Search

Abstract Cytokines operate in concert to maintain immune homeostasis and coordinate immune responses. In cases of ER+ breast cancer, peripheral immune cells exhibit altered responses to several cytokines, and these alterations are correlated strongly with patient outcomes. To develop a systems-level understanding of this dysregulation, we measured a panel of cytokine responses and receptor abundances in the peripheral blood of healthy controls and ER+ breast cancer patients across immune cell types. Using tensor factorization to model this multidimensional data, we found that breast cancer patients exhibited widespread alterations in response, including drastically reduced response to IL-10 and heightened basal levels of pSmad2/3 and pSTAT4. ER+ patients also featured upregulation of PD-L1, IL6Rα, and IL2Rα, among other receptors. Despite this, alterations in response to cytokines were not explained by changes in receptor abundances. Thus, tensor factorization helped to reveal a coordinated reprogramming of the immune system that was consistent across our cohort.

Abstract Myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD) is diagnosed by serum MOG‐immunoglobulin G (MOG‐IgG) in association with typical demyelination. 111/1127 patients with paired CSF/serum samples were seropositive for MOG‐IgG. Only 7/1016 (0.7%) seronegative patients had CSF‐restricted MOG‐IgG. While 3/7 patients had longitudinally extensive transverse myelitis, four had a confirmed alternate diagnosis (three multiple sclerosis, one CNS vasculitis). In a national referral setting, CSF‐restricted MOG‐IgG had a low sensitivity (2.63%, 95%CI 0.55–7.50%) and low positive predictive value (1.97%, 95%CI 0.45–8.13%). We strongly recommend serum as the preferred diagnostic biospecimen, and urge caution in the interpretation of CSF‐restricted MOG‐IgG in patients without clinico‐radiological features consistent with MOGAD.

Abstract Objective The first international consensus criteria for optic neuritis (ICON) were published in 2022. We applied these criteria to a prospective, global observational study of acute optic neuritis (ON). Methods We included 160 patients with a first‐ever acute ON suggestive of a demyelinating CNS disease from the Acute Optic Neuritis Network (ACON). We applied the 2022 ICON to all participants and subsequently adjusted the ICON by replacing a missing relative afferent pupillary defect (RAPD) or dyschromatopsia if magnetic resonance imaging pathology of the optical nerve plus optical coherence tomography abnormalities or certain biomarkers are present. Results According to the 2022 ICON, 80 (50%) patients were classified as definite ON, 12 (7%) patients were classified as possible ON, and 68 (43%) as not ON (NON). The main reasons for classification as NON were absent RAPD (52 patients, 76%) or dyschromatopsia (49 patients, 72%). Distribution of underlying ON etiologies was as follows: 78 (49%) patients had a single isolated ON, 41 (26%) patients were diagnosed with multiple sclerosis, 25 (16%) patients with myelin oligodendrocyte glycoprotein antibody‐associated disease, and 15 (9%) with neuromyelitis optica spectrum disorder. The application of the adjusted ON criteria yielded a higher proportion of patients classified as ON (126 patients, 79%). Interpretation According to the 2022 ICON, almost half of the included patients in ACON did not fulfill the requirements for classification of definite or possible ON, particularly due to missing RAPD and dyschromatopsia. Thorough RAPD examination and formal color vision testing are critical to the application of the 2022 ICON.

Background In adults with large‐vessel occlusion stroke, the extent of the baseline infarct measured using the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) predicts outcome and is used during patient selection for mechanical thrombectomy. The relationship between ASPECTS and clinical outcome is unknown in pediatric large‐vessel occlusion stroke. Methods Secondary analysis of a retrospective multicenter case–control study assessing mechanical thrombectomy versus medical management alone for pediatric large‐vessel occlusion stroke across 5 centers in Australia and Canada from 2011 to 2022. ASPECTS was measured on baseline computed tomography or magnetic resonance imaging–diffusion‐weighted imaging while blinded to clinical outcome and treatment status. The relationship between ASPECTS and pediatric modified Rankin scale scores at 3 months following stroke was assessed using ordinal logistic regression. Results In total, n = 24 thrombectomy patients (F = 10, mean age, 11.3 years [SD, 4.36]) and n = 24 control patients (F = 10, mean age, 10.2 years [SD, 4.32) were included. Mean ASPECTS was 6.3 (SD, 2.37) in the thrombectomy group and 6.1 (SD, 2.64) in the control group. In patients undergoing thrombectomy, baseline ASPECTS significantly correlated with pediatric modified Rankin scale scores at 3 months (odds ratio, 1.58 [95% CI, 1.10–2.27]; P = 0.013). In control patients, there was no significant correlation (odds ratio, 1.17 [95% CI, 0.87–1.55]; P = 0.298). Six of 7 thrombectomy patients with a large baseline infarct (ASPECTS

Abstract Dose optimization of sirolimus may further improve outcomes in allogeneic hematopoietic cell transplant (HCT) patients receiving post‐transplantation cyclophosphamide (PTCy) to prevent graft‐versus‐host disease (GVHD). Sirolimus exposure–response association studies in HCT patients (i.e., the association of trough concentration with clinical outcomes) have been conflicting. Sirolimus has important effects on T‐cells, including conventional (Tcons) and regulatory T‐cells (Tregs), both of which have been implicated in the mechanisms by which PTCy prevents GVHD, but there is an absence of validated biomarkers of sirolimus effects on these cell subsets. Considering the paucity of existing biomarkers and the complexities of the immune system, we conducted a literature review to inform a quantitative systems pharmacology (QSP) model of GVHD. The published literature presented multiple challenges. The sirolimus pharmacokinetic models insufficiently describe sirolimus distribution to relevant physiological compartments. Despite multiple publications describing sirolimus effects on Tcons and Tregs in preclinical and human ex vivo models, consistent parameters relating sirolimus concentrations to circulating Tcons and Tregs could not be found. Each aspect presents a challenge in building a QSP model of sirolimus and its temporal effects on T‐cell subsets and GVHD prevention. To optimize GVHD prevention regimens, phase I studies and systematic studies of immunosuppressant concentration–effect association are needed for QSP modeling.

IntroductionGenetic predisposition to autoimmune encephalitis with antibodies against N-methyl-D-aspartate receptor (NMDAR) is poorly understood. Given the diversity of associated environmental factors (tumors, infections), we hypothesized that human leukocyte antigen (HLA) and killer-cell immunoglobulin-like receptors (KIR), two extremely polymorphic gene complexes key to the immune system, might be relevant for the genetic predisposition to anti-NMDAR encephalitis. Notably, KIR are chiefly expressed by Natural Killer (NK) cells, recognize distinct HLA class I allotypes and play a major role in anti-tumor and anti-infection responses.MethodsWe conducted a Genome Wide Association Study (GWAS) with subsequent control-matching using Principal Component Analysis (PCA) and HLA imputation, in a multi-ethnic cohort of anti-NMDAR encephalitis (n=479); KIR and HLA were further sequenced in a large subsample (n=323). PCA-controlled logistic regression was then conducted for carrier frequencies (HLA and KIR) and copy number variation (KIR). HLA-KIR interaction associations were also modeled. Additionally, single cell sequencing was conducted in peripheral blood mononuclear cells from 16 cases and 16 controls, NK cells were sorted and phenotyped.ResultsAnti-NMDAR encephalitis showed a weak HLA association with DRB1*01:01~DQA1*01:01~DQB1*05:01 (OR=1.57, 1.51, 1.45; respectively), and DRB1*11:01 (OR=1.60); these effects were stronger in European descendants and in patients without an underlying ovarian teratoma. More interestingly, we found increased copy number variation of KIR2DL5B (OR=1.72), principally due to an overrepresentation of KIR2DL5B*00201. Further, we identified two allele associations in framework genes, KIR2DL4*00103 (25.4% vs. 12.5% in controls, OR=1.98) and KIR3DL3*00302 (5.3% vs. 1.3%, OR=4.44). Notably, the ligands of these KIR2DL4 and KIR3DL3, respectively, HLA-G and HHLA2, are known to act as immune checkpoint with immunosuppressive functions. However, we did not find differences in specific KIR-HLA ligand interactions or HLA-G polymorphisms between cases and controls. Similarly, gene expression of CD56dim or CD56bright NK cells did not differ between cases and controls.DiscussionOur observations for the first time suggest that the HLA-KIR axis might be involved in anti-NMDAR encephalitis. While the genetic risk conferred by the identified polymorphisms appears small, a role of this axis in the pathophysiology of this disease appears highly plausible and should be analyzed in future studies.

Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) is a routine method to noninvasively quantify perfusion dynamics in tissues. The standard practice for analyzing DCE-MRI data is to fit an ordinary differential equation to each voxel. Recent advances in data science provide an opportunity to move beyond existing methods to obtain more accurate measurements of fluid properties. Here, we developed a localized convolutional function regression that enables simultaneous measurement of interstitial fluid velocity, diffusion, and perfusion in 3D. We validated the method computationally and experimentally, demonstrating accurate measurement of fluid dynamics in situ and in vivo. Applying the method to human MRIs, we observed tissue-specific differences in fluid dynamics, with an increased fluid velocity in breast cancer as compared to brain cancer. Overall, our method represents an improved strategy for studying interstitial flows and interstitial transport in tumors and patients. We expect that our method will contribute to the better understanding of cancer progression and therapeutic response.

Summary: Background: Kabuki syndrome (KS) is a genetic disorder caused by DNA mutations in KMT2D, a lysine methyltransferase that methylates histones and other proteins, and therefore modifies chromatin structure and subsequent gene expression. Ketones, derived from the ketogenic diet, are histone deacetylase inhibitors that can ‘open’ chromatin and encourage gene expression. Preclinical studies have shown that the ketogenic diet rescues hippocampal memory neurogenesis in mice with KS via the epigenetic effects of ketones. Methods: Single-cell RNA sequencing and mass spectrometry-based proteomics were used to explore molecular mechanisms of disease in individuals with KS (n = 4) versus controls (n = 4). Findings: Pathway enrichment analysis indicated that loss of function mutations in KMT2D are associated with ribosomal protein dysregulation at an RNA and protein level in individuals with KS (FDR

Introduction: Down syndrome is due to trisomy 21 and is characterized by intellectual disability, dysmorphic facial features, congenital malformations, and gastrointestinal abnormalities. There is an increased appreciation of congenital portosystemic shunts in Down syndrome patients. Congenital portosystemic shunts have been associated with many defects in body systems, including cardiac, metabolic, and neurological. Case Presentation: Herein, we describe a portosystemic shunt in a Down syndrome patient that resulted in hyperammonemia with altered mental status and choreiform movements. Computed tomography angiography of the abdomen and pelvis identified a connection between the right portal vein and inferior vena cava. An 18 mm Amplatzer PFO closure device was placed within the congenital shunt, significantly improving symptoms. The patient has no sequelae from the related shunt or the device at the 2-year follow-up. We extensively reviewed the literature and identified cases of portosystemic shunts in Down syndrome patients. Shunts can either be extrahepatic or intrahepatic and are classified by vasculature connections. Conclusion: From our literature review and case presentation, we identify other conditions in patients, including cardiac and gastrointestinal defects. We then review the available treatment options, whether observation or surgical, depending on the patient’s clinical picture.

IntroductionCancer combination treatments involving immunotherapies with targeted radiation therapy are at the forefront of treating cancers. However, dosing and scheduling of these therapies pose a challenge. Mathematical models provide a unique way of optimizing these therapies. MethodsUsing a preclinical model of multiple myeloma as an example, we demonstrate the capability of a mathematical model to combine these therapies to achieve maximum response, defined as delay in tumor growth. Data from mice studies with targeted radionuclide therapy (TRT) and chimeric antigen receptor (CAR)-T cell monotherapies and combinations with different intervals between them was used to calibrate mathematical model parameters. The dependence of progression-free survival (PFS), overall survival (OS), and the time to minimum tumor burden on dosing and scheduling was evaluated. Different dosing and scheduling schemes were evaluated to maximize the PFS and optimize timings of TRT and CAR-T cell therapies. ResultsTherapy intervals that were too close or too far apart are shown to be detrimental to the therapeutic efficacy, as TRT too close to CAR-T cell therapy results in radiation related CAR-T cell killing while the therapies being too far apart result in tumor regrowth, negatively impacting tumor control and survival. We show that splitting a dose of TRT or CAR-T cells when administered in combination is advantageous only if the first therapy delivered can produce a significant benefit as a monotherapy. DiscussionMathematical models are crucial tools for optimizing the delivery of cancer combination therapy regimens with application along the lines of achieving cure, maximizing survival or minimizing toxicity.

Abstract Objective Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease with a complex etiology that lacks biomarkers predicting disease progression. The objective of this study was to use longitudinal cerebrospinal fluid (CSF) samples to identify biomarkers that distinguish fast progression (FP) from slow progression (SP) and assess their temporal response. Methods We utilized mass spectrometry (MS)‐based proteomics to identify candidate biomarkers using longitudinal CSF from a discovery cohort of SP and FP ALS patients. Immunoassays were used to quantify and validate levels of the top biomarkers. A state‐transition mathematical model was created using the longitudinal MS data that also predicted FP versus SP. Results We identified a total of 1148 proteins in the CSF of all ALS patients. Pathway analysis determined enrichment of pathways related to complement and coagulation cascades in FPs and synaptogenesis and glucose metabolism in SPs. Longitudinal analysis revealed a panel of 59 candidate markers that could segregate FP and SP ALS. Based on multivariate analysis, we identified three biomarkers (F12, RBP4, and SERPINA4) as top candidates that segregate ALS based on rate of disease progression. These proteins were validated in the discovery and a separate validation cohort. Our state‐transition model determined that the overall variance of the proteome over time was predictive of the disease progression rate. Interpretation We identified pathways and protein biomarkers that distinguish rate of ALS disease progression. A mathematical model of the CSF proteome determined that the change in entropy of the proteome over time was predictive of FP versus SP.

Abstract Efficacious stem cell-based therapies for traumatic brain injury (TBI) depend on successful delivery, migration, and engraftment of stem cells to induce neuroprotection. L-myc expressing human neural stem cells (LMNSC008) demonstrate an inherent tropism to injury sites after intranasal (IN) administration. We hypothesize that IN delivered LMNSC008 cells migrate to primary and secondary injury sites and modulate biomarkers associated with neuroprotection and tissue regeneration. To test this hypothesis, immunocompetent adult female rats received either controlled cortical impact injury or sham surgery. LMNSC008 cells or a vehicle were administered IN on postoperative days 7, 9, 11, 13, 15, and 17. The distribution and migration of eGFP-expressing LMNSC008 cells were quantified over 1 mm-thick optically cleared (CLARITY) coronal brain sections from TBI and SHAM controls. NSC migration was observed along white matter tracts projecting toward the hippocampus and regions of TBI. ELISA and Nanostring assays revealed a shift in tissue gene expression in LMNSC008 treated rats relative to controls. LMNSC008 treatment reduced expression of genes and pathways involved in inflammatory response, microglial function, and various cytokines and receptors. Our proof-of-concept studies, although preliminary, support the rationale of using intranasal delivery of LMNSC008 cells for functional studies in preclinical models of TBI and provide support for potential translatability in TBI patients.

Abstract Objective Infection‐triggered encephalopathy syndromes (ITES) are potentially devastating neuroinflammatory conditions. Although some ITES syndromes have recognisable MRI neuroimaging phenotypes, there are otherwise few biomarkers of disease. Early detection to enable immune modulatory treatments could improve outcomes. Methods We measured CSF neopterin, quinolinic acid, kynurenine and kynurenine/tryptophan ratio using a liquid chromatography coupled to tandem mass spectrometry (LC–MS/MS) system. The CSF of 18 children with ITES were compared with acute encephalitis (n = 20), and three control groups, namely epilepsy (n = 20), status epilepticus (n = 18) and neurogenetic controls (n = 20). Results The main ITES phenotypes in 18 patients were acute encephalopathy with biphasic seizures and late restricted diffusion (AESD, n = 4), febrile infection‐related epilepsy syndrome (FIRES n = 4) and other ITES phenotypes. Influenza A was the most common infectious trigger (n = 5), and 50% of patients had a preceding notable neurodevelopmental or family history. CSF neopterin, quinolinic acid and kynurenine were elevated in ITES group compared to the three control groups (all p

Oncological outcomes are improving in gastrointestinal cancer with advancements in systemic therapies, and there is notable potential in combining immunotherapy and radiation therapy (RT) to allow for further improvements. Various preclinical and early phase II studies have shown promising synergy with immunotherapy and RT in gastrointestinal cancer. A few recent phase III studies have shown improved survival with the addition of immunotherapy to standard treatment for gastrointestinal cancer. The timing, duration, sequencing, and integration with other anti-cancer treatments are still areas of ongoing research. We have reviewed the published and ongoing studies of the combinations of immunotherapy and RT in gastrointestinal cancers.

Abstract Background Several cytotoxic chemotherapies have demonstrated efficacy in improving recurrence‐free survival (RFS) following resection of Stage II–IV colorectal cancer (CRC). However, the temporal dynamics of response to such adjuvant therapy have not been systematically quantified. Methods The Cochrane Central Register of Trials, Medline (PubMed) and Web of Science were queried from database inception to February 23, 2023 for Phase III randomized controlled trials (RCTs) where there was a significant difference in RFS between adjuvant chemotherapy and surgery only arms. Summary data were extracted from published Kaplan–Meier curves using DigitizeIT. Absolute differences in RFS event rates were compared at matched intervals using multiple paired t‐tests. Results The initial search yielded 1469 manuscripts. After screening, 18 RCTs were eligible (14 Stage II/III; 4 Stage IV), inclusive of 16,682 patients. In the absence of adjuvant chemotherapy, the greatest rate of recurrence was observed in the first year (mean RFS event rate; 0–0.5 years: 0.22 ± 0.21; 0.5–1 years: 0.20 ± 0.09). Adjuvant chemotherapy was associated with significant decreases in the RFS event rates for the intervals 0–0.5 years (0.09 ± 0.09 vs. 0.22 ± 0.21, p

In times of rapid change and rising human pressures on marine systems, information about the future state of the ocean can provide decision-makers with time to avoid adverse impacts and maximise opportunities. An ecological forecast predicts changes in ecosystems and its components due to environmental forcing such as climate variability and change, extreme weather conditions, pollution, or habitat change. Here, we summarise examples from several sectors and a range of locations. We describe the need, approach, forecast performance, delivery system, and end user uptake. This examination shows that near-term ecological forecasts are needed by end users, decisions are being made based on forecasts, and there is an urgent need to develop operational information systems to support sustainable ocean management. An operational information system is critical for connecting to decision makers and providing an enduring approach to forecasting and proactive decision making. These operational systems require significant investment and ongoing maintenance but are key to delivering ecological forecasts for societal benefits. Iterative forecasting practices could provide continuous improvement by incorporating evaluation and feedback to overcome the limitations of the imperfect model and incomplete observations to achieve better forecast outcomes and accuracy.

Abstract Introduction Biomedical progress has facilitated breakthrough advanced neurotherapeutic interventions, whose potential to improve outcomes in rare neurological diseases has increased hope among people with lived experiences and their carers. Nevertheless, gene, somatic cell and other advanced neurotherapeutic interventions carry significant risks. Rare disease patient organizations (RDPOs) may enhance patient experiences, inform expectations and promote health literacy. However, their perspectives are understudied in paediatric neurology. If advanced neurotherapeutics is to optimize RDPO contributions, it demands further insights into their roles, interactions and support needs. Methods We used a mixed‐methodology approach, interviewing 20 RDPO leaders representing paediatric rare neurological diseases and following them up with two online surveys featuring closed and open‐ended questions on advanced neurotherapeutics (19/20) and negative mood states (17/20). Qualitative and quantitative data were analysed using thematic discourse analysis and basic descriptive statistics, respectively. Results Leaders perceived their roles to be targeted at educational provision (20/20), community preparation for advanced neurotherapeutic clinical trials (19/20), information simplification (19/20) and focused research pursuits (20/20). Although most leaders perceived the benefits of collaboration between stakeholders, some cited challenges around collaborative engagement under the following subthemes: conflicts of interest, competition and logistical difficulties. Regarding neurotherapeutics, RDPO leaders identified support needs centred on information provision, valuing access to clinician experts and highlighting a demand for co‐developed, centralized, high‐level and understandable, resources that may improve information exchange. Leaders perceived a need for psychosocial support within themselves and their communities, proposing that this would facilitate informed decision‐making, reduce associated psychological vulnerabilities and maintain hope throughout neurotherapeutic development. Conclusion This study provides insights into RDPO research activities, interactions and resource needs. It reveals a demand for collaboration guidelines, central information resources and psychosocial supports that may address unmet needs and assist RDPOs in their advocacy. Patient or Public Contribution In this study, RDPO leaders were interviewed and surveyed to examine their perspectives and roles in advanced neurotherapeutic development. Some participants sent researchers postinterview clarification emails regarding their responses to questions.

Lung segmentation plays an important role in computer-aided detection and diagnosis using chest radiographs (CRs). Currently, the U-Net and DeepLabv3+ convolutional neural network architectures are widely used to perform CR lung segmentation. To boost performance, ensemble methods are often used, whereby probability map outputs from several networks operating on the same input image are averaged. However, not all networks perform adequately for any specific patient image, even if the average network performance is good. To address this, we present a novel multi-network ensemble method that employs a selector network. The selector network evaluates the segmentation outputs from several networks; on a case-by-case basis, it selects which outputs are fused to form the final segmentation for that patient. Our candidate lung segmentation networks include U-Net, with five different encoder depths, and DeepLabv3+, with two different backbone networks (ResNet50 and ResNet18). Our selector network is a ResNet18 image classifier. We perform all training using the publicly available Shenzhen CR dataset. Performance testing is carried out with two independent publicly available CR datasets, namely, Montgomery County (MC) and Japanese Society of Radiological Technology (JSRT). Intersection-over-Union scores for the proposed approach are 13% higher than the standard averaging ensemble method on MC and 5% better on JSRT.

Abstract Periodical cicadas (Hemiptera: Magicicada) have coevolved with obligate bacteriome-inhabiting microbial symbionts, yet little is known about gut microbial symbiont composition or differences in composition among allochronic Magicicada broods (year classes) which emerge parapatrically or allopatrically in the eastern United States. Here, 16S rRNA amplicon sequencing was performed to determine gut bacterial community profiles of three periodical broods, including II (Connecticut and Virginia, 2013), VI (North Carolina, 2017), and X (Maryland, 2021, and an early emerging nymph collected in Ohio, 2017). Results showed similarities among all nymphal gut microbiomes and between morphologically distinct 17-year Magicicada, namely Magicicada septendecim (Broods II and VI) and 17-year Magicicada cassini (Brood X) providing evidence of a core microbiome, distinct from the microbiome of burrow soil inhabited by the nymphs. Generally, phyla Bacteroidetes [Bacteroidota] (> 50% relative abundance), Actinobacteria [Actinomycetota], or Proteobacteria [Pseudomonadota] represented the core. Acidobacteria and genera Cupriavidus, Mesorhizobium, and Delftia were prevalent in nymphs but less frequent in adults. The primary obligate endosymbiont, Sulcia (Bacteroidetes), was dominant amongst core genera detected. Chryseobacterium were common in Broods VI and X. Chitinophaga, Arthrobacter, and Renibacterium were common in Brood X, and Pedobacter were common to nymphs of Broods II and VI. Further taxonomic assignment of unclassified Alphaproteobacteria sequencing reads allowed for detection of multiple copies of the Hodgkinia 16S rRNA gene, distinguishable as separate operational taxonomic units present simultaneously. As major emergences of the broods examined here occur at 17-year intervals, this study will provide a valuable comparative baseline in this era of a changing climate.

In the last decade animal agriculture has received significant scrutiny for its many negative environmental consequences. In response to these myriad concerns a wide range of voices have advocated for diets that include less animal products (meat, dairy, eggs), often arguing that animal-based diets are inherently more resource intensive than those based on plants. Prominent in this discourse is a narratives formation developed by a slew of venture capital-backed food technology startups known as alternative protein that I refer to as the bad animal narrative. This narrative argues that livestock are fundamentally bad technology, and the solution to the many environmental problems of animal agriculture is to replace livestock with novel technologies to produce animal product alternatives that will satisfy consumer demand while also solving one of the fundamental environmental challenges of modern agriculture. In this paper I use discourse analysis frameworks from political ecology and science and technology studies to examine a large corpus of publicly available text that includes alternative protein company websites, mission statements, blogs, and connected media pieces, as well as life cycle assessment reports documenting the environmental impacts of alternative protein products as well as conventionally and alternatively produced livestock. This analysis finds that the bad animal narrative places blame on livestock without clearly providing evidence, and it rests on a set of problematic assumptions about the current food system and its possible futures. Analysis of life cycle assessment statistics finds that the industrial system, rather than livestock themselves, is the chief driver of the environmental problems of animal agriculture. The paper concludes with a consideration of the future food system envisioned by the bad animal narrative and its implications for sustainability.

Convolutional neural networks (CNNs) have become instrumental in advancing multi-frame image super-resolution (SR), a technique that merges multiple low-resolution images of the same scene into a high-resolution image. In this paper, a novel deep learning multi-frame SR algorithm is introduced. The proposed CNN model, named Exponential Fusion of Interpolated Frames Network (EFIF-Net), seamlessly integrates fusion and restoration within an end-to-end network. Key features of the new EFIF-Net include a custom exponentially weighted fusion (EWF) layer for image fusion and a modification of the Residual Channel Attention Network for restoration to deblur the fused image. Input frames are registered with subpixel accuracy using an affine motion model to capture the camera platform motion. The frames are externally upsampled using single-image interpolation. The interpolated frames are then fused with the custom EWF layer, employing subpixel registration information to give more weight to pixels with less interpolation error. Realistic image acquisition conditions are simulated to generate training and testing datasets with corresponding ground truths. The observation model captures optical degradation from diffraction and detector integration from the sensor. The experimental results demonstrate the efficacy of EFIF-Net using both simulated and real camera data. The real camera results use authentic, unaltered camera data without artificial downsampling or degradation.

Abstract Background Individuals with psychiatric disorders (PD) have a high prevalence of tobacco use. Patients with PD also potentially receive substandard care in comparison to the general population. Previous research has shown that individuals with PD have a decreased risk of receiving a tobacco related (TR) cancer diagnosis. To further assess this trend, this study assesses the survival of patients with a TR cancer with or without a PD. Materials and methods Our study utilized multiple databases, with methods described elsewhere,6 to identify people in British Columbia that have been diagnosed with psychiatric disorders and appendicitis (our control group). From these groups, we selected individuals who also had a TR cancer. We subsequently extracted information pertaining to these patients from these databases. Results Thirty-nine thousand eight hundred forty-one patients with cancer were included in our study. Analyses of these patients were controlled for by age, gender, cancer type and diagnosis year. This analysis displayed shorter survival time among patients who were diagnosed with depression (HR = 1.16; p = 0.01; 95% CI: 1.04–1.29), schizophrenia (HR = 1.62; p

Abstract This paper is written in response to the paper “How green is blue hydrogen?” by R. W. Howarth and M. Z. Jacobson. It aims at highlighting and discussing the method and assumptions of that paper, and thereby providing a more balanced perspective on blue hydrogen, which is in line with current best available practices and future plant specifications aiming at low CO2 emissions. More specifically, in this paper, we show that: (i) the simplified method that Howarth and Jacobson used to compute the energy balance of blue hydrogen plants leads to significant overestimation of CO2 emissions and natural gas (NG) consumption and (ii) the assumed methane leakage rate is at the high end of the estimated emissions from current NG production in the United States and cannot be considered representative of all‐NG and blue hydrogen value chains globally. By starting from the detailed and rigorously calculated mass and energy balances of two blue hydrogen plants in the literature, we show the impact that methane leakage rate has on the equivalent CO2 emissions of blue hydrogen. On the basis of our analysis, we show that it is possible for blue hydrogen to have significantly lower equivalent CO2 emissions than the direct use of NG, provided that hydrogen production processes and CO2 capture technologies are implemented that ensure a high CO2 capture rate, preferably above 90%, and a low‐emission NG supply chain.

Single-cell sequencing technologies have revolutionized molecular and cellular biology and stimulated the development of computational tools to analyze the data generated from these technology platforms. However, despite the recent explosion of computational analysis tools, relatively few mathematical models have been developed to utilize these data. Here we compare and contrast two cell state geometries for building mathematical models of cell state-transitions with single-cell RNA-sequencing data with hematopoeisis as a model system; (i) by using partial differential equations on a graph representing intermediate cell states between known cell types, and (ii) by using the equations on a multi-dimensional continuous cell state-space. As an application of our approach, we demonstrate how the calibrated models may be used to mathematically perturb normal hematopoeisis to simulate, predict, and study the emergence of novel cell states during the pathogenesis of acute myeloid leukemia. We particularly focus on comparing the strength and weakness of the graph model and multi-dimensional model.

In the development of cell-based cancer therapies, quantitative mathematical models of cellular interactions are instrumental in understanding treatment efficacy. Efforts to validate and interpret mathematical models of cancer cell growth and death hinge first on proposing a precise mathematical model, then analyzing experimental data in the context of the chosen model. In this work, we present the first application of the sparse identification of non-linear dynamics (SINDy) algorithm to a real biological system in order discover cell-cell interaction dynamics in in vitro experimental data, using chimeric antigen receptor (CAR) T-cells and patient-derived glioblastoma cells. By combining the techniques of latent variable analysis and SINDy, we infer key aspects of the interaction dynamics of CAR T-cell populations and cancer. Importantly, we show how the model terms can be interpreted biologically in relation to different CAR T-cell functional responses, single or double CAR T-cell-cancer cell binding models, and density-dependent growth dynamics in either of the CAR T-cell or cancer cell populations. We show how this data-driven model-discovery based approach provides unique insight into CAR T-cell dynamics when compared to an established model-first approach. These results demonstrate the potential for SINDy to improve the implementation and efficacy of CAR T-cell therapy in the clinic through an improved understanding of CAR T-cell dynamics.

Summary: Background: Defining the presence of acute and chronic brain inflammation remains a challenge to clinicians due to the heterogeneity of clinical presentations and aetiologies. However, defining the presence of neuroinflammation, and monitoring the effects of therapy is important given its reversible and potentially damaging nature. We investigated the utility of CSF metabolites in the diagnosis of primary neuroinflammatory disorders such as encephalitis and explored the potential pathogenic role of inflammation in epilepsy. Methods: Cerebrospinal fluid (CSF) collected from 341 paediatric patients (169 males, median age 5.8 years, range 0.1–17.1) were examined. The patients were separated into a primary inflammatory disorder group (n = 90) and epilepsy group (n = 80), who were compared with three control groups including neurogenetic and structural (n = 76), neurodevelopmental disorders, psychiatric and functional neurological disorders (n = 63), and headache (n = 32). Findings: There were statistically significant increases of CSF neopterin, kynurenine, quinolinic acid and kynurenine/tryptophan ratio (KYN/TRP) in the inflammation group compared to all control groups (all p

Abstract Schistosomiasis is a medically significant disease caused by helminth parasites of the genus Schistosoma. The schistosome life cycle requires chemically mediated interactions with an intermediate (aquatic snail) and definitive (human) host. Blocking parasite development within the snail stage requires improved understanding of the interactions between the snail host and the Schistosoma water-borne free-living form (miracidium). Innovations in snail genomics and aquatic chemical communication provide an ideal opportunity to explore snail-parasite coevolution at the molecular level. Rhodopsin G protein-coupled receptors (GPCRs) are of particular interest in studying how trematode parasites navigate towards their snail hosts. The potential role of GPCRs in parasites makes them candidate targets for new antihelminthics that disrupt the intermediate host life-cycle stages, thus preventing subsequent human infections. A genomic-bioinformatic approach was used to identify GPCR orthologs between the snail Biomphalaria glabrata and miracidia of its obligate parasite Schistosoma mansoni. We show that 8 S. mansoni rhodopsin GPCRs expressed within the miracidial stage share overall amino acid similarity with 8 different B. glabrata rhodopsin GPCRs, particularly within transmembrane domains, suggesting conserved structural features. These GPCRs include an orphan peptide receptor as well as several with strong sequence homologies with rhabdomeric opsin receptors, a serotonin receptor, a sulfakinin (SK) receptor, an allatostatin-A (buccalin) receptor and an FMRFamide receptor. Buccalin and FMRFa peptides were identified in water conditioned by B. glabrata, and we show synthetic buccalin and FMRFa can stimulate significant rates of change of direction and turn-back responses in S. mansoni miracidia. Ortholog GPCRs were identified in S. mansoni miracidia and B. glabrata. These GPCRs may detect similar ligands, including snail-derived odorants that could facilitate miracidial host finding. These results lay the foundation for future research elucidating the mechanisms by which GPCRs mediate host finding which can lead to the potential development of novel anti-schistosome interventions.

Cell fate commitment involves transcription factor activity and changes in chromatin architecture. Here the authors show that CAF-1 maintains lineage fidelity by controlling chromatin accessibility at specific sites; suppressing CAF-1 triggers differentiation of myeloid stem and progenitor cells into a mixed lineage state.

Mining began in the Picher field, in the Oklahoma and Kansas portion of the Tri-State Lead-Zinc Mining District in the United States, during the 1900s and ceased in the 1970s, producing an estimated 1.5 million metric tons (m-tons) of lead and 8 million m-tons of zinc. Over 400 historical maps of the underground mine workings were compiled into a single, easily editable map. This map was used to create 3D renderings for calculation of underground mine workings area and volume estimates. The workings have an estimated volume of 9,870 ha-meters (80,000 ac-ft), covering an area of 1,440 hectares (3,560 acres). The map and subsequent calculations should be considered to be based on the minimum extent of the mining field due to the likelihood that many historical maps were likely lost or destroyed. The format of the map allows for continuous updates as new information becomes available.

Abstract This paper presents a motion-sensing device with the capability of harvesting energy from low-frequency motion activities. Based on the high surface area reverse electrowetting-on-dielectric (REWOD) energy harvesting technique, mechanical modulation of the liquid generates an AC signal, which is modeled analytically and implemented in Matlab and COMSOL. A constant DC voltage is produced by using a rectifier and a DC–DC converter to power up the motion-sensing read-out circuit. A charge amplifier converts the generated charge into a proportional output voltage, which is transmitted wirelessly to a remote receiver. The harvested DC voltage after the rectifier and DC–DC converter is found to be 3.3 V, having a measured power conversion efficiency (PCE) of the rectifier as high as 40.26% at 5 Hz frequency. The energy harvester demonstrates a linear relationship between the frequency of motion and the generated output power, making it highly suitable as a self-powered wearable motion sensor.

Several molecular biomarkers have been identified to guide induction treatment selection for localized pancreatic ductal adenocarcinoma (PDAC). SMAD4 alterations and low GATA6 expression/modified “Moffitt” basal-like phenotype have each been associated with inferior survival uniquely for patients receiving 5-FU-based therapies. SMAD4 may directly regulate the expression of GATA6 in PDAC, pointing to a common predictive biomarker. To evaluate the relationship between SMAD4 mutations and GATA6 expression in human PDAC tumors, patients with paired SMAD4 mutation and GATA6 mRNA expression data in the TCGA and CPTAC were identified. In 321 patients (TCGA: n = 180; CPTAC: n = 141), the rate of SMAD4 alterations was 26.8%. The rate of SMAD4 alteration did not vary per tertile of normalized GATA6 expression (TCGA: p = 0.928; CPTAC: p = 0.828). In the TCGA, SMAD4 alterations and the basal-like phenotype were each associated with worse survival (log rank p = 0.077 and p = 0.080, respectively), but their combined presence did not identify a subset with uniquely inferior survival (p = 0.943). In the CPTAC, the basal-like phenotype was associated with significantly worse survival (p < 0.001), but the prognostic value was not influenced by the combined presence of SMAD4 alterations (p = 0.960). SMAD4 alterations were not associated with poor clinico-pathological features such as poor tumor grade, advanced tumor stage, positive lymphovascular invasion (LVI), or positive perineural invasion (PNI), compared with SMAD4-wildtype. Given that SMAD4 mutations were not associated with GATA6 expression or Moffitt subtype in two independent molecularly characterized PDAC cohorts, distinct biomarker-defined clinical trials are necessary.

CD11c+T-bet+ B cells have been linked with different autoimmune diseases, but targeting these cells has been challenging. Here the authors use an adenosine 2A receptor agonist to deplete these B cells and to inhibit or reverse autoimmune symptoms and pathology in mice.

Neural stem cells (NSCs) offer a potential solution to treating brain tumors. This is because NSCs can circumvent the blood-brain barrier and migrate to areas of damage in the central nervous system, including tumors, stroke, and wound injuries. However, for successful clinical application of NSC treatment, a sufficient number of viable cells must reach the diseased or damaged area(s) in the brain, and evidence suggests that it may be affected by the paths the NSCs take through the brain, as well as the locations of tumors. To study the NSC migration in brain, we develop a mathematical model of therapeutic NSC migration towards brain tumor, that provides a low cost platform to investigate NSC treatment efficacy. Our model is an extension of the model developed in Rockne et al. (PLoS ONE 13, e0199967, 2018) that considers NSC migration in non-tumor bearing naive mouse brain. Here we modify the model in Rockne et al. in three ways: (i) we consider three-dimensional mouse brain geometry, (ii) we add chemotaxis to model the tumor-tropic nature of NSCs into tumor sites, and (iii) we model stochasticity of migration speed and chemosensitivity. The proposed model is used to study migration patterns of NSCs to sites of tumors for different injection strategies, in particular, intranasal and intracerebral delivery. We observe that intracerebral injection results in more NSCs arriving at the tumor site(s), but the relative fraction of NSCs depends on the location of injection relative to the target site(s). On the other hand, intranasal injection results in fewer NSCs at the tumor site, but yields a more even distribution of NSCs within and around the target tumor site(s).

Optic neuritis (ON) often occurs at the presentation of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD). The recommended treatment of high-dose corticosteroids for ON is based on a North American study population, which did not address treatment timing or antibody serostatus. The Acute Optic Neuritis Network (ACON) presents a global, prospective, observational study protocol primarily designed to investigate the effect of time to high-dose corticosteroid treatment on 6-month visual outcomes in ON. Patients presenting within 30 days of the inaugural ON will be enrolled. For the primary analysis, patients will subsequently be assigned into the MS-ON group, the aquapotin-4-IgG positive ON (AQP4-IgG+ON) group or the MOG-IgG positive ON (MOG-IgG+ON) group and then further sub-stratified according to the number of days from the onset of visual loss to high-dose corticosteroids (days-to-Rx). The primary outcome measure will be high-contrast best-corrected visual acuity (HC-BCVA) at 6 months. In addition, multimodal data will be collected in subjects with any ON (CIS-ON, MS-ON, AQP4-IgG+ON or MOG-IgG+ON, and seronegative non-MS-ON), excluding infectious and granulomatous ON. Secondary outcomes include low-contrast best-corrected visual acuity (LC-BCVA), optical coherence tomography (OCT), magnetic resonance imaging (MRI) measurements, serum and cerebrospinal fluid (CSF) biomarkers (AQP4-IgG and MOG-IgG levels, neurofilament, and glial fibrillary protein), and patient reported outcome measures (headache, visual function in daily routine, depression, and quality of life questionnaires) at presentation at 6-month and 12-month follow-up visits. Data will be collected from 28 academic hospitals from Africa, Asia, the Middle East, Europe, North America, South America, and Australia. Planned recruitment consists of 100 MS-ON, 50 AQP4-IgG+ON, and 50 MOG-IgG+ON. This prospective, multimodal data collection will assess the potential value of early high-dose corticosteroid treatment, investigate the interrelations between functional impairments and structural changes, and evaluate the diagnostic yield of laboratory biomarkers. This analysis has the ability to substantially improve treatment strategies and the accuracy of diagnostic stratification in acute demyelinating ON.Trial registrationClinicalTrials.gov, identifier: NCT05605951.

Summary: Modern artificial neural networks (ANNs) have long been designed on foundations of mathematics as opposed to their original foundations of biomimicry. However, the structure and function of these modern ANNs are often analogous to real-life biological networks. We propose that the ubiquitous information-theoretic principles underlying the development of ANNs are similar to the principles guiding the macro-evolution of biological networks and that insights gained from one field can be applied to the other. We generate hypotheses on the bow-tie network structure of the Janus kinase - signal transducers and activators of transcription (JAK-STAT) pathway, additionally informed by the evolutionary considerations, and carry out ANN simulation experiments to demonstrate that an increase in the network’s input and output complexity does not necessarily require a more complex intermediate layer. This observation should guide novel biomarker discovery—namely, to prioritize sections of the biological networks in which information is most compressed as opposed to biomarkers representing the periphery of the network.

Mental health and neurodevelopmental disorders are extremely common across the lifespan and are characterized by a complicated range of symptoms that affect wellbeing. There are relatively few drugs available that target disease mechanisms for any of these disorders. Instead, therapeutics are focused on symptoms and syndromes, largely driven by neurotransmitter hypotheses, such as serotonin or dopamine hypotheses of depression. Emerging evidence suggests that maternal inflammation during pregnancy plays a key role in neurodevelopmental disorders, and inflammation can influence mental health expression across the lifespan. It is now recognized that commonly used psychiatric drugs (anti-depressants, anti-psychotics, and mood stabilizers) have anti-inflammatory properties. In this review, we bring together the human evidence regarding the anti-inflammatory mechanisms for these main classes of psychiatric drugs across a broad range of mental health disorders. All three classes of drugs showed evidence of decreasing levels of pro-inflammatory cytokines, particularly IL-6 and TNF-α, while increasing the levels of the anti-inflammatory cytokine, IL-10. Some studies also showed evidence of reduced inflammatory signaling via nuclear factor- (NF-)κB and signal transducer and activator of transcription (STAT) pathways. As researchers, clinicians, and patients become increasingly aware of the role of inflammation in brain health, it is reassuring that these psychiatric drugs may also abrogate this inflammation, in addition to their effects on neurotransmission. Further studies are required to determine whether inflammation is a driver of disease pathogenesis, and therefore should be a therapeutic target in future clinical trials.

Neurodevelopmental disorders (NDDs), including autism-spectrum disorders (ASD) and Tourette syndrome (TS) are common brain conditions which often co-exist, and have no approved treatments targeting disease mechanisms. Accumulating literature implicates the immune system in NDDs, and transcriptomics of post-mortem brain tissue has revealed an inflammatory signal. We interrogated two RNA-sequencing datasets of ASD and TS and identified differentially expressed genes, to explore commonly enriched pathways through GO, KEGG, and Reactome. The DEGs [False Discovery Rate (FDR)

Prenatal brain development is a highly orchestrated process, making it a very vulnerable window to perturbations. Maternal stress and subsequent inflammation during pregnancy leads to a state referred to as, maternal immune activation (MIA). If persistent, MIA can pose as a significant risk factor for the manifestation of neurodevelopmental disorders (NDDs) such as autism spectrum disorder and schizophrenia. To further elucidate this association between MIA and NDD risk, rodent models have been used extensively across laboratories for many years. However, there are few uniform approaches for rodent MIA models which make not only comparisons between studies difficult, but some established approaches come with limitations that can affect experimental outcomes. Here, we provide researchers with a comprehensive review of common experimental variables and potential limitations that should be considered when designing an MIA study based in a rodent model. Experimental variables discussed include: innate immune stimulation using poly I:C and LPS, environmental gestational stress paradigms, rodent diet composition and sterilization, rodent strain, neonatal handling, and the inclusion of sex-specific MIA offspring analyses. We discuss how some aspects of these variables have potential to make a profound impact on MIA data interpretation and reproducibility.

Milk production by dairy cows is sensitive to increased levels of stress hormones such as glucocorticoids (GC) that also regulate the transcription of several genes required for milk synthesis. Whereas previous studies identified that an exogenous GC such as dexamethasone (DEX) transiently suppresses milk yield in several species without any pronounced effect on milk protein or fat percentage, the mechanism underlying this effect has not been established. In this study we sought to establish changes within the mammary glands of non-pregnant dairy cows in their second lactation (n = 3–4; 648–838 kg) following a single dose of exogenous DEX. Changes in the udder were monitored by serial biopsy of alternating quarters, concurrent with quarter-level monitoring of milk yield and composition. Dexamethasone increased serum glucose levels from 12–36 h (p

Background: Individuals with psychiatric disorders (PD) have a high prevalence of tobacco use. Therefore, we assessed the hazard of receiving a tobacco-related (TR) cancer diagnosis among individuals with PD. Methods: Several population-based provincial databases were used to identify individuals in BC diagnosed with depression, schizophrenia, bipolar disorder, anxiety disorders, or multiple PD between 1990 and 2013. A primary population proxy comparison group (appendicitis) was also identified and matched to the psychiatric cohort based on age at cohort entry, gender, year of cohort entry, and postal code. We linked individuals in the cohort and comparison groups with the BC Cancer Registry. Using a competing risks approach, we estimated the effect of having a PD on the risk of receiving a TR cancer diagnosis, in light of the competing risk of mortality. Results: In total, 165,289 patients were included. Individuals with depression (HR = 0.81; p < 0.01; 95% CI: 0.73–0.91), anxiety disorders (HR = 0.84; p = 0.02; 95% CI: 0.73–0.97), or multiple PD (HR = 0.74; p < 0.01; 95% CI: 0.66–0.83) had a statistically significant lower risk of a TR cancer diagnosis compared to the comparison group. Individuals with schizophrenia (HR = 0.86; p = 0.40; 95% CI: 0.62–1.21) or bipolar disorder (HR = 0.58; p = 0.12; 95% CI: 0.29–1.14), however, showed no evidence of a statistically significant difference from the comparison group. Interpretation: We found that individuals with depression, anxiety disorders, or multiple PD diagnoses had a significantly reduced risk of receiving a tobacco-related cancer diagnosis. These results were unexpected and could be explained by individuals with a PD having barriers to a cancer diagnosis rather than a true decreased incidence.

miR-126 is highly expressed in inv(16) Acute myeloid leukemia (AML) but its role is unclear. Here, the authors show that the aberrant expression of miR-126 in inv(16) AML is directly due to the CBFB-MYH11 fusion gene and that it can promote AML development and leukemia stem cell maintenance, highlighting miR-126 as a therapeutic target for inv(16) AML patients

Schistosomiasis, caused by infection with Schistosoma digenetic trematodes, is one of the deadliest neglected tropical diseases in the world. The Schistosoma lifecycle involves the miracidial infection of an intermediate freshwater snail host, such as Biomphalaria glabrata. Dispersing snail host-derived Schistosoma miracidia attractants has been considered a method of minimising intermediate host infections and, by extension, human schistosomiasis. The attractiveness of B. glabrata to miracidia is known to be reduced following infection; however, the relationship between duration of infection and attractiveness is unclear. Excretory-secretory proteins (ESPs) most abundant in attractive snail conditioned water (SCW) are key candidates to function as miracidia attractants. This study analysed SCW from B. glabrata that were naïve (uninfected) and at different time-points post-miracidia exposure (PME; 16h, 1-week, 2-weeks and 3-weeks PME) to identify candidate ESPs mediating Schistosoma mansoni miracidia behaviour change, including aggregation and chemoklinokinesis behaviour (random motion, including slowdown and increased turning rate and magnitude). Miracidia behaviour change was only observed post-addition of naïve and 3W-PME SCW, with other treatments inducing significantly weaker behaviour changes. Therefore, ESPs were considered attractant candidates if they were shared between naïve and 3W-PME SCW (or exclusive to the former), contained a predicted N-terminal signal peptide and displayed low identity (

Summary: Background: Epileptic (previously infantile) spasms is the most common epileptic encephalopathy occurring during infancy and is frequently associated with abnormal neurodevelopmental outcomes. Epileptic spasms have a diverse range of known (genetic, structural) and unknown aetiologies. High dose corticosteroid treatment for 4 weeks often induces remission of spasms, although the mechanism of action of corticosteroid is unclear. Animal models of epileptic spasms have shown decreased brain kynurenic acid, which is increased after treatment with the ketogenic diet. We quantified kynurenine pathway metabolites in the cerebrospinal fluid (CSF) of infants with epileptic spasms and explored clinical correlations. Methods: A panel of nine metabolites in the kynurenine pathway (tryptophan, kynurenine, kynurenic acid, 3-hydroxykynurenine, xanthurenic acid, anthranilic acid, 3-hydroxyanthranilic acid, quinolinic acid, and picolinic acid) were measured using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). CSF collected from paediatric patients less than 3 years of age with epileptic spasms (n=34, 19 males, mean age 0.85, median 0.6, range 0.3–3 yrs) were compared with other epilepsy syndromes (n=26, 9 males, mean age 1.44, median 1.45, range 0.3–3 yrs), other non-inflammatory neurological diseases (OND) (n=29, 18 males, mean age 1.47, median 1.6, range 0.1–2.9 yrs) and inflammatory neurological controls (n=12, 4 males, mean age 1.80, median 1.80, range 0.8–2.5 yrs). Findings: There was a statistically significant decrease of CSF kynurenic acid in patients with epileptic spasms compared to OND (p

Non-small cell lung cancer (NSCLC) has a high rate of brain metastasis. The purpose of this study was to assess the differential distribution of brain metastases from primary NSCLC based on mutation status. Brain MRI scans of patients with brain metastases from primary NSCLC were retrospectively analyzed. Brain metastatic tumors were grouped according to mutation status of their primary NSCLC and the neuroimaging features of these brain metastases were analyzed. A total of 110 patients with 1386 brain metastases from primary NSCLC were included in this study. Gray matter density at the tumor center peaked at ~0.6 for all mutations. The median depths of tumors were 7.9 mm, 8.7 mm and 9.1 mm for EGFR, ALK and KRAS mutation groups, respectively (p = 0.044). Brain metastases for the EGFR mutation-positive group were more frequently located in the left cerebellum, left cuneus, left precuneus and right precentral gyrus. In the ALK mutation-positive group, brain metastases were more frequently located in the right middle occipital gyrus, right posterior cingulate, right precuneus, right precentral gyrus and right parietal lobe. In the KRAS mutation-positive patient group, brain metastases were more frequently located in the posterior left cerebellum. Our study showed differential spatial distribution of brain metastases in patients with NSCLC according to their mutation status. Information regarding distribution of brain metastases is clinically relevant as it could be helpful to guide treatment planning for targeted therapy, and for predicting prognosis.

Colicodendron scabridum, comúnmente llamado sapote, es una de las especies arbóreas más abun-dantes en los bosques neotropicales estacionalmente secos y un importante alimento para la fauna. Se investigó su fenología reproductiva y su relación con la temperatura y precipitación en siete sitios de Cerro Venado en Lambayeque, Perú, entre 257 y 353 m de altitud; se instalaron siete transectos de 2 m x 300 m, con quince individuos de la especie por transecto. La duración de la floración y fructificación es variable entre individuos, sitios y años. Fructifican entre 85 y 97 % de los árboles. En promedio, el período de fructificación es más corto que el de floración y está desplazado en tres meses. Se empleó la prueba de correlación cruzada para evaluar la relación entre la floración y fructificación con el pro-medio mensual de temperatura y precipitación. La floración tiene una fuerte correlación negativa con la temperatura media mensual. En contraste, la frecuencia de árboles con frutos mostró una relación positiva con la temperatura. La precipitación no se correlacionó con la floración ni con la fructificación. Los resultados sugieren que la temperatura podría determinar el período de producción de frutos de la especie, afectando la disponibilidad de alimento para la vida silvestre. Las variaciones fenológicas registradas son relevantes para las decisiones de conservación de la especie.

Abstract Background During acute myeloid leukemia (AML) growth, the bone marrow (BM) niche acquires significant vascular changes that can be offset by therapeutic blast cytoreduction. The molecular mechanisms of this vascular plasticity remain to be fully elucidated. Herein, we report on the changes that occur in the vascular compartment of the FLT3-ITD+ AML BM niche pre and post treatment and their impact on leukemic stem cells (LSCs). Methods BM vasculature was evaluated in FLT3-ITD+ AML models (Mll PTD/WT/Flt3 ITD/ITD mouse and patient-derived xenograft) by 3D confocal imaging of long bones, calvarium vascular permeability assays, and flow cytometry analysis. Cytokine levels were measured by Luminex assay and miR-126 levels evaluated by Q-RT-PCR and miRNA staining. Wild-type (wt) and Mll PTD/WT/Flt3 ITD/ITD mice with endothelial cell (EC) miR-126 knockout or overexpression served as controls. The impact of treatment-induced BM vascular changes on LSC activity was evaluated by secondary transplantation of BM cells after administration of tyrosine kinase inhibitors (TKIs) to Mll PTD/WT/Flt3 ITD/ITD mice with/without either EC miR-126 KO or co-treatment with tumor necrosis factor alpha (TNFα) or anti-miR-126 miRisten. Results In the normal BM niche, CD31+Sca-1high ECs lining arterioles have miR-126 levels higher than CD31+Sca-1low ECs lining sinusoids. We noted that during FLT3-ITD+ AML growth, the BM niche lost arterioles and gained sinusoids. These changes were mediated by TNFα, a cytokine produced by AML blasts, which induced EC miR-126 downregulation and caused depletion of CD31+Sca-1high ECs and gain in CD31+Sca-1low ECs. Loss of miR-126high ECs led to a decreased EC miR-126 supply to LSCs, which then entered the cell cycle and promoted leukemia growth. Accordingly, antileukemic treatment with TKI decreased the BM blast-produced TNFα and increased miR-126high ECs and the EC miR-126 supply to LSCs. High miR-126 levels safeguarded LSCs, as shown by more severe disease in secondary transplanted mice. Conversely, EC miR-126 deprivation via genetic or pharmacological EC miR-126 knock-down prevented treatment-induced BM miR-126high EC expansion and in turn LSC protection. Conclusions Treatment-induced CD31+Sca-1high EC re-vascularization of the leukemic BM niche may represent a LSC extrinsic mechanism of treatment resistance that can be overcome with therapeutic EC miR-126 deprivation. Graphic abstract

Abstract Background Describe and evaluate an implementation science network focused on HIV prevention and treatment in New England. Methods In 2014, we established a partnership among university researchers and community stakeholders to stimulate and support HIV-related implementation research. We solicited information from Network members through surveys, interviews at Network events, and dialog with participants. In 2017, we conducted a sociocentric network assessment of collaborations on research projects, grants, manuscripts, and consultations. Results We identified 988 connections made through the Network that resulted in 185 manuscripts published and 15 grants funded. Our experience indicated that eight factors were instrumental in building and sustaining the Network: (1) acknowledging different perspectives, (2) balancing content and expertise, (3) encouraging consistent engagement, (4) providing seed funding, (5) membership flexibility, (6) maintenance of Network interactions, (7) supporting local HIV prevention and treatment efforts, and (8) maintaining productive relationships with health departments and community-based organizations. Conclusions Developing and maintaining a regional network on implementation science for HIV prevention and treatment is feasible and can facilitate new and productive partnerships among researchers and community organizations and members.

High-grade (WHO grades III-IV) glioma remains one of the most lethal human cancers. Adoptive transfer of tumor-targeting chimeric antigen receptor (CAR)-redirected T cells for high-grade glioma has revealed promising indications of anti-tumor activity, but objective clinical responses remain elusive for most patients. A significant challenge to effective immunotherapy is the highly heterogeneous structure of these tumors, including large variations in the magnitudes and distributions of target antigen expression, observed both within individual tumors and between patients. To obtain a more detailed understanding of immunotherapy target antigens within patient tumors, we immunochemically mapped at single cell resolution three clinically-relevant targets, IL13Rα2, HER2 and EGFR, on tumor samples drawn from a 43-patient cohort. We observed that within individual tumor samples, expression of these antigens was neither random nor uniform, but rather that they mapped into local neighborhoods – phenotypically similar cells within regions of cellular tumor – reflecting not well understood properties of tumor cells and their milieu. Notably, tumor cell neighborhoods of high antigen expression were not arranged independently within regions. For example, in cellular tumor regions, neighborhoods of high IL13Rα2 and HER2 expression appeared to be reciprocal to those of EGFR, while in areas of pseudopalisading necrosis, expression of IL13Rα2 and HER2, but not EGFR, appeared to reflect the radial organization of tumor cells around hypoxic cores. Other structural features affecting expression of immunotherapy target antigens remain to be elucidated. This structured but heterogeneous organization of antigen expression in high grade glioma is highly permissive for antigen escape, and combinatorial antigen targeting is a commonly suggested potential mitigating strategy. Deeper understanding of antigen expression within and between patient tumors will enhance optimization of combination immunotherapies, the most immediate clinical application of the observations presented here being the importance of including (wild-type) EGFR as a target antigen.

Abstract Increasing demand for self-powered wearable sensors has spurred an urgent need to develop energy harvesting systems that can reliably and sufficiently power these devices. Within the last decade, reverse electrowetting-on-dielectric (REWOD)-based mechanical motion energy harvesting has been developed, where an electrolyte is modulated (repeatedly squeezed) between two dissimilar electrodes under an externally applied mechanical force to generate an AC current. In this work, we explored various combinations of electrolyte concentrations, dielectrics, and dielectric thicknesses to generate maximum output power employing REWOD energy harvester. With the objective of implementing a fully self-powered wearable sensor, a “zero applied-bias-voltage” approach was adopted. Three different concentrations of sodium chloride aqueous solutions (NaCl-0.1 M, NaCl-0.5 M, and NaCl-1.0 M) were used as electrolytes. Likewise, electrodes were fabricated with three different dielectric thicknesses (100 nm, 150 nm, and 200 nm) of Al2O3 and SiO2 with an additional layer of CYTOP for surface hydrophobicity. The REWOD energy harvester and its electrode–electrolyte layers were modeled using lumped components that include a resistor, a capacitor, and a current source representing the harvester. Without using any external bias voltage, AC current generation with a power density of 53.3 nW/cm2 was demonstrated at an external excitation frequency of 3 Hz with an optimal external load. The experimental results were analytically verified using the derived theoretical model. Superior performance of the harvester in terms of the figure-of-merit comparing previously reported works is demonstrated. The novelty of this work lies in the combination of an analytical modeling method and experimental validation that together can be used to increase the REWOD harvested power extensively without requiring any external bias voltage.