 (all other ethnicities), and plus one or more of the following: 1st degree relative with type 2 diabetes, previous gestational diabetes (GDM), previous baby > 4 kg, or high risk ethnicity for GDM. Eligible women who consent to participate will be enrolled in a commercially available preconception intervention (Prepare Plans, LiveSmart UK Ltd). Following an online health assessment and home blood test, women will be provided with individualised lifestyle advice and coaching by dietitians. Process evaluation will provide an assessment of implementation of the intervention. Change in health behaviours and biomarkers of metabolic health will also be examined. Discussion Suboptimal health behaviours amongst women planning pregnancy are widely prevalent in the UK. Personalised health checks and coaching are especially important for women at risk of pregnancy complications. Get Ready! introduces a novel approach to identifying high risk women planning pregnancy and provision of a targeted intervention. Registration Trial sponsor: King’s College London.

Abstract Background The ongoing global malaria eradication campaign requires development of potent, safe, and cost-effective drugs lacking cross-resistance with existing chemotherapies. One critical step in drug development is selecting a suitable clinical candidate from late leads. The process used to select the clinical candidate SJ733 from two potent dihydroisoquinolone (DHIQ) late leads, SJ733 and SJ311, based on their physicochemical, pharmacokinetic (PK), and toxicity profiles is described. Methods The compounds were tested to define their physicochemical properties including kinetic and thermodynamic solubility, partition coefficient, permeability, ionization constant, and binding to plasma proteins. Metabolic stability was assessed in both microsomes and hepatocytes derived from mice, rats, dogs, and humans. Cytochrome P450 inhibition was assessed using recombinant human cytochrome enzymes. The pharmacokinetic profiles of single intravenous or oral doses were investigated in mice, rats, and dogs. Results Although both compounds displayed similar physicochemical properties, SJ733 was more permeable but metabolically less stable than SJ311 in vitro. Single dose PK studies of SJ733 in mice, rats, and dogs demonstrated appreciable oral bioavailability (60–100%), whereas SJ311 had lower oral bioavailability (mice 23%, rats 40%) and higher renal clearance (10–30 fold higher than SJ733 in rats and dogs), suggesting less favorable exposure in humans. SJ311 also displayed a narrower range of dose-proportional exposure, with plasma exposure flattening at doses above 200 mg/kg. Conclusion SJ733 was chosen as the candidate based on a more favorable dose proportionality of exposure and stronger expectation of the ability to justify a strong therapeutic index to regulators.

Abstract In this study we used the Illumina Infinium Methylation array to investigate in a cohort of matched archival human tissue samples (n = 32) from 14 individuals with soft tissue sarcomas if genome-wide methylation changes occur during metastatic and recurrent (Met/Rec) disease. A range of sarcoma types were selected for this study: leiomyosarcoma (LMS), myxofibrosarcoma (MFS), rhabdomyosarcoma (RMS) and synovial sarcoma (SS). We identified differential methylation in all Met/Rec matched samples, demonstrating that epigenomic differences develop during the clonal evolution of sarcomas. Differentially methylated regions and genes were detected, not been previously implicated in sarcoma progression, including at PTPRN2 and DAXX in LMS, WT1-AS and TNXB in SS, VENTX and NTRK3 in pleomorphic RMS and MEST and the C14MC / miR-379/miR-656 in MFS. Our overall findings indicate the presence of objective epigenetic differences across primary and Met/Rec human tissue samples not previously reported.

As quantum computing devices become more complex, they enter the realm of correlated noise, which is difficult to characterise and mitigate. Here, the authors demonstrate, over a range of superconducting devices, a method for non-Markovian dynamics characterisation based on the process tensor framework.

Abstract Quantitative shape analysis of juvenile pyroclasts is applied in volcanology to reconstruct the dynamics and styles of eruptions, and to explore the details of tephra transport, dispersal, and emplacement. Morphometric analyses often include comparison of multiple data sets with a set of dimensionless shape parameters. Here we present “DendroScan”, an open source Matlab program that provides the user with all the multivariate statistical methods needed to produce such morphometric comparisons. Serving as a statistical “toolbox”, DendroScan conducts Levene-, t-, and equivalence tests, presenting the results in ad hoc interpretable graphs. Furthermore, it is designed to conduct dendrogrammatic analyses of particle morphometry, a recently developed approach for the inter-comparison of multiple morphometric data sets. DendroScan produces tree diagrams, in which the analysed samples are sorted according to their morphometric dissimilarity, allowing the user to identify, e.g., samples that are statistically equivalent. To demonstrate DendroScan’s potential, ten experimental samples are compared with volcanic ash samples generated by the Havre 2012 deep-sea eruption in the Kermadec arc (New Zealand). We show how, using DendroScan-based results, information on the eruptive mechanism can be inferred, and how the cooling history of the experimental melt is reflected in the dissimilarity of thermally granulated fragments.

Pluto is covered by numerous deposits of methane. Here, the authors show that the formation of methane frost on mountain tops and crater rims in Pluto’s equatorial regions completely differ from those forming snow-capped mountains on Earth.