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Introduction and objectives Hereditary transthyretin amyloidosis (hATTR) is a disease caused by mutations in the transthyretin gene that frequently shows cardiac involvement due to amyloid deposition in the myocardium. Our objective was to identify cardiac involvement in a Spanish cohort. Methods Retrospective multicenter study of patients diagnosed with hATTR with cardiac involvement from Spanish centers. We collected demographic, clinical, and genetic data. Results A total of 181 patients from 26 centers were included (65.2% men, with a median age at diagnosis of 62 years). The most frequent mutations were Val50Met (67.7%) and Val142Ile (12.4%). The main reason for consultation was extracardiac symptoms (69%), mainly neurological. The mean N-terminal pro-B-type natriuretic peptide level was 2145±3586 pg/mL. The most characteristic electrocardiogram findings were a pseudoinfarct pattern (25.9%) and atrioventricular block (25.3%). Mean ventricular thickness was 15.4±4.1mm. Longitudinal strain was reduced in basal segments by 29.4%. Late diffuse subendocardial enhancement was observed in 58.8%. Perugini grade 2 or 3 uptake was observed in 75% of scintigraphy scans. During follow-up, 24.9% of the patients were admitted for heart failure, 34.3% required a pacemaker, and 31.6% required a liver transplant. One third (32.5%) died during follow-up, mainly due to heart failure (28.8%). The presence of non-Val50Met mutations was associated with a worse prognosis. Conclusions HATTR cardiac amyloidosis in Spain shows heterogeneous genetic and clinical involvement. The prognosis is poor, mainly due to cardiac complications. Consequently early diagnosis and treatment are vital.

Accumulating evidence suggests that the molecular circadian clock is crucial in blood pressure (BP) control. Circadian rhythms are controlled by the central clock, which resides in the suprachiasmatic nucleus of the hypothalamus and peripheral clocks throughout the body. Both light and food cues entrain these clocks but whether these cues are important for the circadian rhythm of BP is a growing area of interest. The peripheral clocks in the smooth muscle, perivascular adipose tissue, liver, adrenal gland, and kidney have been recently implicated in the regulation of BP rhythm. Dysregulation of the circadian rhythm of BP is associated with adverse cardiorenal outcomes and increased risk of cardiovascular mortality. In this review, we summarize the most recent advances in peripheral clocks as BP regulators, highlight the adverse outcomes of disrupted circadian BP rhythm in hypertension, and provide insight into potential future work in areas exploring the circadian clock in BP control and chronotherapy. A better understanding of peripheral clock function in regulating the circadian rhythm of BP will help pave the way for targeted therapeutics in the treatment of circadian BP dysregulation and hypertension.

Taxonomy is a foundational scientific discipline, shaping not only the work of biologists and ecologists, but also how people see and understand the living world around us. In its most basic form, taxonomy is the science of precise categorization of the diversity of life on Earth into a rigorous system of scientific names and taxonomic concepts that allows for common understanding of the full extent and relationships of this diversity. Like many other scientific disciplines, taxonomy has evolved, developing over the centuries an agreed set of rules, norms, and shared strategies for definition, classification, and nomenclature of the life forms on Earth — what governance scholars would refer to as the “institution of taxonomy.” There are long-established and widely accepted governance systems in place for some aspects of taxonomy, for example the International Code of Zoological Nomenclature, which establishes rules for the establishment and use of scientific names for organisms known as “animals”. Other aspects of taxonomy, including the development and aggregation of species lists, currently lack similar governance institutions. Since the initial development of Linnaean taxonomy, a diversity of approaches have been adopted for critical taxonomic decisions about synonymy and classification, introducing pluralism to taxonomic principles at different levels and resulting in disagreements about species hypotheses and development of species lists. While the basic principles of Linnaean taxonomy—that species are the fundamental units of taxonomy, binomial names of species, the international codes for naming of species—have wide agreement and adherence, there is variation in implementation of the process of taxonomy, such as from application of different species concepts that result in differences in hypothesized species boundaries and potentially overlapping or conflicting species definitions. When developing species lists, these differences can result in inconsistencies from one list to another depending on the preferences of the list developer. For users of species lists, these differences can cause confusion and uncertainty, with potential effects on issues ranging from conservation to medicine (Thomson et al. this issue). Recent debates within the discipline have pointed to the potential benefits of a unified governance system for the development of taxonomic lists across all taxonomic communities leading to a single, accepted list of all life on Earth. To address this challenge, a group of taxonomists, philosophers of science, and governance scholars have established the Working Group on the Governance of Taxonomic Lists under the auspices of the International Union of Biological Sciences to investigate the development of a governance system for the aggregation of a single list of all life on Earth. As a part of this work, the Working Group is conducting a survey of taxonomists, scientists who utilize taxonomy in their work or research, and other users of taxonomic information to determine 1) if there is agreement that a single list is needed, 2) what form such a list should take, and 3) what governance mechanisms are most acceptable to taxonomists and users of taxonomic information. The results of the survey will be published in peer reviewed journals and used to inform the work of the Working Group going forward.

[Extract] We recruited every player from a squad of professional basketballers involved in a ‘super-spreader’ event that lead to a majority being infected with COVID-19 following a single training session in Melbourne, Australia. We compared those athletes who tested positive to COVID-19 by polymerase chain reaction diagnostic testing (16 athletes) to athletes who (i) tested negative and (ii) had no symptoms suggestive of COVID-19 infection (n = 8).

Species lists are widely used in legislation and regulation to manage and conserve biodiversity. In this paper, we explore the issues caused by the lack of an adequately governed and universally accepted list of the world’s species. These include lack of quality control, duplicated effort, conflicts of interest, lack of currency, and confusion in the scientific use of taxonomic information. If species lists are to fulfill their role efficiently, then the governance systems underlying their creation must keep pace. Fortunately, modernization of species list governance is now possible as a result of advances in biodiversity informatics and two decades of experience working to create the backbone of a global species list.

Indigenous self-determination, land rights and caring for Country programs are enabling Indigenous peoples across the world to re-establish customary roles in biodiversity conservation and cultural fire management. In Australia, Indigenous-controlled lands form the majority of the protected area estate, harbour almost 60% of listed threatened species and maintain high levels of biodiversity. This study used cross-cultural (Indigenous and Western academic) methods to monitor the impact of Indigenous cultural burning v. wildfire on the threatened plant, Backwater grevillea (Grevillea scortechinii subsp. sarmentosa). Cultural burning resulted in lower mature grevillea mortality and less impact on reproductive output than wildfire. Both fires stimulated a mass germination but the cultural burn preserved a multi-aged population while the wildfire killed 99.6% of mature shrubs. Comparison of fuel load changes resulting from cultural burning, hazard reduction burning and wildfire indicated that fuel loads were reduced by all fire treatments, although the cultural burn was less severe than other fires. Our case study of the Backwater grevillea and its Banbai custodians provides an example where Indigenous rangers have adopted a plant into their cultural management framework. They are conserving this threatened species using culturally driven, holistic management that is locally focused and supported by cross-cultural knowledge.

Governance is the act of governing or organizing, that is a system of rules, norms, or shared strategies to guide or regulate the actions of the governed. Since the initial development of Linnaean taxonomy, a diversity of approaches have been adopted for critical taxonomic decisions, introducing pluralism to taxonomic principles and resulting in disagreements about the development of species lists. These disagreements are in part a product of the fragmented governance structure that has developed for the creation of taxonomic lists. To address these challenges and achieve the goal of a single, accepted list of life on Earth, a new governance structure for the development of taxonomic lists is needed. Here, we introduce three high-level categories of governance structure—fragmentation, monocentric governance, and polycentric governance—which differ in the way decision-making power is distributed and coordinated. We then show the problems caused by the fragmented governance structure currently in place for the development of taxonomic lists and consider the potential for a new approach grounded in either monocentric or polycentric governance. Both monocentric and polycentric approaches have the potential to address the problems inherent in the existing fragmented system. Ultimately, the best governance system for taxonomic lists will be the one that the taxonomic community is prepared to accept.

Background Altered tumor suppressor genes (TSG-alt) in prostate cancer are associated with worse outcomes. The prognostic value of TSG-alt in metastatic, hormone-sensitive prostate cancer (M1-HSPC) is unknown. We evaluated the effects of TSG-alt on outcomes in M1-HSPC and their prognostic impact by first-line treatment. Methods We retrospectively identified patients with M1-HSPC at our institution treated with first-line androgen deprivation therapy plus docetaxel (ADT + D) or abiraterone acetate (ADT + A). TSG-alt was defined as any alteration in one or more TSG. The main outcomes were Kaplan–Meier-estimated progression-free survival (PFS) and overall survival, analyzed with the log-rank test. Clinical characteristics were compared with the χ2 test and Kruskal–Wallis rank sum test. Cox regression was used for univariate and multivariable analyses. Results We identified 97 patients with M1-HSPC: 48 (49%) with ADT + A and 49 (51%) with ADT + D. Of 96 patients with data available, 33 (34%) had 1 TSG-alt, 16 (17%) had 2 TSG-alt, and 2 (2%) had 3 TSG-alt. The most common alterations were in TP53 (36%) and PTEN (31%); 6% had RB1 alterations. Median PFS was 13.1 (95% CI, 10.3–26.0) months for patients with normal TSGs (TSG-normal) vs. 7.8 (95% CI, 5.8–10.5) months for TSG-alt (P = 0.005). Median PFS was lower for patients with TSG-alt vs TSG-normal for those with ADT + A (TSG-alt: 8.0 [95% CI, 5.8–13.8] months vs. TSG-normal: 23.2 [95% CI, 13.1–not estimated] months), but not with ADT + D (TSG-alt: 7.8 [95% CI, 5.7–12.9] months vs. TSG-normal: 9.5 [95% CI, 4.8–24.7] months). On multivariable analysis, only TSG-alt predicted worse PFS (hazard ratio, 2.37; 95% CI, 1.42–3.96; P Conclusions The presence of TSG-alt outperforms clinical criteria for predicting early progression during first-line treatment of M1-HSPC. ADT + A was less effective in patients with than without TSG-alt. Confirmation of these findings may establish the need for inclusion of molecular stratification in treatment algorithms.

Taxonomy—the delimitation, naming, classification and documentation of species and other taxa—is an often-misunderstood discipline. Complex and at times contested, taxonomy occupies a sometimes discomforting intermediate position on a continuum from descriptive to hypothetico-deductive science. Two aspects of taxonomy that are striking to many observers and users are the degree to which taxonomists often disagree, and the degree of taxonomic revisionism (the replacement of one taxonomic classification with another, exemplified by the phrase ‘taxonomists are always changing the names of things’). Disagreements between taxonomists do not usually indicate taxonomic confusion or chaos, but rather often represent valid disagreements over the best, most effective and most meaningful way to interpret, describe and classify one of the most complex systems that scientists seek to describe and characterise—the patterns of variation of life on Earth. One way to partially manage disagreements among taxonomists is to develop a mechanism to synthesise the flux of taxonomic activity into agreed, broadly accepted, authoritative and scientifically robust global lists of the world’s species and other taxa. A sound understanding of some aspects of the nature of taxonomy is needed to appreciate the opportunities, complexities and limitations of the development and maintenance of such lists.

There is mounting evidence that microbiome composition is intimately and dynamically connected with host energy balance and metabolism. The gut microbiome is emerging as a novel target for counteracting the chronically positive energy balance in obesity, a disease of pandemic scale which contributes to >70 % of premature deaths. This scoping review explores the potential for therapeutic modulation of gut microbiota as a means of prevention and/or treatment of obesity and obesity-associated metabolic disorders. The evidence base for interventional approaches which have been shown to affect the composition and function of the intestinal microbiome is summarised, including dietary strategies, oral probiotic treatment, faecal microbiota transplantation and bariatric surgery. Evidence in this field is still largely derived from preclinical rodent models, but interventional studies in obese populations have demonstrated metabolic improvements effected by microbiome-modulating treatments such as faecal microbiota transplantation, as well as drawing attention to the unappreciated role of microbiome modulation in well-established anti-obesity interventions, such as dietary change or bariatric surgery. The complex relationship between microbiome composition and host metabolism will take time to unravel, but microbiome modulation is likely to provide a novel strategy in the limited armamentarium of effective treatments for obesity.

It is increasingly reported that a history of concussion may be associated with chronic deleterious consequences. While the pathophysiology that contributes to these consequences is not well understood, neuroinflammation is postulated to be critical. Activation of multi-protein complexes termed inflammasomes, a key component of this inflammatory response, has been reported in more severe TBIs; however, it has not been investigated in milder TBIs, such as concussion. This study investigated serum levels of interleukin (IL)-1β and IL-18 (key proteins activated downstream of these inflammasomes) at acute, sub-acute, and chronic time-points post-concussion. We recruited 105 Australian footballers (65 male, 40 female) during the pre-season, then prospectively followed these players for the occurrence of concussion during the season. At baseline, 58 footballers reported a previous concussion history, and 47 reported no previous concussion history. Additionally, 25 players sustained a mid-season concussion and were sampled at 2, 6, and 13 days post-concussion. Serum levels of IL-1β and IL-18 were quantified using highly sensitive Simoa HD-X Analyzer assays. At baseline, IL-1β levels were higher in male, but not female, footballers with a previous concussion history compared with footballers with no concussion history. There was also a positive correlation between years of collision sport participation and IL-18 levels in males. No evidence was found in males or females to indicate that IL-1β or IL-18 levels differed at 2, 6, or 13 days post-concussion. These findings provide novel insights into potential sex-specific physiological consequences of concussion, and suggest that neuroinflammation may be persistent chronically following concussion in male athletes.

Mass mortalities in flying-foxes occur in summers that reach extremely hot temperatures. In this study, we examine the spatiotemporal distributions of mortality from pup abandonments and extreme heat events in Australian flying-fox camps during the 2019–20 summer. We recorded data on flying-fox mortality in known affected camps and applied a standard method to estimate the number of deaths. Pup mortalities from abandonments were recorded in 10 camps in New South Wales. A minimum estimate of 2612 flying-foxes died in pup abandonments, the majority of which occurred in one camp in Bomaderry. Die-offs from extreme heat events were recorded in 40 camps associated with eight separate heat events in south-eastern Australia. A minimum estimate of 72 175 flying-foxes died during these heat events, which all occurred within the range of the threatened grey-headed flying-fox (Pteropus poliocephalus). Further, 409 and 2251 live flying-foxes were taken into care from pup abandonments and heat events respectively. The minimum mortality estimated represents the highest recorded mortality of Australian flying-foxes within a single summer. This highlights a need to restore vegetation in flying-fox foraging areas and camps, address anthropogenic climate change and gather more empirical data to inform heat stress interventions to minimise flying-fox mortalities.

Background Lameness is a debilitating condition in equine athletes that leads to more performance limitation and loss of use than any other medical condition. There are a limited number of non-terminal experimental models that can be used to study early inflammatory and synovial fluid biophysical changes that occur in the equine joint. Here, we compare the well-established carpal IL-1β-induced synovitis model to a tarsal intra-articular lavage model, focusing on serial changes in synovial fluid inflammatory cytokines/chemokines and the synovial fluid lubricating molecules lubricin/proteoglycan 4 and hyaluronic acid. The objectives of this study were to evaluate clinical signs; synovial membrane and synovial fluid inflammation; and synovial fluid lubricants and biophysical properties in response to carpal IL-1β synovitis and tarsal intra-articular lavage. Results Hyaluronic acid (HA) concentrations, especially high molecular weight HA, and synovial fluid viscosity decreased after both synovitis and lavage interventions. Synovial fluid lubricin concentrations increased 17–20-fold for both synovitis and lavage models, with similar changes in both affected and contralateral joints, suggesting that repeated arthrocentesis alone resulted in elevated synovial fluid lubricin concentrations. Synovitis resulted in a more severe inflammatory response based on clinical signs (temperature, heart rate, respiratory rate, lameness and joint effusion) and clinicopathological and biochemical parameters (white blood cell count, total protein, prostaglandin E2, sulfated glycosaminoglycans, tumor necrosis factor-α and CC chemokine ligands − 2, − 3, − 5 and − 11) as compared to lavage. Conclusions Synovial fluid lubricin increased in response to IL-1β synovitis and joint lavage but also as a result of repeated arthrocentesis. Frequent repeated arthrocentesis is associated with inflammatory changes, including increased sulfated glycosaminoglycan concentrations and decreased hyaluronic acid concentrations. Synovitis results in more significant inflammatory changes than joint lavage. Our data suggests that synovial fluid lubricin, TNF-α, CCL2, CCL3, CCL5, CCL11 and sGAG may be useful biomarkers for synovitis and post-lavage joint inflammation. Caution should be exercised when performing repeated arthrocentesis clinically or in experimental studies due to the inflammatory response and loss of HA and synovial fluid viscosity.

PurposeOnline resources can be helpful for students and can augment the content presented in learning environments. A team consisting of four biologists, a graduate student, instructional designer and media developers collaborated on the design, development and evaluation of first-year biology online tutorials in a Canadian University. The tutorials were designed to address knowledge gaps resulting in low success rates and attrition of first-year students in biology. The decrease in the number of students in STEM has alarmed educators, prompting a call for efforts to increase STEM majors in universities. Large class sizes, such as first year biology with ∼900 registrants annually, with detail-oriented, content-heavy loads, can result in low success rates and attrition.Design/methodology/approachActive learning methods, including online formative assessments, which encourage student engagement in course material, can be effective in large introductory science classes, and thus, the authors provided engagement with tutorial online resources. The authors identified the tutorial topics by analyzing previous years' tests, student feedback and pedagogical research in undergraduate biology. The top five topics identified as common misconceptions or troublesome concepts within the course were selected. Standard instructional design processes were used to produce high-quality online tutorials. Tutorials included learning materials, videos, animations, self-assessments, reflective questions and badges to facilitate deep learning of the topics. Effectiveness of the tutorials was evaluated using quantitative methods and quasi-experimental design to compare the student learning results between the control year (without tutorials) and the year when tutorials were offered. Pre- and posttests measuring conceptual understanding were administered to assess gains in student learning. Additionally, student engagement was measured using the Classroom Survey of Student Engagement (CLASSE), and data from learning management system was collected.FindingsResults of the study show that the tutorials were an effective means of providing supplementary assistance to students as well as fostering a gain in students' levels of engagement with the course. Data analysis indicates that there was a significant increased gain in learning of core concepts in biology. Specifically, using formative online assessments resulted in measurable learning gains in students who participated voluntarily, in comparison to students who chose not to engage in self-paced quiz testing.Originality/valueAs seen from the description earlier, the tutorials, and this project, provide suitable university-level complexity to address specific learning gaps in the first year course. They provide a valuable service to students in terms of representing content in an alternate format and motivating students as they engaged with videos and self-assessment most frequently. The project adds to the teaching and learning environment with respect to program design, mode of delivery and scheduling by providing self-paced tutorials that focus on specific concepts in biology. Students may review these resources whenever and as often as they feel necessary to better master the concepts. This makes the content applicable for the various preferences for approaches to learning and accommodation requirements found in students. Importantly, using formative online assessments resulted in measurable learning gains in students who participated voluntarily, in comparison to students who chose not to engage in self-paced quiz testing.

Urea is the major nitrogen-containing product of protein metabolism, and the urea cycle is intrinsically linked to nitric oxide (NO) production via the common substrate L-arginine. Urea accumulates in the brain in neurodegenerative states, including Alzheimer's and Huntington's disease. Urea transporter B (UT-B, SLC14A1) is the primary transport protein for urea in the CNS, identified most abundantly in astrocytes. Moreover, enhanced expression of the Slc14a1 gene has been reported under neurodegenerative conditions. While the role of UT-B in disease pathology remains unclear, UT-B-deficient mice display behavioural impairment coupled with urea accumulation, NO disruption and neuronal loss. Recognising the role of inflammation in neurodegenerative disease pathology, the current short study evaluates the role of UT-B in regulating inflammatory responses. Using the specific inhibitor UTBinh-14, we investigated the impact of UT-B inhibition on LPS-induced changes in BV2 microglia and N2a neuroblastoma cells. We found that UTBinh-14 significantly attenuated LPS-induced production of TNFα and IL-6 from BV2 cells, accompanied by reduced release of NO. While we observed a similar reduction in supernatant concentration of IL-6 from N2a cells, the LPS-stimulated NO release was further augmented by UTBinh-14. These changes were accompanied by a small, but significant downregulation in UT-B expression in both cell types following incubation with LPS, which was not restored by UTBinh-14. Taken together, the current evidence implicates UT-B in regulation of inflammatory responses in microglia and neuronal-like cells. Moreover, our findings offer support for the further investigation of UT-B as a novel therapeutic target for neuroinflammatory conditions.

Genetic factors play an important role in the susceptibility to pancreatic cancer (PC). However, established loci explain a small proportion of genetic heritability for PC; therefore, more progress is needed to find the missing ones. We aimed at identifying single nucleotide polymorphisms (SNPs) affecting PC risk through effects on micro-RNA (miRNA) function. We searched in silico the genome for SNPs in miRNA seed sequences or 3 prime untranslated regions (3'UTRs) of miRNA target genes. Genome-wide association data of PC cases and controls from the Pancreatic Cancer Cohort (PanScan) Consortium and the Pancreatic Cancer Case–Control (PanC4) Consortium were re-analyzed for discovery, and genotyping data from two additional consortia (PanGenEU and PANDoRA) were used for replication, for a total of 14,062 cases and 11,261 controls. None of the SNPs reached genome-wide significance in the meta-analysis, but for three of them the associations were in the same direction in all the study populations and showed lower value of p in the meta-analyses than in the discovery phase. Specifically, rs7985480 was consistently associated with PC risk (OR = 1.12, 95% CI 1.07–1.17, p = 3.03 × 10−6 in the meta-analysis). This SNP is in linkage disequilibrium (LD) with rs2274048, which modulates binding of various miRNAs to the 3'UTR of UCHL3, a gene involved in PC progression. In conclusion, our results expand the knowledge of the genetic PC risk through miRNA-related SNPs and show the usefulness of functional prioritization to identify genetic polymorphisms associated with PC risk.

The global biogeography of polychaete worms has never been assessed previously. In the present study, we studied the world distribution patterns of polychaetes based on datasets obtained from the Global Biodiversity Information Facility, the Ocean Biogeographic Information System and our recently published checklist of Indonesian polychaete species. Polychaete biogeographic regions were visualized using ‘Infomap Bioregions’, and the latitudinal species richness gradient of the animals was examined using 3 metrics, i.e. alpha, gamma and estimated species richness (the last metric was adjusted for sampling bias). We identified 11 major polychaete biogeographic regions. The North Atlantic, Australia and Indonesia were the top 3 species-rich biogeographic regions in the world. The total number of polychaete species was higher in the southern hemisphere (~2100 species, 67 families) than in the northern hemisphere (~1800 species, 75 families) despite significantly more data in the latter (>500000 records compared to >26000 records). Contrary to the classical idea of a unimodal distribution pattern, the latitudinal gradient of polychaetes was generally bimodal with a pronounced dip north of the Equator (15°N). We suggest that the slightly higher peak of species richness in the southern (30°S) than in the northern (60°N) hemisphere reflects higher southern endemicities. These patterns are unlikely to be due to sampling bias but rather represent a natural phenomenon, and we found them most significantly correlated with sea temperature.

OBJECTIVE While the global prevalence of antibiotic-resistant Helicobacter pylori (H. pylori) is increasing, there is much regional variation, and local data are required to guide eradication therapy. We performed a systematic review and meta-analysis to determine rates of H. pylori antibiotic resistance in Australia and New Zealand. STUDY DESIGN Random effects meta-analysis of data from 15 published studies and three published abstracts reporting prevalence of primary or secondary H. pylori antibiotic resistance in Australasia. DATA SOURCES PubMed, EMBASE, MEDLINE, PROSPERO, and the Cochrane Library were searched until August, 2020. DATA SYNTHESIS Fifteen published studies and three published abstracts were identified; one study was excluded due to high risk of bias. Seventeen studies conducted between 1996 and 2013 were included in the final analysis, 12 reporting primary and five reporting secondary antibiotic resistance. Prevalence of primary resistance was clarithromycin 7.4% (95% confidence interval [CI], 5.3-9.7%), metronidazole 50.0% (95%CI, 23.9-56.1%), fluoroquinolones 3.7% (95%CI, 0.004-14.8%), and both amoxicillin and tetracycline

Jellyfish have provided insight into important components of animal propulsion, such as suction thrust, passive energy recapture, vortex wall effects, and the rotational mechanics of turning. These traits are critically important to jellyfish because they must propel themselves despite severe limitations on force production imposed by rudimentary cnidarian muscular structures. Consequently, jellyfish swimming can occur only by careful orchestration of fluid interactions. Yet these mechanics may be more broadly instructive because they also characterize processes shared with other animal swimmers, whose structural and neurological complexity can obscure these interactions. In comparison with other animal models, the structural simplicity, comparative energetic efficiency, and ease of use in laboratory experimentation allow jellyfish to serve as favorable test subjects for exploration of the hydrodynamic bases of animal propulsion. These same attributes also make jellyfish valuable models for insight into biomimetic or bioinspired engineeringof swimming vehicles. Here, we review advances in understanding of propulsive mechanics derived from jellyfish models as a pathway toward the application of animal mechanics to vehicle designs.

Ascidian tunicates frequently display rapid expansion when introduced beyond their native range and are considered successful invaders. This invasive potential may be exacerbated by a warming climate, allowing for the occupation of environmental niches previously held by native species. Research into tunicate invasion ecology is prevalent, but less is known about their role in pathogen maintenance. This study investigated the impact of invasive tunicates on the maintenance of pathogens that affect commercial bivalves, including the cultured species Ostrea edulis (European flat oyster) and Crassostrea gigas (Pacific oyster), and the fished species Cerastoderma edule (Common cockle). Focal pathogens included ostreid herpesvirus OsHV-1 μVar, Vibrio aestuarianus, Bonamia ostreae and Minchinia spp. The range of pathogens in their molluscan hosts was determined and the tunicates Botrylloides violaceus, Didemnum vexillum and Styela clava were then screened for these same pathogens, using both field samples from oyster culture sites and marinas and a series of laboratory cohabitation trials. Sample sites reflected areas close to and further away from known pathogen sources. PCR, Sanger sequencing and histology confirmed the presence of B. ostreae and Minchinia mercenariae-like in S. clava, and V. aestuarianus was confirmed by qPCR in B. violaceus and D. vexillum. Furthermore, histology confirmed Minchinia mercenariae-like sporonts in S. clava suggesting that the tunicate can facilitate replication of this species. S. clava also maintained B. ostreae in tanks with no oysters present. The results indicate that tunicates can act as reservoirs of infection in areas where disease occurs and potentially transport diseases to uninfected sites.

Ewing sarcoma is an aggressive malignant neoplasm with high propensity for metastasis and poor clinical outcomes. The EWS/Fli1 oncofusion is the disease driver in > 90% of cases, but presents a difficult therapeutic target. Moreover, EWS/Fli1 plays a complex role in disease progression, with inhibitory effects on critical steps of metastasis. Like many other pediatric cancers, Ewing sarcoma is a disease marked by epigenetic dysregulation. Epigenetic mechanisms present alternative targeting opportunities, but their contributions to Ewing sarcoma metastasis and disease progression remain poorly understood. Here, we show that the epigenetic regulators KDM5A and PHF2 promote growth and metastatic properties in Ewing sarcoma, and, strikingly, activate expression many pro-metastatic genes repressed by EWS/Fli1. These genes include L1CAM, which is associated with adverse outcomes in Ewing sarcoma, and promotes migratory and invasive properties. KDM5A and PHF2 retain their growth promoting effects in more metastatically potent EWS/Fli1low cells, and PHF2 promotes both invasion and L1CAM expression in this cell population. Furthermore, KDM5A and PHF2 each contribute to the increased metastatic potency of EWS/Fli1low cells in vivo. Together, these studies identify KDM5A and PHF2 as novel disease-promoting factors, and potential new targets, in Ewing sarcoma, including the more metastatically potent EWS/Fli1low cell population.

Introduction and objectives: Treatment with intravenous iron in patients with heart failure (HF) and iron deficiency (ID) improves symptoms, however its impact on survival and safety is unknown. We aimed to evaluate the management of ID and anemia with intravenous iron in patients with HF and long-term safety of intravenous iron. Methods: We evaluated anemia and ID in patients with chronic HF at 3 university hospitals. Anemia was defined using the World Health Organization definition and ID was defined as ferritin

Rationale: Coronavirus disease (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood. Objectives: To define the cytokine profile of COVID-19 and to identify evidence of immunometabolic alterations in those with severe illness. Methods: Levels of IL-1β, IL-6, IL-8, IL-10, and sTNFR1 (soluble tumor necrosis factor receptor 1) were assessed in plasma from healthy volunteers, hospitalized but stable patients with COVID-19 (COVIDstable patients), patients with COVID-19 requiring ICU admission (COVIDICU patients), and patients with severe community-acquired pneumonia requiring ICU support (CAPICU patients). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of AAT (alpha-1 antitrypsin) to COVID-19 was also evaluated. Measurements and Main Results: IL-1β, IL-6, IL-8, and sTNFR1 were all increased in patients with COVID-19. COVIDICU patients could be clearly differentiated from COVIDstable patients, and demonstrated higher levels of IL-1β, IL-6, and sTNFR1 but lower IL-10 than CAPICU patients. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2 (pyruvate kinase M2), phosphorylated PKM2, HIF-1α (hypoxia-inducible factor-1α), and lactate. The production and sialylation of AAT increased in COVID-19, but this antiinflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P

In an effort to minimize the amount of hay wasted from a round bale, horse owners generally surround the bale with a round-bale feeder. While often necessary as a supplemental feed source, this feeding technique restricts the space each horse has to feed, altering a horse's natural eating behavior. The objective of this study was to evaluate the influence of the round-bale feeder type on stress, agonistic behaviors, and horse preference of feeder types. Two feeder treatments were evaluated: (1) round bale surrounded by a ring feeder (ring feeder; BW Hayhuts LLC, Palm Coast, FL). Two horse herds (n = 5 horses per herd) were evaluated using a crossover experimental design, where each herd received each treatment for one week to evaluate behavior and cortisol concentrations. After this, each herd had access to both feeder treatments at the same time to evaluate preference. Feeding horses with the enclosed feeder resulted in fewer total agonistic threats (P

Viral latency of human immunodeficiency virus type 1 (HIV-1) has become a major hurdle to a cure in the highly effective antiretroviral therapy (ART) era. The clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system has successfully been demonstrated to excise or inactivate integrated HIV-1 provirus from infected cells by targeting the long terminal repeat (LTR) region. However, the guide RNAs (gRNAs) have classically avoided transcription factor binding sites (TFBSs) that are readily observed and known to be important in human promoters. Although conventionally thought unfavorable due to potential impact on human promoters, our computational pipeline identified gRNA sequences that were predicted to inactivate HIV-1 transcription by targeting the nuclear factor κB (NF-κB) binding sites (gNFKB0, gNFKB1) with a high safety profile (lack of predicted or observed human edits) and broad-spectrum activity (predicted coverage of known viral sequences). Genome-wide, unbiased identification of double strand breaks (DSBs) enabled by sequencing (GUIDE-seq) showed that the gRNAs targeting NF-κB binding sites had no detectable CRISPR-induced off-target edits in HeLa cells. 5′ LTR-driven HIV-1 transcription was significantly reduced in three HIV-1 reporter cell lines. These results demonstrate a working model to specifically target well-known TFBSs in the HIV-1 LTR that are readily observed in human promoters to reduce HIV-1 transcription with a high-level safety profile and broad-spectrum activity., Graphical Abstract, CRISPR has demonstrated potential for treating HIV latency. Guide RNA (gRNA) design has conventionally avoided transcription factor binding sites (TFBS) readily observed on the HIV-1 long terminal repeat due to potential impact on human promoters. This study has demonstrated that TFBS on the HIV-1 LTR, specifically NF-κB binding sites, could serve as potential target sites that significantly inactivate HIV-1 transcription. More importantly, these HIV-1-specific gRNAs designed by our custom bioinformatic pipeline did not induce CRISPR-mediated off-target edits in human cells using the genome-wide, unbiased identification of DSBs enabled by sequencing (GUIDE-seq).

Fibrillin-rich microfibrils (FRMs) constitute integral components of the dermal elastic fibre network with a distinctive ultrastructural 'beads-on-a-string' appearance that can be visualised using atomic force microscopy and characterised by measurement of their length and inter-bead periodicity. Their deposition within the dermis in photoprotected skin appears to be contingent on skin ethnicity, and influences the ultrastructure of papillary - but not reticular - dermal FRMs. Truncation and depletion of FRMs at the dermal-epidermal junction of skin occurs early in photoageing in people with lightly pigmented skin; a process of accelerated skin ageing that arises due to chronic sun exposure. Accumulation of ultraviolet radiation (UVR)-induced damage, either by the action of enzymes, oxidation or direct photon absorption, results in FRM remodelling and changes to ultrastructure. In the current study, the direct effect of UVR exposure on FRM ultrastructure was assayed by isolating FRMs from the papillary and reticular dermis of photoprotected buttock skin of individuals of either black African or white Northern European ancestry and exposing them to solar-simulated radiation (SSR). Exposure to SSR resulted in significant reduction in inter-bead periodicity for reticular dermis-derived FRMs across both cohorts. In contrast, papillary dermal FRMs exhibited significantly increased inter-bead periodicity, with the magnitude of damage greater for African FRMs, as compared to Northern European FRMs. Our data suggest that FRMs of the dermis should be considered as two distinct populations that differentially accrue damage in response to SSR. Furthermore, papillary dermal FRMs derived from black African subjects show greater change following UVR challenge, when extracted from skin. Future studies should focus on understanding the consequences of UVR exposure in vivo, regardless of skin ethnicity, on the molecular composition of FRMs and how this UVR-induced remodelling may affect the role FRMs play in skin homeostasis.

Meningiomas are the most common primary intracranial tumors, but the molecular drivers of meningioma tumorigenesis are poorly understood. We hypothesized that investigating intratumor heterogeneity in meningiomas would elucidate biologic drivers and reveal new targets for molecular therapy. To test this hypothesis, here we perform multiplatform molecular profiling of 86 spatially-distinct samples from 13 human meningiomas. Our data reveal that regional alterations in chromosome structure underlie clonal transcriptomic, epigenomic, and histopathologic signatures in meningioma. Stereotactic co-registration of sample coordinates to preoperative magnetic resonance images further suggest that high apparent diffusion coefficient (ADC) distinguishes meningioma regions with proliferating cells enriched for developmental gene expression programs. To understand the function of these genes in meningioma, we develop a human cerebral organoid model of meningioma and validate the high ADC marker genes CDH2 and PTPRZ1 as potential targets for meningioma therapy using live imaging, single cell RNA sequencing, CRISPR interference, and pharmacology., Meningiomas are heterogeneous tumours. Here, the authors analysed genetic, epigenetic, and transcriptomic features across spatially-distinct meningioma samples to identify molecular programs underlying tumorigenesis that can be detected preoperatively using magnetic resonance imaging.

Background A Comprehensive Geriatric Assessment (CGA) has been proposed to assess prognosis and to adapt oncological care in older patients with cancer. However, few biological markers are incorporated in the CGA. Methods This comparative study on older patients with cancer was realized before final therapeutic decision and during a CGA that included biological markers. Our objective study was to know if the serum vitamin B12–C-reactive protein index (BCI) can help to estimate early death and unplanned hospitalization. Associations between BCI and unplanned hospitalization or mortality were analyzed using ordered multivariate logistic regression. Findings We included 621 older cancer adults in outpatient care with a median age of 81 years (range, 70–98 years) from September 2015 to May 2018. In this study, 5.6% of patients died within 3 months, 8.8% had unplanned hospitalization within 1 month, and 11.4% had unplanned hospitalization within 3 months. Hypercobalaminemia was present in 83 patients (13.4%), and 34 patients (5.5%) had BCI >40,000. According to the multivariate analysis, BCI was a prognostic factor of mortality within 3 months and unplanned hospitalizations at 1 and 3 months. Impaired activities of daily living (ADL) and palliative care were also risk factors for mortality within 3 months. Impaired instrumental ADL, low albumin level, and palliative care were risk factors for unplanned hospitalization at 1 month. Interpretation BCI could be routinely added to the CGA process, as part of a pretreatment workup, in order to assess more precisely the frailties and to adapt oncological care in older patients treated for cancer. Implications for Practice Aging comes with an increase of frailties and comorbidities. To identify frailties in older patients with cancer, this study used a Comprehensive Geriatric Assessment, which allowed for the adaptation of each treatment plan in accordance with the individual needs of the patients. However, biological characteristics were not included in this assessment. This study showed that hypercobalaminemia and vitamin B12 -C-reactive protein index may be potential markers for cancer with poor prognosis, particularly in the older population. These biological markers can be used in geriatric oncology and general medicine.

Fusion‐positive rhabdomyosarcoma (FP‐RMS) is an aggressive pediatric cancer. The chromatin factor KDM3A and the downstream transcription factor Ets1 comprise a new epigenetic axis that works together with, as well as independently of, the driver PAX3/FOXO1 oncofusion to upregulate disease‐promoting gene expression and phenotypic properties in FP‐RMS. These findings offer new insights into potential ways to target aggressive properties in this disease., Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and young adults. RMS exists as two major disease subtypes, oncofusion‐negative RMS (FN‐RMS) and oncofusion‐positive RMS (FP‐RMS). FP‐RMS is characterized by recurrent PAX3/7‐FOXO1 driver oncofusions and is a biologically and clinically aggressive disease. Recent studies have revealed FP‐RMS to have a strong epigenetic basis. Epigenetic mechanisms represent potential new therapeutic vulnerabilities in FP‐RMS, but their complex details remain to be defined. We previously identified a new disease‐promoting epigenetic axis in RMS, involving the chromatin factor KDM3A and the Ets1 transcription factor. In the present study, we define the KDM3A and Ets1 FP‐RMS transcriptomes and show that these interface with the recently characterized PAX3/FOXO1‐driven gene expression program. KDM3A and Ets1 positively control numerous known and candidate novel PAX3/FOXO1‐induced RMS‐promoting genes, including subsets under control of PAX3/FOXO1‐associated superenhancers (SE), such as MEST. Interestingly, KDM3A and Ets1 also positively control a number of known and candidate novel FP‐RMS‐promoting, but not PAX3/FOXO1‐dependent, genes. Epistatically, Ets1 is downstream of, and exerts disease‐promoting effects similar to, both KDM3A and PAX3/FOXO1. MEST also manifests disease‐promoting properties in FP‐RMS, and KDM3A and Ets1 each impacts activation of the PAX3/FOXO1‐associated MEST SE. Taken together, our studies show that the KDM3A/Ets1 epigenetic axis plays an important role in disease promotion in FP‐RMS, and provide insight into potential new ways to target aggressive phenotypes in this disease.

Tunneled central venous catheters (TCVCs) are colonized by Gram-positive organisms and form biofilm. Lipoteichoic acid (LTA) is a Gram-positive cell wall component that can be measured in serum. The purpose of this pilot study was to characterize LTA concentrations in hemodialysis (HD) patients with TCVCs compared to other access types and to evaluate biofilm morphology and microbiology in TCVCs removed by clinical decision. The study enrolled patients with TCVCs (18), grafts (19), and fistulas (18). Blood samples were collected before HD, at 30 minutes, 2 hours, and end of HD. Catheters removed by clinical decision were evaluated by scanning electron microscopy (SEM) for biofilm morphology, and portions of the catheter were cultured. LTA was detectable in all samples and concentrations increased significantly in all access types during HD (p0.05 for all comparisons). Patients with TCVCs that had a30% increase in LTA concentration from baseline also had the greatest rate of increase (slope) compared to grafts and fistulas (p = 0.03 and p = 0.04, respectively). Catheters removed by clinical decision (n = 7) and examined by SEM had deposition of fibrin. Cultures revealed polymicrobial colonization. TCVCs had the highest rate of increase of LTA during HD. Further studies to determine the source of LTA in patients with AVG and AVF are warranted.

BackgroundPregnancy is accompanied by immune suppression. We hypothesized that Mycobacterium tuberculosis-specific inflammatory responses used to identify latent tuberculosis infection (LTBI) lose positivity during pregnancy. We also hypothesized that isoniazid preventive therapy (IPT) may revert LTBI diagnoses because of its sterilizing activity.Methods944 women with human immunodeficiency virus infection (HIV) participating in a randomized, double-blind, placebo-controlled study comparing 28 weeks of IPT antepartum versus postpartum, were tested by QuantiFERON-gold-in-tube (QGIT) antepartum and by QGIT and tuberculin skin test (TST) at delivery and postpartum. Serial QGIT positivity was assessed by logistic regression using generalized estimating equations.ResultsFrom entry to delivery, 68 (24%) of 284 QGIT-positive women reverted to QGIT-negative or indeterminate. Of these, 42 (62%) recovered QGIT positivity postpartum. The loss of QGIT positivity during pregnancy was explained by decreased interferon gamma (IFNγ) production in response to TB antigen and/or mitogen. At delivery, LTBI was identified by QGIT in 205 women and by TST in 113 women. Corresponding numbers postpartum were 229 and 122 women. QGIT and TST kappa agreement coefficients were 0.4 and 0.5, respectively. Among QGIT-positive women antepartum or at delivery, 34 (12%) reverted to QGIT-negative after IPT. There were no differences between women who initiated IPT antepartum or postpartum.ConclusionsDecreased IFNγ responses in pregnancy reduced QGIT positivity, suggesting that this test cannot reliably rule out LTBI during pregnancy. TST was less affected by pregnancy, but had lower positivity compared to QGIT at all time points. IPT was associated with loss of QGIT positivity, the potential clinical consequences of which need to be investigated.

In a substantial fraction of cancers TERT promoter (TERTp) mutations drive expression of the catalytic subunit of telomerase, contributing to their proliferative immortality. We conducted a pan-cancer analysis of cell lines and find a TERTp mutation expression signature dominated by epithelial-to-mesenchymal transition and MAPK signaling. These data indicate that TERTp mutants are likely to generate distinctive tumor microenvironments and intercellular interactions. Analysis of high-throughput screening tests of 546 small molecules on cell line growth indicated that TERTp mutants displayed heightened sensitivity to specific drugs, including RAS pathway inhibitors, and we found that inhibition of MEK1 and 2, key RAS/MAPK pathway effectors, inhibited TERT mRNA expression. Consistent with an enrichment of mesenchymal states in TERTp mutants, cell lines and some patient tumors displayed low expression of the central adherens junction protein E-cadherin, and we provide evidence that its expression in these cells is regulated by MEK1/2. Several mesenchymal transcription factors displayed elevated expression in TERTp mutants including ZEB1 and 2, TWIST1 and 2, and SNAI1. Of note, the developmental transcription factor SNAI2/SLUG was conspicuously elevated in a significant majority of TERTp-mutant cell lines, and knock-down experiments suggest that it promotes TERT expression. Implications: Cancers harboring TERT promoter mutations are often more lethal, but the basis for this higher mortality remains unknown. Our study identifies that TERTp mutants, as a class, associate with a distinct gene and protein expression signature likely to impact their biological and clinical behavior and provide new directions for investigating treatment approaches for these cancers.

Although fibrotic stroma forms an integral component of pancreatic diseases, whether fibroblasts programmed by different types of pancreatic diseases are phenotypically distinct remains unknown. Here, we show that fibroblasts isolated from patients with pancreatic ductal adenocarcinoma (PDAC), chronic pancreatitis (CP), periampullary tumors, and adjacent normal (NA) tissue (N = 34) have distinct mRNA and miRNA profiles. Compared with NA fibroblasts, PDAC-associated fibroblasts were generally less sensitive to an antifibrotic stimulus (NPPB) and more responsive to positive regulators of activation such as TGFβ1 and WNT. Of the disease-associated fibroblasts examined, PDAC- and CP-derived fibroblasts shared greatest similarity, yet PDAC-associated fibroblasts expressed higher levels of tenascin C (TNC), a finding attributable to miR-137, a novel regulator of TNC. TNC protein and transcript levels were higher in PDAC tissue versus CP tissue and were associated with greater levels of stromal activation, and conditioned media from TNC-depleted PDAC-associated fibroblasts modestly increased both PDAC cell proliferation and PDAC cell migration, indicating that stromal TNC may have inhibitory effects on PDAC cells. Finally, circulating TNC levels were higher in patients with PDAC compared with CP. Our characterization of pancreatic fibroblast programming as disease-specific has consequences for therapeutic targeting and for the manner in which fibroblasts are used in research. Significance: Primary fibroblasts derived from various types of pancreatic diseases possess and retain distinct molecular and functional characteristics in culture, providing a series of cellular models for treatment development and disease-specific research.

Of the more than 150 ctenophore species, the oceanic ctenophore Eurhamphaea vexilligera is notable for its bright orange-yellow ink, secreted from numerous small vesicles that line its substomodeal comb rows. To date, in situ observations by scuba divers have proved the most fruitful method of observing these animals' natural behavior. We present the results of one such contemporary scuba-based observation of E. vexilligera, conducted in the Gulf Stream waters off the coast of Florida, using high-resolution photography and video. Utilizing underwater camera systems purpose built for filming gelatinous zooplankton, we observed E. vexilligera ink release and swimming behavior in situ. From these data, we describe the timeline and mechanics of E. vexilligera ink release in detail, as well as the animal's different swimming behaviors and resulting ink dispersal patterns. We also describe a rolling swimming behavior, accompanied and possibly facilitated by a characteristic change in overall body shape. These observations provide further insight into the behavioral ecology of this distinctive ctenophore and may serve as the foundation for future kinematic studies.

Studying the biogeography of amphipod crustaceans is of interest because they play an important role at lower trophic levels in ecosystems. Because they lack a planktonic larval stage, it has been hypothesized that marine benthic amphipod crustaceans may have short dispersal distances, high endemicity, and spatial turnover in species composition, and consequently high global species richness. In this study, we examined over 400000 distribution records of 4876 amphipod species, and identified 12 regions of endemicity. The number and percent of endemic species peaked at 30°-35°S and coincided with 3 of these regions of high endemicity: Australia, New Zealand, and southern Africa. Pelagic species of marine amphipod crustaceans were more cosmopolitan than benthic species. The latitudinal patterns of richness (alpha, gamma, and ES50) and species turnover were at least bimodal. Most occurrence records and greater alpha and gamma richness were in mid-latitudes, reflecting sampling bias. Both ES50 and beta diversity had similar richness in the tropics, mid-latitudes, and on the Antarctic shelf around 70°S. These 2 indices exhibited a sharp dip in the deep Southern Ocean at 55°S. ES50 peaked at 30°-35°S and a small dip was apparent near the equator at 5°-10°N. Beta diversity was driven mostly by turnover rather than nestedness. These findings support the need for conservation in each realm of species endemicity—and for amphipods, particularly in Antarctica and the coastal mid-latitudes (30°-35°S) of the Southern Hemisphere.

Subsurface soil acidity is a serious constraint to crop production and is inherently difficult to correct through conventional application of lime. Thus, new approaches to ameliorate subsurface soil acidity are needed. A column leaching experiment was established to determine whether the plant residues, when combined with lime, could facilitate lime dissolution and alkalinity movement down soil columns (10 cm in diameter × 45 cm long) to ameliorate acid subsurface soil layers. Five plant residues from canola (Brassica nappus L.), field pea (Pisum sativum L.), lucerne (Medicago sativa L.), oats (Avena sativa L.) and vetch (Vicia villosa L.) (C/N ratios of 52, 13, 16, 53 and 12, respectively) were mixed with soil (18 g dry matter kg−1) in the top of soil columns (0–10 cm) either limed (target pH 7 in CaCl2) or non-limed and incubated for 3 months at 25°C. Soil columns were leached six times over the 3-month incubation period and destructively sampled at 1 and 3 months for chemical analysis. The soil amended with plant residues created favourable pH gradients and facilitated downward movement of alkalinity when lime was added. However, net increases in pH in the 10–12-cm layer after 3 months were only observed in two non-legume residue-amended treatments (canola and oat residues, 0.22–0.43 pH unit increase), but not in three legume residue-amended treatments (field pea, lucerne and vetch residues), although those treatments had the greatest pH increase in the short term (1 month). In conclusion, surface incorporation of lime in combination with plant residues accelerated the amelioration of subsurface acidity in the immediate zone (10–12 cm) below the amended layer. Canola and oat residues were superior in terms of increased soil pH over a longer term (3 months), possibly due to their higher C/N ratios. Highlights: Can plant residues, combined with lime, facilitate alkalinity movement down soil columns? Few studies have examined leaching, alkalinity movement and pH gradients using agricultural soils. Lucerne and vetch had the greatest pH increase (1 month) but canola and oat persisted (3 months). Alkalinity movement was faster when lime and plant residues were combined than when applied alone.

Objectives Previous studies noted discordance of programmed death‐1 (PD‐1) and one of its ligands (PD‐L1) across patient‐matched primary and metastatic clear cell renal cell carcinoma (ccRCC). There are inconsistencies if the primary or metastatic tumor has higher expression, and whether metastatic tumor expression is associated with patient outcome. Thus, we examined PD‐1 and PD‐L1 in patient‐matched tumors using a large number of ccRCC patients with long follow‐up. Materials and Methods We analyzed PD‐1 and PD‐L1 using immunohistochemistry in patient‐matched primary and metastatic tumors from 110 ccRCC patients. Concordance was assessed among longitudinal metastatic tumors, as well as across patient‐matched primary and metastatic tumors. Cox proportional hazards regression was used to evaluate the associations of metastatic tumor expression with cancer‐specific survival. Results We observed inter‐metastatic tumor heterogeneity of PD‐1 in 25 (69%) of the 36 patients and of PD‐L1 in seven (19%) patients. Concordance between patient‐matched primary and metastatic tumors was 73% (Kappa = 0.16, 95% CI: −0.003‐0.32). Similarly, concordance of PD‐L1 between metastatic and patient‐matched primary tumors was 78% (Kappa = 0.27, 95% CI: 0.09‐0.46). Both markers demonstrated higher expression in primary vs metastatic tumors. Metastatic tumor expression of PD‐1 was significantly associated with metastatic location (P, We examined PD‐1 and PD‐L1 in patient‐matched tumors in a large cohort of ccRCC with long‐term follow‐up. The expression of PD‐1 and PD‐L1 was discordant across patient‐matched ccRCC tumors, with higher expression in primary tumors. Higher PD‐1 expression was associated with metastatic location and lower cancer‐specific survival.

ObjectiveTo investigate baseline use of biologic or targeted synthetic (b/ts) disease-modifying antirheumatic drugs (DMARDs) and COVID-19 outcomes in rheumatoid arthritis (RA).MethodsWe analysed the COVID-19 Global Rheumatology Alliance physician registry (from 24 March 2020 to 12 April 2021). We investigated b/tsDMARD use for RA at the clinical onset of COVID-19 (baseline): abatacept (ABA), rituximab (RTX), Janus kinase inhibitors (JAKi), interleukin 6 inhibitors (IL-6i) or tumour necrosis factor inhibitors (TNFi, reference group). The ordinal COVID-19 severity outcome was (1) no hospitalisation, (2) hospitalisation without oxygen, (3) hospitalisation with oxygen/ventilation or (4) death. We used ordinal logistic regression to estimate the OR (odds of being one level higher on the ordinal outcome) for each drug class compared with TNFi, adjusting for potential baseline confounders.ResultsOf 2869 people with RA (mean age 56.7 years, 80.8% female) on b/tsDMARD at the onset of COVID-19, there were 237 on ABA, 364 on RTX, 317 on IL-6i, 563 on JAKi and 1388 on TNFi. Overall, 613 (21%) were hospitalised and 157 (5.5%) died. RTX (OR 4.15, 95% CI 3.16 to 5.44) and JAKi (OR 2.06, 95% CI 1.60 to 2.65) were each associated with worse COVID-19 severity compared with TNFi. There were no associations between ABA or IL6i and COVID-19 severity.ConclusionsPeople with RA treated with RTX or JAKi had worse COVID-19 severity than those on TNFi. The strong association of RTX and JAKi use with poor COVID-19 outcomes highlights prioritisation of risk mitigation strategies for these people.

Kors et al. reveal that peroxisome–ER associations via the ACBD5-VAPB tether are regulated by phosphorylation and GSK3β in mammalian cells. Phosphorylation sites in the FFAT-like motif of ACBD5 affect the binding to VAPB—and thus peroxisome–ER contact sites—differently., Peroxisomes and the endoplasmic reticulum (ER) cooperate in cellular lipid metabolism. They form membrane contacts through interaction of the peroxisomal membrane protein ACBD5 (acyl-coenzyme A–binding domain protein 5) and the ER-resident protein VAPB (vesicle-associated membrane protein–associated protein B). ACBD5 binds to the major sperm protein domain of VAPB via its FFAT-like (two phenylalanines [FF] in an acidic tract) motif. However, molecular mechanisms, which regulate formation of these membrane contact sites, are unknown. Here, we reveal that peroxisome–ER associations via the ACBD5-VAPB tether are regulated by phosphorylation. We show that ACBD5-VAPB binding is phosphatase-sensitive and identify phosphorylation sites in the flanking regions and core of the FFAT-like motif, which alter interaction with VAPB—and thus peroxisome–ER contact sites—differently. Moreover, we demonstrate that GSK3β (glycogen synthase kinase-3 β) regulates this interaction. Our findings reveal for the first time a molecular mechanism for the regulation of peroxisome–ER contacts in mammalian cells and expand the current model of FFAT motifs and VAP interaction.

Background Transthyretin amyloid cardiomyopathy results from the accumulation of wild-type (ATTRwt) or variant (ATTRv) transthyretin amyloid fibrils in the myocardium. THAOS (Transthyretin Amyloidosis Outcomes Survey) is a global, longitudinal, observational survey of patients with ATTRv and ATTRwt amyloidosis and asymptomatic patients with transthyretin mutations. Objectives This study explored temporal trends in ATTRwt amyloidosis diagnoses using data from THAOS. Methods Using THAOS data from December 2007 to January 2020, the following comparisons were made according to year: ATTRwt amyloidosis diagnoses in the United States versus rest of the world, ATTRwt versus ATTRv amyloidosis with cardiac-associated mutations diagnoses, and ATTRwt amyloidosis diagnoses by tissue biopsy versus bone scintigraphy. Results There were 1,069 patients with ATTRwt amyloidosis and 525 with ATTRv amyloidosis with cardiac mutations enrolled in THAOS. The median time from symptom onset to ATTRwt amyloidosis diagnosis did not change over the past 5 years (>60 months from 2015–2019). ATTRwt amyloidosis diagnoses increased from 2 in 2005 to >100 per year from 2016, with a more pronounced increase in the United States compared with the rest of the world. Diagnoses of ATTRwt amyloidosis by tissue biopsy increased yearly and peaked in 2014 before declining, whereas diagnoses by bone scintigraphy increased markedly since 2011. ATTRv amyloidosis with cardiac mutation diagnoses increased from 3 in 2005 to 37 in 2011, then plateaued. The proportion of patients with ATTRwt amyloidosis diagnosed with New York Heart Association functional class III/IV heart failure decreased from 2012 (46.4%) to 2019 (16.0%). Conclusions In the past decade, ATTRwt amyloidosis diagnoses increased worldwide. Despite the growing utilization of bone scintigraphy, patients are diagnosed several years after symptom onset. (Transthyretin Amyloidosis Outcomes Survey [THAOS]; NCT00628745), Central Illustration

Background Intratumoral heterogeneity is a hallmark of diffuse gliomas. DNA methylation profiling is an emerging approach in the clinical classification of brain tumors. The goal of this study is to investigate the effects of intratumoral heterogeneity on classification confidence. Methods We used neuronavigation to acquire 133 image-guided and spatially separated stereotactic biopsy samples from 16 adult patients with a diffuse glioma (7 IDH-wildtype and 2 IDH-mutant glioblastoma, 6 diffuse astrocytoma, IDH-mutant and 1 oligodendroglioma, IDH-mutant and 1p19q codeleted), which we characterized using DNA methylation arrays. Samples were obtained from regions with and without abnormalities on contrast-enhanced T1-weighted and fluid-attenuated inversion recovery MRI. Methylation profiles were analyzed to devise a 3-dimensional reconstruction of (epi)genetic heterogeneity. Tumor purity was assessed from clonal methylation sites. Results Molecular aberrations indicated that tumor was found outside imaging abnormalities, underlining the infiltrative nature of this tumor and the limitations of current routine imaging modalities. We demonstrate that tumor purity is highly variable between samples and explains a substantial part of apparent epigenetic spatial heterogeneity. We observed that DNA methylation subtypes are often, but not always, conserved in space taking tumor purity and prediction accuracy into account. Conclusion Our results underscore the infiltrative nature of diffuse gliomas and suggest that DNA methylation subtypes are relatively concordant in this tumor type, although some heterogeneity exists.

After decades during which the treatment of acute myeloblastic leukemia was limited to variations around a skeleton of cytarabine/anthracycline, targeted therapies appeared. These therapies, first based on monoclonal antibodies, also rely on specific inhibitors of various molecular abnormalities. A significant but modest prognosis improvement has been observed thanks to these new treatments that are limited by a high rate of relapse, due to the intrinsic chemo and immune-resistance of leukemia stem cell, together with the acquisition of these resistances by clonal evolution. Relapses are also influenced by the equilibrium between the pro or anti-tumor signals from the bone marrow stromal microenvironment and immune effectors. What should be the place of the targeted therapeutic options in light of the tumor heterogeneity inherent to leukemia and the clonal drift of which this type of tumor is capable? Novel approaches by single cell analysis and next generation sequencing precisely define clonal heterogeneity and evolution, leading to a personalized and time variable adapted treatment. Indeed, the evolution of leukemia, either spontaneous or under therapy selection pressure, is a very complex phenomenon. The model of linear evolution is to be forgotten because single cell analysis of samples at diagnosis and at relapse show that tumor escape to therapy occurs from ancestral as well as terminal clones. The determination by the single cell technique of the trajectories of the different tumor sub-populations allows the identification of clones that accumulate factors of resistance to chemo/immunotherapy (“pan-resistant clones”), making possible to choose the combinatorial agents most likely to eradicate these cells. In addition, the single cell technique identifies the nature of each cell and can analyze, on the same sample, both the tumor cells and their environment. It is thus possible to evaluate the populations of immune effectors (T-lymphocytes, natural killer cells) for the leukemia stress-induced alteration of their functions. Finally, the single cells techniques are an invaluable tool for evaluation of the measurable residual disease since not only able to quantify but also to determine the most appropriate treatment according to the sensitivity profile to immuno-chemotherapy of remaining leukemic cells.

This economic evaluation examines national retail sales of alcohol and cannabis before and during the COVID-19 pandemic in Canada.

Highlights • A multi-frequency study of ultrasound (US) and nisin for microbial inactivation. • US impacts E. coli at 500 kHz only; L. innocua resists all frequencies studied. • Nisin applied before US enhances inactivation of E. coli but not when applied after. • Attributed to outer membrane destabilisation by US allowing nisin penetration. • System structure (viscosity) reduces US inactivation efficacy., Ultrasound, alone or in combination with natural antimicrobials, is a novel food processing technology of interest to replace traditional food decontamination methods, as it is milder than classical sterilisation (heat treatment) and maintains desirable sensory characteristics. However, ultrasound efficacy can be affected by food structure/composition, as well as the order in which combined treatments are applied. More specifically, treatments which target different cell components could result in enhanced inactivation if applied in the appropriate order. The microbial properties i.e. Gram positive/Gram negative can also impact the treatment efficacy. This work presents a systematic study of the combined effect of ultrasound and nisin on the inactivation of the bacteria Listeria innocua (Gram positive) and Escherichia coli (Gram negative), at a range of cavitation conditions (44, 500, 1000 kHz). The order of treatment application was varied, and the impact of system structure was also investigated by varying the concentration of Xanthan gum used to create the food model systems (0 – 0.5% w/v). Microbial inactivation kinetics were monitored, and advanced microscopy and flow cytometry techniques were utilised to quantify the impact of treatment on a cellular level. Ultrasound was shown to be effective against E. coli at 500 kHz only, with L. innocua demonstrating resistance to all frequencies studied. Enhanced inactivation of E. coli was observed for the combination of nisin and ultrasound at 500 kHz, but only when nisin was applied before ultrasound treatment. The system structure negatively impacted the inactivation efficacy. The combined effect of ultrasound and nisin on E. coli was attributed to short-lived destabilisation of the outer membrane as a result of sonication, allowing nisin to penetrate the cytoplasmic membrane and facilitate cell inactivation.

Background: The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC etiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNP) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported. Methods: We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analyzed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using Multi-marker Analysis of GenoMic Annotation (MAGMA) software. Results: In the discovery phase, we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk (P < 0.05). In the second phase, none of the findings were replicated. In the gene-level analysis, we observed that three genes (TERT, SUGCT, and SURF1) involved in the mitochondrial metabolism showed an association below the Bonferroni-corrected threshold of statistical significance (P = 0.05/1588 = 3.1 × 10−5). Conclusions: Even though the mitochondrial metabolism might be involved in PDAC etiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk. Impact: This large case–control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk.

Although pancreatic ductal adenocarcinoma (PDAC) survival is poor, there are differences in patients’ response to the treatments. Detection of predictive biomarkers explaining these differences is of the utmost importance. In a recent study two genetic markers (CD44-rs353630 and CHI3L2-rs684559) were reported to be associated with survival after PDAC resection. We attempted to replicate the associations in 1856 PDAC patients (685 resected with stage I/II) from the PANcreatic Disease ReseArch (PANDoRA) consortium. We also analysed the combined effect of the two genotypes in order to compare our results with what was previously reported. Additional stratified analyses considering TNM stage of the disease and whether the patients received surgery were also performed. We observed no statistically significant associations, except for the heterozygous carriers of CD44-rs353630, who were associated with worse OS (HR = 5.01; 95% CI 1.58–15.88; p = 0.006) among patients with stage I disease. This association is in the opposite direction of those reported previously, suggesting that data obtained in such small subgroups are hardly replicable and should be considered cautiously. The two polymorphisms combined did not show any statistically significant association. Our results suggest that the effect of CD44-rs353630 and CHI3L2-rs684559 cannot be generalized to all PDAC patients.

Extra-embryonic mesoderm (ExM)-composed of the earliest cells that traverse the primitive streak-gives rise to the endothelium as well as haematopoietic progenitors in the developing yolk sac. How a specific subset of ExM becomes committed to a haematopoietic fate remains unclear. Here we demonstrate using an embryonic stem cell model that transient expression of the T-box transcription factor Eomesodermin (Eomes) governs haemogenic competency of ExM. Eomes regulates the accessibility of enhancers that the transcription factor stem cell leukaemia (SCL) normally utilizes to specify primitive erythrocytes and is essential for the normal development of Runx1+ haemogenic endothelium. Single-cell RNA sequencing suggests that Eomes loss of function profoundly blocks the formation of blood progenitors but not specification of Flk-1+ haematoendothelial progenitors. Our findings place Eomes at the top of the transcriptional hierarchy regulating early blood formation and suggest that haemogenic competence is endowed earlier during embryonic development than was previously appreciated.

SUMMARY Precision oncology uses genomic evidence to match patients with treatment but often fails to identify all patients who may respond. The transcriptome of these “hidden responders” may reveal responsive molecular states. We describe and evaluate a machine-learning approach to classify aberrant pathway activity in tumors, which may aid in hidden responder identification. The algorithm integrates RNA-seq, copy number, and mutations from 33 different cancer types across The Cancer Genome Atlas (TCGA) PanCanAtlas project to predict aberrant molecular states in tumors. Applied to the Ras pathway, the method detects Ras activation across cancer types and identifies phenocopying variants. The model, trained on human tumors, can predict response to MEK inhibitors in wild-type Ras cell lines. We also present data that suggest that multiple hits in the Ras pathway confer increased Ras activity. The transcriptome is underused in precision oncology and, combined with machine learning, can aid in the identification of hidden responders., In Brief Way et al. develop a machine-learning approach using PanCanAtlas data to detect Ras activation in cancer. Integrating mutation, copy number, and expression data, the authors show that their method detects Ras-activating variants in tumors and sensitivity to MEK inhibitors in cell lines.

The application of aptamers in biomedicine is emerging as an essential technology in the field of cancer research. As small single-stranded DNA or RNA ligands with high specificity and low immunogenicity for their targets, aptamers provide many advantages in cancer therapeutics over protein-based molecules, such as antibodies. Vimentin is an intermediate filament protein that is overexpressed in endothelial cells of cancerous tissue. High expression levels of vimentin have been associated with increased capacity for migration and invasion of the tumor cells. We have selected and identified thioated aptamers with high specificity for vimentin using human ovarian cancer tissues. Tentative binding motifs were chosen for two vimentin aptamers based on predicted secondary structures. Each of these shorter, tentative binding motifs was synthesized, purified, and characterized via cell binding assays. Two vimentin binding motifs with high fidelity binding were selected and further characterized via cell and tissue binding assays, as well as flow cytometric analysis. The equilibrium binding constants of these small thioated aptamer constructs were also determined. Future applications for the vimentin binding aptamer motifs include conjugation of the aptamers to synthetic dyes for use in targeted imaging and therapy, and ultimately more detailed and precise monitoring of treatment response and tumor progression in ovarian pathology.