bluuebunny/crossref_metadata_2025 huggingface dataset:
Indication and outcome of lupus anticoagulant and antiphospholipid antibodies testing in routine clinical practice
Authors: Kempers Eva K , Dalm Virgil A S H , van Rijn Marie Josee E , Mulders Annemarie G M G J , Leebeek Frank W G , de Maat Moniek P M , Jansen A J Gerard
Published: December 2021

Objectives

Lupus anticoagulans (LACs) and aPLs, both further summarized as aPL, are frequently assessed in routine daily clinical practice in diagnostic workups for suspected autoimmune diseases or to test for underlying risk factors in patients with thrombosis or obstetric complications. The aim of this study was to determine the prevalence of aPL positivity in patients with an indication for aPL testing in routine clinical practice.

Methods

In this retrospective single-centre study, indication for aPL testing, aPL test results and clinical data were collected for patients tested between June 2015 and April 2018.

Results

During the study period, 16 847 single aPL tests were performed in 2139 patients. In 212 patients one or more positive aPL test was found, confirmed in 43.9% with a second positive test. Indications for aPL testing were diagnostic workup/follow-up of autoimmune diseases (33.6%), thrombosis (21.4%) and obstetric complications (28%). Seventy-four patients (3.5% of all patients) fulfilled the criteria of APS, of whom 51% were newly diagnosed. Second positive aPL titres and titres of APS patients were significantly higher compared with positive aPL titres at the first measurement (P < 0.05). Patients with indications of arterial thrombosis and diagnostic workup/follow-up of autoimmune diseases had significantly higher levels of aCL IgG and anti-β2 glycoprotein I (β2GPI) IgG compared with patients with other indications.

Conclusion

The prevalence of one or more positive aPL test was 9.9% and APS was diagnosed in 3.5% of the patients. Patients with arterial thrombosis had significantly higher anti-β2GPI IgG and aCL IgG, which should be confirmed in future studies.
Fragility fractures and prescriptions of medications for osteoporosis in patients with polymyalgia rheumatica: results from the PMR Cohort Study
Authors: Sokhal Balamrit Singh , Hider Samantha L , Paskins Zoe , Mallen Christian D , Muller Sara
Published: December 2021

Objectives

PMR is a common indication for long-term glucocorticoid treatment, leading to an increased risk of osteoporosis and fragility fractures. Guidelines recommend calcium and vitamin D for all patients, in addition to anti-resorptive agents for high-risk patients. The aim of this study was to investigate falls and fragility fracture history and the use of medications for osteoporosis in a PMR cohort.

Methods

Six hundred and fifty-two people with incident PMR responded to a postal survey. Self-reported data on falls, fragility fracture history and medication were collected at baseline. Follow-up data on fragility fractures (hip, wrist and spine) and falls were collected at 12 and 24 months. Logistic regression was used to assess the association between baseline characteristics and fractures.

Results

Fewer than 50% of respondents received osteoporosis treatments, including supplements. One hundred and twelve (17.2%) participants reported a fragility fracture at baseline, 72 participants reported a fracture at 12 months, and 62 reported a fracture at 24 months. Baseline history of falls was most strongly associated with fracture at 12 (odds ratio 2.35; 95% CI: 1.35, 4.12) and 24 months (1.91; 1.05, 3.49) when unadjusted for previous fractures.

Conclusion

Fracture reporting is common in people with PMR. To improve fracture prevention, falls assessment and interventions need to be considered. A history of falls could help to inform prescribing decisions around medications for osteoporosis. Future research should consider both pharmacological and non-pharmacological approaches to reducing fracture risk.
The Battisti Case: A Legal-Historical Reconstruction
Authors: Fischel de Andrade José H
Published: November 2021

The Battisti Case constitutes a rare high-profile case of decision-making and judicial ruling on the (hardly ever explored) interpretation and implementation of refugee law by political, technical, and judicial actors in Latin America. It concerns an Italian citizen, Cesare Battisti, sentenced twice to life imprisonment who, after escaping from prison, fled to Mexico, France, Brazil, and Bolivia. Even though Italy had twice attempted to have Mr Battisti extradited from both France (1991 and 2003) and Brazil (2007 and 2017), his extradition has never been materialised. In 2019 he was removed from Bolivia to Italy, where he has been serving his sentences. This study analyses the facts prior to the 2007 Italian extradition request, Mr Battisti’s application for refugee status, the Brazilian Supreme Court’s main extradition ruling, the presidential decision on his non-extradition, Mr Battisti’s last years in Brazil and removal from Bolivia, and his confession and the execution of his prison sentence. This piece analyses a case where several parties seem to be in the wrong: the prosecuted criminal and former protecting States have misused the asylum regime, and the country where the prisoner is serving his sentence is seemingly aggravating his situation as a result of his “personal condition”.
Retrospective analysis of cohort risk factors and feeding phase timing associated with noninfectious heart disease deaths in U.S. feedlot cattle
Authors: Johnson Blaine T , Amrine David E , Larson Robert L , Weaber Robert L , White Brad J
Published: December 2021

Heart disease, specifically congestive heart failure, has become of increased interest to geneticists and cattle feeders. Data on cohort associations of risk factors related to heart disease and when heart disease deaths occur in U.S. feedlot cattle are limited. The study objectives were to 1) determine potential associations between feedlot cohort demographics and the risk of at least one noninfectious heart disease (NIHD) death occurrence and 2) determine potential association between feedlot cohort demographics and the timing of NIHD deaths during the feeding phase. Data were downloaded from commercial feedyard software and analyzed by constructing a generalized linear mixed model for both analyses. A binomial and Gaussian distributions for risk of NIHD death and timing of NIHD were utilized as link functions for their respective models. Our study population consisted of 28,950 cohorts (representing 4,596,205 cattle) that were placed in 22 U.S. commercial feedlots from January 01, 2016, to January 01, 2019. There were 3,282 cases of NIHD deaths from a population of 75,963 cattle that died during the 3-yr study period. Average cohort arrival weight’s effect on NIHD probability was influenced by arrival quarter and arrival year of placement (P < 0.01). Cohorts with steers were associated with a greater probability of at least one NIHD death (2.38%) compared with heifers (1.95%; P < 0.01). Increasing cohort size was associated with an increased probability of a cohort having at least one NIHD death (P < 0.01). The probability of a cohort having at least one NIHD death increased with increasing DOF categories from 1.51% in cattle fed 100 to 175 d, to 2.12% in cattle fed 176 to 250 d, and 2.87% for cattle fed 251 to 326 d. Cattle > 326 DOF were no different in the probability of a NIHD death compared with the other feeding categories. Timing of a NIHD death had a mean and median occurrence of 110 DOF with an interquartile range of 64 to 153 DOF. The effect of arrival weight on days at death was influenced by year placed with heavier cattle generally decreasing the model adjusted means of DOF at NIHD death. Arrival quarter was influenced by year placed on model adjusted means on the timing of a NIHD death. Steers with NIHD died later compared with heifers (P < 0.01) diagnosed with NIHD. In conclusion, multiple factors are associated with the probability and timing of a NIHD death. Probability of having at least one NIHD death within a cohort was low, and half of the deaths occurred before 110 DOF.
Effects of forage inclusion and cattle breed on apparent digestibility and ruminal pH of steers fed a whole shelled corn-based diet
Authors: Carvalho Pedro H V , Westphalen Mariana F , Silva Flavia A S , Felix Tara L
Published: December 2021

Objectives were to evaluate the effects of cattle breed, Holstein or Angus, and forage inclusion on total tract digestibility and ruminal pH in cattle fed a whole shelled corn-based diet. Six Holstein and six Angus steers were assigned to a 2 × 3 factorial arrangement of treatments. Factors included breed, Holstein or Angus, and forage inclusion at 0%, 8%, or 16% forage (dry matter [DM] basis). Steers were fed in a replicated 3 × 3 Latin square, split-plot design. Each period consisted of 14 d diet adaptation followed by 7 d of sample collection. Data were analyzed using the MIXED procedures in SAS (v9.4 SAS Inst. Inc., Cary, NC). Repeated measures were used to analyze changes in ruminal pH over time. There was no interaction of breed × diet (P ≥ 0.19) on dry matter intake (DMI) or digestibility; however, Holstein steers had greater (P = 0.03) DMI than Angus steers. Despite the impact of breed on intake, there was no effect (P ≥ 0.33) of breed on diet digestibility. Digestibility of DM increased (linear; P < 0.01) as forage was removed from the diet, but there were no differences (P ≥ 0.32) in Neutral Detergent Fiber (NDF) and starch digestibility. However, due to the change in diet, NDF intake digested on a grams per day basis increased (P ≤ 0.01) and starch intake digested (g/d) decreased (P = 0.01) as forage inclusion increased. There was a tendency for breed × diet interaction (P = 0.08) on ruminal pH. Holstein steers fed 8% or 16% forage had greater ruminal pH than Holstein steers fed 0% forage; but, ruminal pH of Angus steers was not altered by diet.
Intellectual Curiosity and Action Initiation are Subtypes of Apathy Affected in Huntington Disease Gene Expansion Carriers
Authors: Hendel Rebecca K. , Hellem Marie N.N. , Hjermind Lena E. , Nielsen Jørgen E. , Vogel Asmus
Published: December 2021

Background:

Apathy is a prevalent behavioral syndrome of Huntington disease (HD) that can result in severe loss of function for the individual with HD and substantial caregiver distress. Research-based evidence of apathy is characterized by methodological differences, and there is a deficiency in the evidence concerning the subtypes of apathy.

Objective:

To characterize apathy in premanifest and motor-manifest HD gene expansion carriers and controls using the Short Problem Behaviors Assessment for Huntington’s Disease (PBA–s) and the Lille Apathy Rating Scale (LARS).

Method:

We included 82 HD gene expansion carriers (premanifest and motor manifest) and 32 controls (Mini-Mental State Examination score ≥24 and Montreal Cognitive Assessment score ≥19) in the study. We quantified apathy using the PBA–s and the LARS and performed correlation analyses between the global LARS score and motor function, cytosine-adenine-guanine repeat length, cytosine-adenine-guanine Age Product score, and neuropsychiatric and cognitive symptoms.

Results:

The motor-manifest HD gene expansion carriers scored significantly higher than the controls on the global score and the Intellectual Curiosity and Action Initiation subscales of the LARS. Apathy was present in 28% of the HD gene expansion carriers (including 7 premanifest). The apathetic participants had a significantly higher motor score, significantly higher scores on the neuropsychiatric instruments, and significantly lower cognitive scores compared with the controls.

Conclusion:

Apathy is a frequent syndrome that is found in individuals with HD. Apathy has a specific expression, with symptoms such as reduced initiation, voluntary actions, and interests, that might be related to the underlying neuropathology. Apathy is related to disease progression, neuropsychiatric symptoms, and cognitive impairments.
Trevor Evans. 26 April 1927—10 October 2010
Authors: Brown L. M. , Mills I. M.
Published: December 2021

Trevor Evans was responsible for revealing the main physical processes which take place in natural diamond both in the upper mantle of the earth, where it is stabilized by high pressure and temperature, and as it is ejected by volcanic action to the surface. By measuring the activation energies required for graphitization, he clarified the reason for its very long life as a metastable crystal, valuable both as a gemstone and as an industrial abrasive. He learned how to make diamond specimens for examination in the transmission electron microscope, which enabled his discovery of dislocation loops and platelet precipitates in nitrogen-containing (type 1) stones. In a series of exacting laboratory experiments under geologically relevant conditions he pioneered the study of the emergence of nitrogen from solution to precipitation during the ejection process. In synthetic diamonds, using high-energy electron irradiation, he was able to reproduce the sequence of all the various types of nitrogen aggregation found in natural diamond. His work played a major role underpinning the characterization of gemstones, explaining many features of their colour. For many years he led diamond research in the UK, supported by De Beers. His work stimulated and has been confirmed by research in many other laboratories around the world.
Requirements for a global lidar system: spaceborne lidar with wall-to-wall coverage
Authors: Hancock Steven , McGrath Ciara , Lowe Christopher , Davenport Ian , Woodhouse Iain
Published: December 2021

Lidar is the optimum technology for measuring bare-Earth elevation beneath, and the structure of, vegetation. Consequently, airborne laser scanning (ALS) is widely employed for use in a range of applications. However, ALS is not available globally nor frequently updated due to its high cost per unit area. Spaceborne lidar can map globally but energy requirements limit existing spaceborne lidars to sparse sampling missions, unsuitable for many common ALS applications. This paper derives the equations to calculate the coverage a lidar satellite could achieve for a given set of characteristics (released open-source), then uses a cloud map to determine the number of satellites needed to achieve continuous, global coverage within a certain time-frame. Using the characteristics of existing in-orbit technology, a single lidar satellite could have a continuous swath width of 300 m when producing a 30 m resolution map. Consequently, 12 satellites would be needed to produce a continuous map every 5 years, increasing to 418 satellites for 5 m resolution. Building 12 of the currently in-orbit lidar systems is likely to be prohibitively expensive and so the potential of technological developments to lower the cost of a global lidar system (GLS) are discussed. Once these technologies achieve a sufficient readiness level, a GLS could be cost-effectively realized.
The new normal? Redaction bias in biomedical science
Authors: Grimes David Robert , Heathers James
Published: December 2021

A concerning amount of biomedical research is not reproducible. Unreliable results impede empirical progress in medical science, ultimately putting patients at risk. Many proximal causes of this irreproducibility have been identified, a major one being inappropriate statistical methods and analytical choices by investigators. Within this, we formally quantify the impact of inappropriate redaction beyond a threshold value in biomedical science. This is effectively truncation of a dataset by removing extreme data points, and we elucidate its potential to accidentally or deliberately engineer a spurious result in significance testing. We demonstrate that the removal of a surprisingly small number of data points can be used to dramatically alter a result. It is unknown how often redaction bias occurs in the broader literature, but given the risk of distortion to the literature involved, we suggest that it must be studiously avoided, and mitigated with approaches to counteract any potential malign effects to the research quality of medical science.
Waterbird solves the string-pull test
Authors: Lamarre Jessika , Wilson David R.
Published: December 2021

String-pulling is among the most widespread cognitive tasks used to test problem-solving skills in mammals and birds. The task requires animals to comprehend that pulling on a non-valuable string moves an otherwise inaccessible food reward to within their reach. Although at least 90 avian species have been administered the string-pull test, all but five of them were perching birds (passeriformes) or parrots (psittaciformes). Waterbirds (Aequorlitornithes) are poorly represented in the cognitive literature, yet are known to engage in complex foraging behaviours. In this study, we tested whether free-living ring-billed gulls (Larus delawarensis), a species known for their behavioural flexibility and foraging innovativeness, could solve a horizontal string-pull test. Here, we show that 25% (26/104) of the ring-billed gulls that attempted to solve the test at least once over a maximum of three trials were successful, and that 21% of them (22/104) succeeded during their first attempt. Ring-billed gulls are thus the first waterbird known to solve a horizontal single-string-rewarded string-pull test. Since innovation rate and problem-solving are associated with species' ability to endure environmental alterations, we suggest that testing the problem-solving skills of other species facing environmental challenges will inform us of their vulnerability in a rapidly changing world.
Integrals and series related to propagators of neural and haemodynamic waves
Authors: Robinson P. A.
Published: December 2021

The propagator, or Green function, of a class of neural activity fields and of haemodynamic waves is evaluated exactly. The results enable a number of related integrals to be evaluated, along with series expansions of key results in terms of Bessel functions of the second kind. Connections to other related equations are also noted.
Marine heatwave challenges solutions to human–wildlife conflict
Authors: Samhouri Jameal F. , Feist Blake E. , Fisher Mary C. , Liu Owen , Woodman Samuel M. , Abrahms Briana , Forney Karin A. , Hazen Elliott L. , Lawson Dan , Redfern Jessica , Saez Lauren E.
Published: December 2021

Despite the increasing frequency and magnitude of extreme climate events, little is known about how their impacts flow through social and ecological systems or whether management actions can dampen deleterious effects. We examined how the record 2014–2016 Northeast Pacific marine heatwave influenced trade-offs in managing conflict between conservation goals and human activities using a case study on large whale entanglements in the U.S. west coast's most lucrative fishery (the Dungeness crab fishery). We showed that this extreme climate event diminished the power of multiple management strategies to resolve trade-offs between entanglement risk and fishery revenue, transforming near win–win to clear win–lose outcomes (for whales and fishers, respectively). While some actions were more cost-effective than others, there was no silver-bullet strategy to reduce the severity of these trade-offs. Our study highlights how extreme climate events can exacerbate human–wildlife conflict, and emphasizes the need for innovative management and policy interventions that provide ecologically and socially sustainable solutions in an era of rapid environmental change.
Sex-specific maternal programming of corticosteroid-binding globulin by predator odour
Authors: Abuaish Sameera , Lavergne Sophia G. , Hing Benjamin , St-Cyr Sophie , Spinieli Richard L. , Boonstra Rudy , McGowan Patrick O.
Published: December 2021

Predation is a key organizing force in ecosystems. The threat of predation may act to programme the endocrine hypothalamic–pituitary–adrenal axis during development to prepare offspring for the environment they are likely to encounter. Such effects are typically investigated through the measurement of corticosteroids (Cort). Corticosteroid-binding globulin (CBG) plays a key role in regulating the bioavailability of Cort, with only free unbound Cort being biologically active. We investigated the effects of prenatal predator odour exposure (POE) in mice on offspring CBG and its impact on Cort dynamics before, during and after restraint stress in adulthood. POE males, but not females, had significantly higher serum CBG at baseline and during restraint and lower circulating levels of Free Cort. Restraint stress was associated with reduced liver transcript abundance ofSerpinA6(CBG-encoding gene) only in control males. POE did not affectSerpinA6promoter DNA methylation. Our results indicate that prenatal exposure to a natural stressor led to increased CBG levels, decreased per cent of Free Cort relative to total and inhibited restraint stress-induced downregulation of CBG transcription. These changes suggest an adaptive response to a high predator risk environment in males but not females that could buffer male offspring from chronic Cort exposure.
Climate causes shifts in grey seal phenology by modifying age structure
Authors: Bull James C. , Jones Owen R. , Börger Luca , Franconi Novella , Banga Roma , Lock Kate , Stringell Thomas B.
Published: December 2021

There are numerous examples of phenological shifts that are recognized both as indicators of climate change and drivers of ecosystem change. A pressing challenge is to understand the causal mechanisms by which climate affects phenology. We combined annual population census data and individual longitudinal data (1992–2018) on grey seals,Halicheorus grypus, to quantify the relationship between pupping season phenology and sea surface temperature. A temperature increase of 2°C was associated with a pupping season advance of approximately seven days at the population level. However, we found that maternal age, rather than sea temperature, accounted for changes in pupping date by individuals. Warmer years were associated with an older average age of mothers, allowing us to explain phenological observations in terms of a changing population age structure. Finally, we developed a matrix population model to test whether our observations were consistent with changes to the stable age distribution. This could not fully account for observed phenological shift, strongly suggesting transient modification of population age structure, for example owing to immigration. We demonstrate a novel mechanism for phenological shifts under climate change in long-lived, age- or stage-structured species with broad implications for dynamics and resilience, as well as population management.
Genetic alteration of humanMYH6is mimicked by SARS-CoV-2 polyprotein: mapping viral variants of cardiac interest
Authors: Anand Praveen , Lenehan Patrick J. , Niesen Michiel , Yoo Unice , Patwardhan Dhruti , Montorzi Marcelo , Venkatakrishnan AJ , Soundararajan Venky
Published: December 2021

Acute cardiac injury has been observed in a subset of COVID-19 patients, but the molecular basis for this clinical phenotype is unknown. It has been hypothesized that molecular mimicry may play a role in triggering an autoimmune inflammatory reaction in some individuals after SARS-CoV-2 infection. Here we investigate if linear peptides contained in proteins that are primarily expressed in the heart also occur in the SARS-CoV-2 proteome. Specifically, we compared the library of 136,704 8-mer peptides from 144 human proteins (including splicing variants) to 9,926 8-mers from all 17 viral proteins in the reference SARS-CoV-2 proteome. No 8-mers were exactly identical between the reference human proteome and the reference SARS-CoV-2 proteome. However, there were 45 8-mers that differed by only one amino acid when compared to the reference SARS-CoV-2 proteome. Interestingly, analysis of protein-coding mutations from 141,456 individuals showed that one of these 8-mers from the SARS-CoV-2 Replicase polyprotein 1a/1ab (KIALKGGK) is identical to aMYH6peptide encoded by the c.5410C>A (Q1804K) genetic variation, which has been observed at low prevalence in Africans/African Americans (0.08%), East Asians (0.3%), South Asians (0.06%) and Latino/Admixed Americans (0.003%). Furthermore, analysis of 4.85 million SARS-CoV-2 genomes from over 200 countries shows that viral evolution has already resulted in 20 additional 8-mer peptides that are identical to human heart-enriched proteins encoded by reference sequences or genetic variants. Whether such mimicry contributes to cardiac inflammation during or after COVID-19 illness warrants further experimental evaluation. We suggest that SARS-CoV-2 variants harboring peptides identical to human cardiac proteins should be investigated as ‘viral variants of cardiac interest’.
Trends and associated factors for Covid-19 hospitalisation and fatality risk in 2.3 million adults in England
Authors: Beaney T , Neves AL , Alboksmaty A , Flott K , Fowler A , Benger JR , Aylin P , Elkin S , Darzi A , Clarke J
Published: December 2021

Background

The Covid-19 case fatality ratio varies between countries and over time but it is unclear whether variation is explained by the underlying risk in those infected. This study aims to describe the trends and risk factors for admission and mortality rates over time in England.

Methods

In this retrospective cohort study, we included all adults (≥18 years) in England with a positive Covid-19 test result between 1stOctober 2020 and 30thApril 2021. Data were linked to primary and secondary care electronic health records and death registrations. Our outcomes were i) one or more emergency hospital admissions and ii) death from any cause, within 28 days of a positive test. Multivariable multilevel logistic regression was used to model each outcome with patient risk factors and time.

Results

2,311,282 people were included in the study, of whom 164,046 (7.1%) were admitted and 53,156 (2.3%) died within 28 days. There was significant variation in the case hospitalisation and mortality risk over time, peaking in December 2020-February 2021, which remained after adjustment for individual risk factors. Older age groups, males, those resident in more deprived areas, and those with obesity had higher odds of admission and mortality. Of risk factors examined, severe mental illness and learning disability had the highest odds of admission and mortality.

Conclusions

In one of the largest studies of nationally representative Covid-19 risk factors, case hospitalisation and mortality risk varied significantly over time in England during the second pandemic wave, independent of the underlying risk in those infected.
Tracking bacteria at high density with FAST, the Feature-Assisted Segmenter/Tracker
Authors: Meacock Oliver J. , Durham William M.
Published: November 2021

Most bacteria live attached to surfaces in densely-packed communities1,2. While new experimental and imaging techniques are beginning to provide a window on the complex processes that play out in these communities, resolving the behaviour of individual cells through time and space remains a major challenge. Although a number of different software solutions have been developed to track microorganisms3–8, these approaches typically rely on a large number of user-defined parameters that must be carefully tuned to effectively track cells. Testing a given parameter combination can take hours to days depending on the size of the dataset, making iterative optimisation impractical. To overcome these limitations, we have developed FAST, the Feature-Assisted Segmenter/Tracker, which uses unsupervised machine learning to optimise tracking while maintaining ease of use. Our approach, rooted in information theory, largely eliminates the need for users to iteratively adjust parameters manually and make qualitative assessments of the resulting cell trajectories. Instead, FAST measures multiple distinguishing “features” for each cell and then autonomously quantifies the amount of unique information each feature provides. We then use these measurements to determine how data from different features should be combined to minimize tracking errors. Comparing our algorithm with a naïve approach that uses cell position alone revealed that FAST produced 4 to 10 times fewer tracking errors. The modular design of FAST combines our novel tracking method with tools for segmentation, extensive data visualisation, lineage assignment, and manual track correction. It is also highly extensible, allowing users to extract custom information from images and seamlessly integrate it into downstream analyses. FAST therefore enables high-throughput, data-rich analyses with minimal user input. It has been released for use either in Matlab or as a compiled stand-alone application, and is available athttps://bit.ly/3vovDHn, along with extensive tutorials and detailed documentation.
Bagaza virus in wild birds, Portugal, 2021
Authors: Queirós João , Barros Sílvia , Sánchez-Cano Alberto , Henriques Margarida , Fagulha Teresa , dos Santos Fábio Abade , Duarte Margarida , Gonçalves Catarina , Gonçalves David , Rodrigues Marisa , Cabrera Teresa Cardona , de Mera Isabel G. Fernández , Gortazar Christian , Höfle Ursula , Célio Alves Paulo
Published: November 2021

Bagaza virus (BAGV) emerged in Spain, in 2010. Since then, BAGV was not reported in other European countries until September 2021, when BAGV was diagnosed by molecular methods in one corn bunting and several red-legged partridges, after abnormal mortality in Southern Portugal. Sequencing revealed high similarity with strains reported previously.
Long-term consequences of alcohol use in early adolescent mice: focus on neuroadaptations in GR, CRF and BDNF
Authors: Sampedro-Piquero P. , Moreno-Fernández R.D. , Begega A. , López M. , Santín L.J.
Published: November 2021

Our aim was to assess the cognitive and emotional state, as well as related-changes in the glucocorticoid receptor (GR), the corticotropin-releasing factor (CRF) and the brain-derived neurotrophic factor (BDNF) expression of adolescent C57BL/6J male mice after a five-week two-bottle choice protocol (postnatal day (pd) 21 to pd52). Additionally, we wanted to analyse whether the behavioural and neurobiological effects observed in late adolescence (pd62) lasted until adulthood (pd84). Behavioural testing revealed that alcohol during early adolescence increased anxiety-like and compulsive-related behaviours, which was maintained in adulthood. Concerning cognition, working memory was only altered in late adolescent mice, whereas object location test performance was impaired in both ages. In contrast, novel object recognition remained unaltered. Immunohistochemical analysis showed that alcohol during adolescence diminished BDNF+ cells in the cingulate cortex, the hippocampal CA1 layer and the central amygdala. Regarding hypothalamic-pituitary-adrenal axis (HPA) functioning, alcohol abuse increased the GR and CRF expression in the hypothalamic paraventricular nucleus and the central amygdala. Besides this, GR density was also higher in the prelimbic cortex and the basolateral amygdala, regardless of the animals’ age. Our findings suggest that adolescent alcohol exposure led to long-term behavioural alterations, along with changes in BDNF, GR and CRF expression in limbic brain areas involved in stress response, emotional regulation, and cognition.
Evolution of resistance to Irinotecan in cancer cells involves generation of topoisomerase-guided mutations in non-coding genome that reduce the chances of DNA breaks
Authors: Kumar Santosh , Gahramanov Valid , Patel Shivani , Yaglom Julia , Kaczmarczyk Lukasz , Alexandrov Ivan , Gerlitz Gabi , Salmon-Divon Mali , Sherman Michael Y.
Published: November 2021

Resistance to chemotherapy is a leading cause of treatment failure. Drug-resistance mechanisms involve mutations in specific proteins or changes in their expression levels. It is commonly understood that resistance mutations happen randomly prior to treatment and are selected during the treatment. However, selection of drug-resistant mutants in culture could be achieved by multiple drug exposures of cloned genetically identical cells, and thus cannot result from selection of pre-existent mutations. Accordingly, adaptation must involve generation of mutations de-novo upon drug treatment. Here we explored the origin of resistance mutations to a widely used Top1 inhibitor irinotecan, which triggers DNA breaks, causing cytotoxicity. Resistance mechanism involved gradual accumulation of recurrent mutations in non-coding regions of DNA at Top1-cleavage sites. Surprisingly, cancer cells had higher number of such sites than reference genome, which may define their increased sensitivity to irinotecan. Homologous recombination repair of DNA double strand breaks at these sites following initial drug exposures gradually reverted cleavage-sensitive “cancer” sequences back to cleavage-resistant “normal” sequences. These mutations reduced generation of DNA breaks upon subsequent exposures, thus gradually increasing the drug resistance. Together, large target size for mutations and their Top1-guided generation lead to their gradual and rapid accumulation, synergistically accelerating development of resistance.

Abstract Figure
Simultaneous pathway engagement of translation in astrocytes, circadian rhythm in GABAergic neurons and cytoskeleton in glutamatergic neurons precede electroencephalographic changes in neurodegenerative prion disease
Authors: Kaczmarczyk Lech , Schleif Melvin , Dittrich Lars , Williams Rhiannan , Koderman Maruša , Bansal Vikas , Rajput Ashish , Schulte Theresa , Jonson Maria , Krost Clemens , Testaquadra Fabio , Bonn Stefan , Jackson Walker S.
Published: November 2021

Selective vulnerability is an enigmatic feature of neurodegenerative diseases (NDs), whereby a widely expressed protein causes lesions in specific brain regions and cell types. This selectivity may arise from cells possessing varying capacities to regain proteostasis when stressed by cytotoxic protein conformers. Using the RiboTag method in mice, translational responses of five neural subtypes to acquired prion disease (PrD) were measured. Pre-onset and disease onset timepoints were chosen based on longitudinal electroencephalography (EEG) that revealed a gradual increase in theta power between 10- and 18-weeks after prion injection, resembling a clinical feature of human PrD. At disease onset, marked by significantly increased theta power and histopathological lesions, mice had pronounced translatome changes in all five cell types despite having a normal outward appearance. Remarkably, at a pre-onset stage, prior to EEG and neuropathological changes, we found that 1) translatomes of astrocytes indicated a sharply reduced synthesis of ribosomal and mitochondrial components, 2) excitatory neurons showed increased expression of cytoskeletal genes, and 3) inhibitory neurons revealed reduced expression of circadian rhythm network genes. Further assessment for the role of circadian rhythms using a jet lag paradigm modestly exacerbated disease. These data demonstrate that early translatome responses to neurodegeneration emerge prior to other signs of disease and are unique to different cell types. Therapeutic strategies may need to target multiple pathways, each in specific populations of cells, early in the disease process.
BCM3D 2.0: Accurate segmentation of single bacterial cells in dense biofilms using computationally generated intermediate image representations
Authors: Zhang Ji , Wang Yibo , Donarski Eric D. , Toma Tanjin T. , Miles Madeline T. , Acton Scott T. , Gahlmann Andreas
Published: November 2021

Accurate detection and segmentation of single cells in three-dimensional (3D) fluorescence timelapse images is essential for observing individual cell behaviors in large bacterial communities called biofilms. Recent progress in machine-learning-based image analysis is providing this capability with every increasing accuracy. Leveraging the capabilities of deep convolutional neural networks (CNNs), we recently developed bacterial cell morphometry in 3D (BCM3D), an integrated image analysis pipeline that combines deep learning with conventional image analysis to detect and segment single biofilm-dwelling cells in 3D fluorescence images. While the first release ofBCM3D(BCM3D 1.0) achieved state-of-the-art 3D bacterial cell segmentation accuracies, low signal-to-background ratios (SBRs) and images of very dense biofilms remained challenging. Here, we presentBCM3D 2.0to address this challenge.BCM3D 2.0is entirely complementary to the approach utilized inBCM3D 1.0. Instead of training CNNs to perform voxel classification, we trained CNNs to translate 3D fluorescence images into intermediate 3D image representations that are, when combined appropriately, more amenable to conventional mathematical image processing than a single experimental image. Using this approach, improved segmentation results are obtained even for very low SBRs and/or high cell density biofilm images. The improved cell segmentation accuracies in turn enable improved accuracies of tracking individual cells through 3D space and time. This capability opens the door to investigating timedependent phenomena in bacterial biofilms at the cellular level.
Avian recolonization of unrestored and restored bogs in Eastern Canada
Authors: Desrochers André , Rochefort Line
Published: November 2021

Over the last several decades, peat has been extracted from bogs of temperate, populated regions of Eastern Canada, leaving large areas devoid of vegetation if unrestored. For the last 25 years, projects have been conducted in these regions to re-establish vegetation and facilitate recolonization by wildlife. We tested whether vegetation structure and bird species assemblages 10 to 20 years post extraction differ among natural, unrestored and restored bogs at the scales of individual sites and entire bogs. We conducted bird counts and vegetation surveys between 1993 and 2019, using both point counts (309 sites) and Autonomous Recording Units (80 sites). According to our vegetation surveys, restoration of sites that were previously used for peat harvesting accelerated the establishment ofSphagnumand herbaceous strata, but ericaceous and tree strata were unaffected over a 17-year period. None of the bird species with large home ranges were associated specifically to natural, unrestored, or restored areas at the bog level. Bird species diversity was similar in restored and natural sites, but lower in unrestored sites. Alder Flycatcher and American Goldfinch occupied restored and unrestored sites more frequently than natural sites, independent of the number of years post extraction. Occupancy of restored sites by Palm and Yellow-rumped Warblers increased over the years, reaching levels similar to those in natural sites 20 years after restoration was implemented. Occupancy of restored sites by Song and Savannah sparrows increased from 1993-2019 and diverged from their declining occupancy of natural sites. Species assemblages of restored and unrestored sites differed significantly from those of natural sites soon after peat extraction ceased or post restoration. But assemblages from restored and unrestored sites became progressively similar to those of natural sites during the first 20 years, especially in restored sites. We conclude that bird species assemblages of restored bog sites are converging toward those of natural sites, and that restoration provides novel habitats for regionally declining species, e.g., Savannah Sparrows.
Thousands of human mutation clusters are explained by short-range template switching
Authors: Löytynoja Ari
Published: November 2021

Variation within human genomes is unevenly distributed, and variants show spatial clustering. DNA- replication-related template switching is a poorly known mutational mechanism capable of causing major chromosomal rearrangements as well as creating short inverted sequence copies that appear as local mutation clusters in sequence comparisons. I reanalyzed haplotype-resolved genome assemblies representing 25 human populations and multinucleotide variants aggregated from 140,000 human sequencing experiments. Local template switching could explain thousands of complex mutation clusters across the human genome, the loci segregating within and between populations. I developed computational tools for identification of template switch events using both short-read sequencing data and genotype data, and for genotyping candidate loci using short-read data. The characteristics of template-switch mutations complicate their detection and, worryingly, widely used analysis pipelines for short-read sequencing data, normally capable of identifying single nucleotide changes, were found to miss template-switch mutations of tens of base pairs, potentially invalidating medical genetic studies searching for a causative allele behind genetic diseases. Combined with the massive sequencing data now available for humans, the novel tools described here enable building catalogs of affected loci and studying the cellular mechanisms behind template switching in both healthy organisms and disease.
Salmonella enterica serovar Typhimurium from Wild Birds in the United States Represent Distinct Lineages Defined by Bird Type
Authors: Fu Yezhi , M’ikanatha Nkuchia M. , Whitehouse Chris A. , Li Shaoting , Deng Xiangyu , Smith Jared C. , Shariat Nikki W. , Nawrocki Erin M. , Dudley Edward G.
Published: November 2021

Salmonella enterica serovar Typhimurium is typically considered a host generalist, however certain strains are associated with specific hosts and show genetic features of host adaptation. Here, we sequenced 131 S. Typhimurium strains from wild birds collected in 30 U.S. states during 1978-2019. We found that isolates from broad taxonomic host groups including passerine birds, water birds (Aequornithes), and larids (gulls and terns) represented three distinct lineages and certain S. Typhimurium CRISPR types presented in individual lineages. We also showed that lineages formed by wild bird isolates differed from most strains originating from domestic animal sources, and genomes from these lineages substantially improved source attribution of Typhimurium genomes to wild birds by a machine learning classifier. Furthermore, virulence gene signatures that differentiated S. Typhimurium from passerines, water birds, and larids were detected. Passerine isolates tended to lack S. Typhimurium-specific virulence plasmids. Isolates from the passerine, water bird, and larid lineages had close genetic relatedness with human clinical isolates, including those from a 2021 U.S. outbreak linked to passerine birds. These observations indicate that S. Typhimurium from wild birds in the U.S. are likely host-adapted, and the representative genomic dataset examined in this study can improve source prediction and facilitate outbreak investigation.

IMPORTANCE

Within-host evolution of S. Typhimurium may lead to pathovars adapted to specific hosts. Here, we report the emergence of disparate avian S. Typhimurium lineages with distinct virulence gene signatures. The findings highlight the importance of wild birds as a reservoir for S. Typhimurium and contribute to our understanding of the genetic diversity of S. Typhimurium from wild birds. Our study indicates that S. Typhimurium may have undergone adaptive evolution within wild birds in the U.S. The representative S. Typhimurium genomes from wild birds, together with the virulence gene signatures identified in these bird isolates, are valuable for S. Typhimurium source attribution and epidemiological surveillance.
The base-editing enzyme APOBEC3A catalyzes cytosine deamination in RNA with low proficiency and high selectivity
Authors: Barka Aleksia , Berríos Kiara N. , Bailer Peter , Schutsky Emily K. , Wang Tong , Kohli Rahul M.
Published: November 2021

Human APOBEC3A (A3A) is a nucleic acid-modifying enzyme that belongs to the cytidine deaminase family. Canonically, A3A catalyzes the deamination of cytosine into uracil in single-stranded DNA, an activity that makes A3A both a critical antiviral defense factor and a useful tool for targeted genome editing. However, off-target mutagenesis by A3A has been readily detected in both cellular DNA and RNA, which has been shown to promote oncogenesis. Given the importance of substrate discrimination for the physiological, pathological, and biotechnological activities of A3A, here we explore the mechanistic basis for its preferential targeting of DNA over RNA. Using a chimeric substrate containing a target ribocytidine within an otherwise DNA backbone, we demonstrate that a single hydroxyl at the sugar of the target base acts as a major selectivity determinant for deamination. To assess the contribution of bases neighboring the target cytosine, we show that overall RNA deamination is greatly reduced relative to that of DNA, but can be observed when ideal features are present, such as preferred sequence context and secondary structure. A strong dependence on idealized substrate features can also be observed with a mutant of A3A (eA3A, N57G) which has been employed for genome editing due to altered selectivity for DNA over RNA. Altogether, our work reveals a relationship between the overall decreased reactivity of A3A and increased substrate selectivity, and our results hold implications both for characterizing off-target mutagenesis and for engineering optimized DNA deaminases for base-editing technologies.
Identification of transcription factors involved in the specification of photoreceptor subtypes
Authors: Angueyra Juan , Kunze Vincent P. , Patak Laura K. , Kim Hailey , Kindt Katie S. , Li Wei
Published: November 2021

During development, retinal progenitors navigate a complex landscape of fate decisions that results in the generation of unique cell types necessary for proper vision. Here, we aim to provide the resources and techniques required to identify fac-tors that are critical for fate decisions in photoreceptors. These factors help create a diversity of photoreceptor subtypes that sustain vision in day and night, enable the discrimination of colors, facilitate the detection of prey and predators, and support other aspects of vision. First, we generate a key resource: a high-quality and deep transcriptomic profile of each photoreceptor subtype in zebrafish. We make this resource openly accessible, easy to explore and integrate it with other currently available photoreceptor transcriptomic datasets. Second, using our transcriptomic profiles, we derive an in-depth map of expression of transcription factors in photoreceptors—potential key players in cell-fate decisions. Third, we explore CRISPR-FØ screening as a fast, efficient and versatile technique to assess the involvement of candidate transcription factors in photoreceptor subtype-specification. We first show that known phenotypes can be easily replicated: loss of S cones in foxq2 mutants and loss of rods in nr2e3 mutants. We then explore four additional transcription factors of unknown function (Skor1a, Sall1a, Lrrfip1a and Xbp1) and find no evidence for their involvement in photoreceptor-subtype specification. Finally, we identify novel functions of Tbx2, demonstrating that it plays a central role in controlling the identity of all photoreceptor sub-types within the retina. Our study provides an open roadmap to discover additional factors involved in this process. This dataset and screening method will be a valuable way to explore the genes involved in many essential aspects of photoreceptor biology.