Au-Pd separation enhances bimetallic catalysis of alcohol oxidation.

In oxidation reactions catalysed by supported metal nanoparticles with oxygen as the terminal oxidant, the rate of the oxygen reduction can be a limiting factor. This is exemplified by the oxidative dehydrogenation of alcohols, an important class of reactions with modern commercial applications1-3. Supported gold nanoparticles are highly active for the dehydrogenation of the alcohol to an aldehyde4 but are less effective for oxygen reduction5,6. By contrast, supported palladium nanoparticles offer high efficacy for oxygen reduction5,6. This imbalance can be overcome by alloying gold with palladium, which gives enhanced activity to both reactions7,8,9; however, the electrochemical potential of the alloy is a compromise between that of the two metals, meaning that although the oxygen reduction can be improved in the alloy, the dehydrogenation activity is often limited. Here we show that by separating the gold and palladium components in bimetallic carbon-supported catalysts, we can almost double the reaction rate compared with that achieved with the corresponding alloy catalyst. We demonstrate this using physical mixtures of carbon-supported monometallic gold and palladium catalysts and a bimetallic catalyst comprising separated gold and palladium regions. Furthermore, we demonstrate electrochemically that this enhancement is attributable to the coupling of separate redox processes occurring at isolated gold and palladium sites. The discovery of this catalytic effect-a cooperative redox enhancement-offers an approach to the design of multicomponent heterogeneous catalysts.

Phosphoregulation of Phase Separation by the SARS-CoV-2 N Protein Suggests a Biophysical Basis for its Dual Functions.

The nucleocapsid (N) protein of coronaviruses serves two major functions: compaction of the RNA genome in the virion and regulation of viral gene transcription. It is not clear how the N protein mediates such distinct functions. The N protein contains two RNA-binding domains surrounded by regions of intrinsic disorder. Phosphorylation of the central disordered region promotes the protein's transcriptional function, but the underlying mechanism is not known. Here, we show that the N protein of SARS-CoV-2, together with viral RNA, forms biomolecular condensates. Unmodified N protein forms partially ordered gel-like condensates and discrete 15-nm particles based on multivalent RNA-protein and protein-protein interactions. Phosphorylation reduces these interactions, generating a more liquid-like droplet. We propose that distinct oligomeric states support the two functions of the N protein: unmodified protein forms a structured oligomer that is suited for nucleocapsid assembly, and phosphorylated protein forms a liquid-like compartment for viral genome processing.

Structural basis of human separase regulation by securin and CDK1-cyclin B1.

In early mitosis, the duplicated chromosomes are held together by the ring-shaped cohesin complex1. Separation of chromosomes during anaphase is triggered by separase-a large cysteine endopeptidase that cleaves the cohesin subunit SCC1 (also known as RAD212-4). Separase is activated by degradation of its inhibitors, securin5 and cyclin B6, but the molecular mechanisms of separase regulation are not clear. Here we used cryogenic electron microscopy to determine the structures of human separase in complex with either securin or CDK1-cyclin B1-CKS1. In both complexes, separase is inhibited by pseudosubstrate motifs that block substrate binding at the catalytic site and at nearby docking sites. As in Caenorhabditis elegans7 and yeast8, human securin contains its own pseudosubstrate motifs. By contrast, CDK1-cyclin B1 inhibits separase by deploying pseudosubstrate motifs from intrinsically disordered loops in separase itself. One autoinhibitory loop is oriented by CDK1-cyclin B1 to block the catalytic sites of both separase and CDK19,10. Another autoinhibitory loop blocks substrate docking in a cleft adjacent to the separase catalytic site. A third separase loop contains a phosphoserine6 that promotes complex assembly by binding to a conserved phosphate-binding pocket in cyclin B1. Our study reveals the diverse array of mechanisms by which securin and CDK1-cyclin B1 bind and inhibit separase, providing the molecular basis for the robust control of chromosome segregation.

The hidden rhythms of the dividing cell.

The cell divides in a series of discrete steps that occur in a specific order. Lu and Cross (2010) now propose that cell-cycle events are ordered by a regulatory system in which a master oscillator, based on cyclin-dependent kinases, entrains a series of peripheral oscillators controlling individual events.

α-Adrenergic regulation of skeletal muscle blood flow during exercise in patients with heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) has been characterized by lower blood flow to exercising limbs and lower peak oxygen utilization ( V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ ), possibly associated with disease-related changes in sympathetic (α-adrenergic) signaling. Thus, in seven patients with HFpEF (70 ± 6 years, 3 female/4 male) and seven controls (CON) (66 ± 3 years, 3 female/4 male), we examined changes (%Δ) in leg blood flow (LBF, Doppler ultrasound) and leg V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ to intra-arterial infusion of phentolamine (PHEN, α-adrenergic antagonist) or phenylephrine (PE, α1-adrenergic agonist) at rest and during single-leg knee-extension exercise (0, 5 and 10 W). At rest, the PHEN-induced increase in LBF was not different between groups, but PE-induced reductions in LBF were lower in HFpEF (-16% ± 4% vs. -26% ± 5%, HFpEF vs. CON; P < 0.05). During exercise, the PHEN-induced increase in LBF was greater in HFpEF at 10 W (16% ± 8% vs. 8% ± 5%; P < 0.05). PHEN increased leg V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ in HFpEF (10% ± 3%, 11% ± 6%, 15% ± 7% at 0, 5 and 10 W; P < 0.05) but not in controls (-1% ± 9%, -4% ± 2%, -1% ± 5%; P = 0.24). The 'magnitude of sympatholysis' (PE-induced %Δ LBF at rest - PE-induced %Δ LBF during exercise) was lower in patients with HFpEF (-6% ± 4%, -6% ± 6%, -7% ± 5% vs. -13% ± 6%, -17% ± 5%, -20% ± 5% at 0, 5 and 10 W; P < 0.05) and was positively related to LBF, leg oxygen delivery, leg V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ , and the PHEN-induced increase in LBF (P < 0.05). Together, these data indicate that excessive α-adrenergic vasoconstriction restrains blood flow and limits V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ of the exercising leg in patients with HFpEF, and is related to impaired functional sympatholysis in this patient group. KEY POINTS: Sympathetic (α-adrenergic)-mediated vasoconstriction is exaggerated during exercise in patients with heart failure with preserved ejection fraction (HFpEF), which may contribute to limitations of blood flow, oxygen delivery and oxygen utilization in the exercising muscle. The ability to adequately attenuate α1-adrenergic vasoconstriction (i.e. functional sympatholysis) within the vasculature of the exercising muscle is impaired in patients with HFpEF. These observations extend our current understanding of HFpEF pathophysiology by implicating excessive α-adrenergic restraint and impaired functional sympatholysis as important contributors to disease-related impairments in exercising muscle blood flow and oxygen utilization in these patients.

Assembly of SARS-CoV-2 ribonucleosomes by truncated N∗ variant of the nucleocapsid protein.

The nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compacts the RNA genome into viral ribonucleoprotein (vRNP) complexes within virions. Assembly of vRNPs is inhibited by phosphorylation of the N protein serine/arginine (SR) region. Several SARS-CoV-2 variants of concern carry N protein mutations that reduce phosphorylation and enhance the efficiency of viral packaging. Variants of the dominant B.1.1 viral lineage also encode a truncated N protein, termed N∗ or Δ(1-209), that mediates genome packaging despite lacking the N-terminal RNA-binding domain and SR region. Here, we use mass photometry and negative stain electron microscopy to show that purified Δ(1-209) and viral RNA assemble into vRNPs that are remarkably similar in size and shape to those formed with full-length N protein. We show that assembly of Δ(1-209) vRNPs requires the leucine-rich helix of the central disordered region and that this helix promotes N protein oligomerization. We also find that fusion of a phosphomimetic SR region to Δ(1-209) inhibits RNA binding and vRNP assembly. Our results provide new insights into the mechanisms by which RNA binding promotes N protein self-association and vRNP assembly, and how this process is modulated by phosphorylation.

Temporal relationships between Staphylococcus aureus colonization, filaggrin expression, and pediatric atopic dermatitis.

BACKGROUND: Atopic dermatitis (AD) is characterized by Staphylococcus aureus (S. aureus) colonization. Longitudinal early life data delineating relationships of S. aureus colonization, barrier function, and AD outcomes are lacking. We define longitudinal S. aureus endotypes and AD pathogenesis in early life. METHODS: We defined longitudinal S. aureus skin colonization phenotypes across two annual visits (non-colonized: V1- V2- , early transient: V1+ V2- , late-onset: V1- V2+ , persistent: V1+ V2+ ) in the Mechanisms of Progression of Atopic Dermatitis to Asthma in Children cohort. We analyzed AD severity, sensitization, and skin barrier function across phenotypes, and performed mediation analyses between colonization and FLG expression. RESULTS: Persistent S. aureus colonization was associated with increased SCORAD at V1 (33.5 vs. 19.0, p = .004) and V2 (40.1 vs.16.9, p < .001), and lower non-lesional (NL) FLG at V2 (1.77 vs. 4.09, p = .029) compared to the non-colonized phenotype, with early transient and late-onset colonization as intermediate phenotypes. Children colonized at V2 demonstrated a decrease in NL-FLG expression from V1 to V2 compared to those non-colonized at V2 (p = .0012), who maintained expression. This effect remained significant even after adjusting for V1 colonization and SCORAD (p = .011). CONCLUSIONS: Our findings are the first to present longitudinal quantitative FLG expression and S. aureus skin colonization in early life and suggest that a decrease in NL-FLG drives later colonization. Hence, therapies to maintain NL-FLG expression may prevent S. aureus colonization. Further, a longitudinal AD endotype of persistent colonization is characterized by increased AD severity, sensitization, and decreasing NL-FLG.

Long-term climatic stability drives accumulation and maintenance of divergent freshwater fish lineages in a temperate biodiversity hotspot.

Anthropogenic climate change is forecast to drive regional climate disruption and instability across the globe. These impacts are likely to be exacerbated within biodiversity hotspots, both due to the greater potential for species loss but also to the possibility that endemic lineages might not have experienced significant climatic variation in the past, limiting their evolutionary potential to respond to rapid climate change. We assessed the role of climatic stability on the accumulation and persistence of lineages in an obligate freshwater fish group endemic to the southwest Western Australia (SWWA) biodiversity hotspot. Using 19,426 genomic (ddRAD-seq) markers and species distribution modelling, we explored the phylogeographic history of western (Nannoperca vittata) and little (Nannoperca pygmaea) pygmy perches, assessing population divergence and phylogenetic relationships, delimiting species and estimating changes in species distributions from the Pliocene to 2100. We identified two deep phylogroups comprising three divergent clusters, which showed no historical connectivity since the Pliocene. We conservatively suggest these represent three isolated species with additional intraspecific structure within one widespread species. All lineages showed long-term patterns of isolation and persistence owing to climatic stability but with significant range contractions likely under future climate change. Our results highlighted the role of climatic stability in allowing the persistence of isolated lineages in the SWWA. This biodiversity hotspot is under compounding threat from ongoing climate change and habitat modification, which may further threaten previously undetected cryptic diversity across the region.

Monsoonal wet season influences the migration tendency of a catadromous fish (barramundi Lates calcarifer).

Many animals exhibit partial migration, which occurs when populations contain coexisting contingents of migratory and resident individuals. This individual-level variation in migration behaviour may drive differences in growth, age at maturity and survival. Therefore, partial migration is widely considered to play a key role in shaping population demography. Otolith chemistry and microstructural analysis were used to identify the environmental- and individual-specific factors that influence migratory behaviour in the facultatively catadromous barramundi (Lates calcarifer) at two distinct life history stages: firstly, as juveniles migrating upstream into fresh water; and secondly, as adults or sub-adults returning to the estuarine/marine spawning habitat. Monsoonal climate played an important role in determining the migration propensity of juveniles: individuals born in the driest year examined (weak monsoon) were more than twice as likely to undergo migration to freshwater than those born in the wettest (strong monsoon) year. In contrast, the ontogenetic timing of return migrations to the estuary by adults and sub-adults was highly variable and not strongly associated with the environmental parameters examined. We propose that scarce resources within saline natal habitats during lower rainfall years may provide an ecological incentive for juveniles to migrate upstream, whereas more abundant resources in higher rainfall years may promote resident life histories within estuaries. We conclude that inter-annual climatic variation, here evidenced by monsoonal strength, likely plays an important role in driving the persistence of diversified life histories within wild barramundi populations.

Effects of coastal development on sawfish movements and the need for marine animal crossing solutions.

Although human-made barriers to animal movement are ubiquitous across many types of ecosystems, the science behind these barriers and how to ameliorate their effects lags far behind in marine environments compared with terrestrial and freshwater realms. Using juvenile sawfish in an Australian nursery habitat as a model system, we aimed to assess the effects of a major anthropogenic development on the movement behavior of coastal species. We compared catch rates and movement behavior (via acoustic telemetry) of juvenile green sawfish (Pristis zijsron) before and after a major coastal structure was built in an important nursery habitat. Acoustic tracking and catch data showed that the development did not affect levels of sawfish recruitment in the nursery, but it did constrain movements of juveniles moving throughout the nursery, demonstrating the reluctance of shoreline-associated species to travel around large or unfamiliar coastal structures. Given the current lack of information on human-made movement barriers in the marine environment, these findings highlight the need for further research in this area, and we propose the development of and experimentation with marine animal crossings as an important area of emerging research.

Efectos del desarrollo costero sobre los movimientos del pez sierra y la necesidad de soluciones para el cruce de animales marinos Resumen Mientras que las barreras construidas por humanos que limitan el movimiento de animales son ubicuas en muchos tipos de ecosistemas, la ciencia que sustenta estas barreras y la reducción de sus impactos está muy retrasada en ambientes marinos en comparación con medios terrestres y dulceacuícolas. Utilizando peces sierra juveniles en un hábitat de vivero australiano como sistema modelo, intentamos evaluar los efectos de un importante desarrollo antropogénico sobre el comportamiento de especies costeras. Comparamos las tasas de captura y el comportamiento de movimiento (mediante telemetría acústica) de peces sierra verdes juveniles (Pristis zijsron) antes y después de que se construyera infraestructura costera en un importante hábitat de vivero. El seguimiento acústico y los datos de captura mostraron que el desarrollo no afectó los niveles de reclutamiento de pez sierra en el vivero, pero sí restringió los movimientos de los juveniles desplazándose por el vivero, lo cual demuestra la renuencia de las especies asociadas a la costa a viajar alrededor de estructuras costeras grandes o desconocidas. Dada la actual falta de información sobre las barreras de movimiento creadas por el hombre en el medio marino, estos hallazgos destacan la necesidad de realizar más investigaciones en esta campo, y proponemos el desarrollo y la experimentación con cruces para animales marinos como un área importante de investigación emergente.

Building a Regulatory Network with Short Linear Sequence Motifs: Lessons from the Degrons of the Anaphase-Promoting Complex.

The anaphase-promoting complex or cyclosome (APC/C) is a ubiquitin ligase that polyubiquitinates specific substrates at precise times in the cell cycle, thereby triggering the events of late mitosis in a strict order. The robust substrate specificity of the APC/C prevents the potentially deleterious degradation of non-APC/C substrates and also averts the cell-cycle errors and genomic instability that could result from mistimed degradation of APC/C targets. The APC/C recognizes short linear sequence motifs, or degrons, on its substrates. The specific and timely modification and degradation of APC/C substrates is likely to be modulated by variations in degron sequence and context. We discuss the extensive affinity, specificity, and selectivity determinants encoded in APC/C degrons, and we describe some of the extrinsic mechanisms that control APC/C-substrate recognition. As an archetype for protein motif-driven regulation of cell function, the APC/C-substrate interaction provides insights into the general properties of post-translational regulatory systems.

Socioecological factors influencing intraspecific variation in ranging dynamics of western lowland gorillas (Gorilla gorilla gorilla) in Ndoki Forest.

Ranging dynamics are physical and behavioral representations of how different socioecological factors affect an organism's spatial decisions and space use strategies. Western lowland gorillas (Gorilla gorilla gorilla) are a model species to investigate the drivers of spatial dynamics based on both the natural variation in socioecological factors within the species and compared with their mountain gorilla counterparts. In this study, we evaluate the influences of resource seasonality and social dynamics on variation in home range size, utilization, and intergroup overlap among multiple gorilla groups over an 8-year study period in the northern Republic of Congo. This study shows that western lowland gorillas can have small home ranges comparable to mountain gorillas, rather than universally larger home ranges as previously supposed, and that home ranges are stable through time. The largest source of variation in space use was the degree of intergroup home range overlap. The study groups did not demonstrate intraspecific variation in range size nor changes in intergroup overlap with respect to seasonality of fruit resources, but all groups demonstrated expansion of monthly range and core area with group size, matching predictions of intragroup feeding competition. These findings highlight the potential impact of intergroup relationships on space use and prompt further research on the role of social dynamics in ranging strategies. In this study, we reveal a greater degree of variability and flexibility in gorilla ranging behavior than previously realized which is relevant to improving comparative studies and informing conservation strategies on behalf of these endangered primates.

Transgenic amyloid precursor protein mouse models of amyloidosis. Incomplete models for Alzheimer's disease but effective predictors of anti-amyloid therapies.

INTRODUCTION: Amyloid precursor protein (APP) transgenic mice are models of Alzheimer's disease (AD) amyloidosis, not all of AD. Diffuse, compacted, and vascular deposits in APP mice mimic those found in AD cases. METHODS: Most interventional studies in APP mice start treatment early in the process of amyloid deposition, consistent with a prevention treatment regimen. Most clinical trials treat patients with established amyloid deposits in a therapeutic treatment regimen. RESULTS: The first treatment to reduce amyloid and cognitive impairment in mice was immunotherapy. The APP mouse models not only predicted efficacy, but presaged the vascular leakage called ARIA. The recent immunotherapy clinical trials that removed amyloid and slowed cognitive decline confirms the utility of these early APP models when used in therapeutic designs. DISCUSSION: New mouse models of AD pathologies will add to the research armamentarium, but the early models have accurately predicted responses to amyloid therapies in humans.

Blood-based biomarkers for Alzheimer's disease and cognitive function from mid- to late life.

INTRODUCTION: We investigated associations of Alzheimer's disease (AD) serum biomarkers with longitudinal changes in cognitive function from mid- to late life among women. METHODS: The study population included 192 women with the median age of 53.3 years at baseline, from the Study of Women's Health Across the Nation Michigan Cohort, followed up over 14 years. Associations between baseline serum amyloid ß (Aß)42, the Aß42/40 ratio, phosphorylated tau181 (p-tau181), and total tau with longitudinal changes in cognition were evaluated using linear mixed effects models. RESULTS: After adjusting for confounders, lower Aß42/40 ratios were associated with faster declines in the Digit Span Backward Test. Higher p-tau181 also showed a borderline statistically significant association with more rapid decline in the Symbol Digit Modalities Test. DISCUSSION: Our findings suggest that mid-life serum AD biomarkers could be associated with accelerated cognitive decline from mid- to late life in women. Future studies with larger samples are needed to validate and extend our findings. HIGHLIGHTS: This study investigates midlife serum AD biomarkers on longitudinal cognitive function changes in women. Mid-life serum AD biomarkers are associated with accelerated cognitive decline. A decrease in the Aß42/40 ratio was associated with a faster decline in the DSB score. A higher p-tau181 concentration was associated with a faster decline in the SDMT score.

Reconstitution of the SARS-CoV-2 ribonucleosome provides insights into genomic RNA packaging and regulation by phosphorylation.

The nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 is responsible for compaction of the ∼30-kb RNA genome in the ∼90-nm virion. Previous studies suggest that each virion contains 35 to 40 viral ribonucleoprotein (vRNP) complexes, or ribonucleosomes, arrayed along the genome. There is, however, little mechanistic understanding of the vRNP complex. Here, we show that N protein, when combined in vitro with short fragments of the viral genome, forms 15-nm particles similar to the vRNP structures observed within virions. These vRNPs depend on regions of N protein that promote protein-RNA and protein-protein interactions. Phosphorylation of N protein in its disordered serine/arginine region weakens these interactions to generate less compact vRNPs. We propose that unmodified N protein binds structurally diverse regions in genomic RNA to form compact vRNPs within the nucleocapsid, while phosphorylation alters vRNP structure to support other N protein functions in viral transcription.

Lithium-Directed Transformation of Amorphous Iridium (Oxy)hydroxides To Produce Active Water Oxidation Catalysts.

The oxygen evolution reaction (OER) is crucial to future energy systems based on water electrolysis. Iridium oxides are promising catalysts due to their resistance to corrosion under acidic and oxidizing conditions. Highly active iridium (oxy)hydroxides prepared using alkali metal bases transform into low activity rutile IrO2 at elevated temperatures (>350 °C) during catalyst/electrode preparation. Depending on the residual amount of alkali metals, we now show that this transformation can result in either rutile IrO2 or nano-crystalline Li-intercalated IrOx. While the transition to rutile results in poor activity, the Li-intercalated IrOx has comparative activity and improved stability when compared to the highly active amorphous material despite being treated at 500 °C. This highly active nanocrystalline form of lithium iridate could be more resistant to industrial procedures to produce PEM membranes and provide a route to stabilize the high populations of redox active sites of amorphous iridium (oxy)hydroxides.

Monocyte migration profiles define disease severity in acute COVID-19 and unique features of long COVID.

BACKGROUND: COVID-19 is associated with a dysregulated immune response but it is unclear how immune dysfunction contributes to the chronic morbidity persisting in many COVID-19 patients during convalescence (long COVID). METHODS: We assessed phenotypical and functional changes of monocytes in COVID-19 patients during hospitalisation and up to 9 months of convalescence following COVID-19, respiratory syncytial virus or influenza A. Patients with progressive fibrosing interstitial lung disease were included as a positive control for severe, ongoing lung injury. RESULTS: Monocyte alterations in acute COVID-19 patients included aberrant expression of leukocyte migration molecules, continuing into convalescence (n=142) and corresponding with specific symptoms of long COVID. Long COVID patients with unresolved lung injury, indicated by sustained shortness of breath and abnormal chest radiology, were defined by high monocyte expression of C-X-C motif chemokine receptor 6 (CXCR6) (p<0.0001) and adhesion molecule P-selectin glycoprotein ligand 1 (p<0.01), alongside preferential migration of monocytes towards the CXCR6 ligand C-X-C motif chemokine ligand 16 (CXCL16) (p<0.05), which is abundantly expressed in the lung. Monocyte CXCR6 and lung CXCL16 were heightened in patients with progressive fibrosing interstitial lung disease (p<0.001), confirming a role for the CXCR6-CXCL16 axis in ongoing lung injury. Conversely, monocytes from long COVID patients with ongoing fatigue exhibited a sustained reduction of the prostaglandin-generating enzyme cyclooxygenase 2 (p<0.01) and CXCR2 expression (p<0.05). These monocyte changes were not present in respiratory syncytial virus or influenza A convalescence. CONCLUSIONS: Our data define unique monocyte signatures that define subgroups of long COVID patients, indicating a key role for monocyte migration in COVID-19 pathophysiology. Targeting these pathways may provide novel therapeutic opportunities in COVID-19 patients with persistent morbidity.

The molecular mechanisms of human separase regulation.

Sister chromatid segregation is the final irreversible step of mitosis. It is initiated by a complex regulatory system that ultimately triggers the timely activation of a conserved cysteine protease named separase. Separase cleaves the cohesin protein ring that links the sister chromatids and thus facilitates their separation and segregation to the opposite poles of the dividing cell. Due to the irreversible nature of this process, separase activity is tightly controlled in all eukaryotic cells. In this mini-review, we summarize the latest structural and functional findings on the regulation of separase, with an emphasis on the regulation of the human enzyme by two inhibitors, the universal inhibitor securin and the vertebrate-specific inhibitor CDK1-cyclin B. We discuss the two fundamentally different inhibitory mechanisms by which these inhibitors block separase activity by occluding substrate binding. We also describe conserved mechanisms that facilitate substrate recognition and point out open research questions that will guide studies of this fascinating enzyme for years to come.

Parasite manipulation of host phenotypes inferred from transcriptional analyses in a trematode-amphipod system.

Manipulation of host phenotypes by parasites is hypothesized to be an adaptive strategy enhancing parasite transmission across hosts and generations. Characterizing the molecular mechanisms of manipulation is important to advance our understanding of host-parasite coevolution. The trematode (Levinseniella byrdi) is known to alter the colour and behaviour of its amphipod host (Orchestia grillus) presumably increasing predation of amphipods which enhances trematode transmission through its life cycle. We sampled 24 infected and 24 uninfected amphipods from a salt marsh in Massachusetts to perform differential gene expression analysis. In addition, we constructed novel genomic tools for O. grillus including a de novo genome and transcriptome. We discovered that trematode infection results in upregulation of amphipod transcripts associated with pigmentation and detection of external stimuli, and downregulation of multiple amphipod transcripts implicated in invertebrate immune responses, such as vacuolar ATPase genes. We hypothesize that suppression of immune genes and the altered expression of genes associated with coloration and behaviour may allow the trematode to persist in the amphipod and engage in further biochemical manipulation that promotes transmission. The genomic tools and transcriptomic analyses reported provide new opportunities to discover how parasites alter diverse pathways underlying host phenotypic changes in natural populations.

Validation of a natural language processing algorithm to identify adenomas and measure adenoma detection rates across a health system: a population-level study.

BACKGROUND AND AIMS: Measuring adenoma detection rates (ADRs) at the population level is challenging because pathology reports are often reported in an unstructured format; further, there is significant variation in reporting methods across institutions. Natural language processing (NLP) can be used to extract relevant information from text-based records. We aimed to develop and validate an NLP algorithm to identify colorectal adenomas that could be used to report ADR at the population level in Ontario, Canada. METHODS: The sampling frame included pathology reports from all colonoscopies performed in Ontario in 2015 and 2016. Two random samples of 450 and 1000 reports were selected as the training and validation sets, respectively. Expert clinicians reviewed and classified reports as adenoma or other. The training set was used to develop an NLP algorithm (to identify adenomas) that was evaluated using the validation set. The NLP algorithm test characteristics were calculated using expert review as the reference. We used the algorithm to measure ADR for all endoscopists in Ontario in 2019. RESULTS: The 1450 pathology reports were derived from 62 laboratories, 266 pathologists, and 532 endoscopists. In the training set, the NLP algorithm for any adenoma had a sensitivity of 99.60% (95% confidence interval (CI), 97.77-99.99), specificity of 99.01% (95% CI, 96.49-99.88), positive predictive value of 99.19% (95% CI, 97.12-99.90), and F1 score of .99. Similar results were obtained for the validation set. The median ADR was 33% (interquartile range, 26%-40%). CONCLUSIONS: When we used a population-based sample from Ontario, our NLP algorithm was highly accurate and was used at the system level to measure ADR.