bluuebunny/crossref_metadata_2025 huggingface dataset:
Limiting the priming dose of a SARS CoV-2 vaccine improves virus-specific immunity
Authors: Sanchez Sarah , Palacio Nicole , Dangi Tanushree , Ciucci Thomas , Penaloza-MacMaster Pablo
Published: April 2021

Since late 2019, SARS-CoV-2 has caused a global pandemic that has infected 128 million people worldwide. Although several vaccine candidates have received emergency use authorization (EUA), there are still a limited number of vaccine doses available. To increase the number of vaccinated individuals, there are ongoing discussions about administering partial vaccine doses, but there is still a paucity of data on how vaccine fractionation affects vaccine-elicited immunity. We performed studies in mice to understand how the priming dose of a SARS CoV-2 vaccine affects long-term immunity to SARS CoV-2. We first primed C57BL/6 mice with an adenovirus-based vaccine encoding SARS CoV-2 spike protein (Ad5-SARS-2 spike), similar to that used in the CanSino and Sputnik V vaccines. This prime was administered either at a low dose (LD) of 106PFU or at a standard dose (SD) of 109PFU, followed by a SD boost in all mice four weeks later. As expected, the LD prime induced lower immune responses relative to the SD prime. However, the LD prime elicited immune responses that were qualitatively superior, and upon boosting, mice that were initially primed with a LD exhibited significantly more potent immune responses. Overall, these data demonstrate that limiting the priming dose of a SARS CoV-2 vaccine may confer unexpected benefits. These findings may be useful for improving vaccine availability and for rational vaccine design.
Genome- and Transcriptome-wide Splicing Associations with Problematic Alcohol Use and Alcohol Use Disorder
Authors: Huggett Spencer B. , Ikeda Ami S. , Yuan Qingyue , Benca-Bachman Chelsie E. , Palmer Rohan H.C.
Published: April 2021

Genetic mechanisms of alternative mRNA splicing have been shown in the brain for a variety of neuropsychiatric traits, but not substance use disorders. Our study used RNA-sequencing data on alcohol use disorder (AUD) in the brain’s reward circuitry (n=56; ages 40-73; 100% ‘Caucasian’; four brain regions) and genome-wide association data on problematic alcohol use (n=435,563, ages 22-90; 100% European-American) to investigate potential genetic links with alcohol-related alternative mRNA splicing. Polygenic scores of problematic alcohol use predicted alternative mRNA brain splicing associated with AUD, which depended on brain region. Across brain regions, we found 714 differentially spliced genes in various putative addiction genes and other novel gene targets. We found 6,463 splicing quantitative trait loci (sQTLs) that were associated with the AUD differentially spliced genes. sQTLs were enriched in loose chromatin genomic regions and downstream gene targets. Additionally, the heritability of problematic alcohol use was significantly enriched for DNA variants in and around differentially spliced genes associated with AUD. Our study also performed splicing transcriptome-wide association studies (TWASs) of problematic alcohol use and other drug use traits that unveiled individual genes for follow-up and robust splicing correlations across SUDs. Finally, we show that differentially spliced genes associated showed significant overlap in primate models of chronic alcohol consumption at the gene-level in similar brain regions. Altogether, our study illuminates substantial genetic contributions of alternative mRNA splicing in relation to problematic alcohol use and AUD.
Automatic Multi-functional Integration Program (AMFIP) towards All-optical Mechanobiology Interrogation
Authors: Luo Qin , Zhang Justin , Lin Gaoming , Huang Miao , Tanaka Mai , Lepler Sharon , Guan Juan , Siemann Dietmar , Tang Xin
Published: April 2021

Automatic operations of multi-functional and time-lapse live-cell imaging are necessary for biomedical studies of active, multi-faceted, and long-term biological phenomena. To achieve automatic control, most existing solutions often require the purchase of extra software programs and hardware that rely on the manufacturers’ own specifications. However, these software programs are usually non-user-programmable and unaffordable for many laboratories. μManager is a widely used open-source software platform for controlling many optoelectronic instruments. Due to limited development since its introduction, μManager lacks compatibility with some of the latest microscopy equipment. To address this unmet need, we have developed a novel software-based automation program, titled Automatic Multi-functional Integration Program (AMFIP), as a new Java-based and hardware-independent plugin for μManager. Without extra hardware, AMFIP enables the functional synchronization of μManager, the Nikon NIS-Elements platform, and other 3rdparty software to achieve automatic operations of most commercially available microscopy systems, including but not limited to Nikon. AMFIP provides a user-friendly and programmable graphical user interface (GUI), opening the door to expanding the customizability for many hardware and software. Users can customize AMFIP according to their own specific experimental requirements and hardware environments. To verify AMFIP’s performance, we applied it to elucidate the relationship between cell spreading and spatial-temporal cellular expression of Yes-associated protein (YAP), a mechanosensitive protein that shuttles between cytoplasm and nucleus upon mechanical stimulation, in an epithelial cell line. We found that the ratio of YAP expression in nucleus and cytoplasm decreases as the spreading area of cells increases, suggesting that the accumulation of YAP in the nucleus decreases throughout the cell spreading processes. In summary, AMFIP provides a new open-source and charge-free solution to integrate multiple hardware and software to satisfy the need of automatic imaging operations in the scientific community.
Piecemeal regulation of convergent neuronal lineages by bHLH transcription factors inC. elegans
Authors: Masoudi Neda , Yemini Eviatar , Schnabel Ralf , Hobert Oliver
Published: April 2021

Classic cell lineage studies in the nematodeCaenorhabditis elegansas well as recent lineage tracing in vertebrates have shown that cells of the same type can be generated by distinct cellular lineages that originate in different parts of the developing embryo (“lineage convergence”). SeveralC. elegansneuron classes composed of left/right or radially symmetric class members display such lineage convergence, in that individual neurons of the same class derive from distinct, non-bilaterally symmetric lineages. We show here that theC. elegansAtonal homologlin-32/Ato, a bHLH transcription factor, is differentially expressed in neuronal lineages that give rise to left/right or radially symmetric class members. Loss oflin-32/Atoresults in the selective loss of the expression of panneuronal markers and terminal selector-type transcription factors that confer neuron class-specific features. We discovered that another bHLH transcription factor, the Achaete Scute-homologhlh-14is expressed in mirror image pattern tolin-32/Atoin a subset of the left/right symmetric neuron pairs and is required to induce neuronal identity and terminal selector expression on the contralateral side of the animal. These findings demonstrate that distinct lineage histories converge via distinct bHLH factors on the level of induction of terminal selector identity determinants, which thus serve as integrators of distinct lineage histories. We also describe neuron-to-neuron identity transformations inlin-32/Atomutants, which we propose to also be the result of misregulation of terminal selector gene expression.
Short-interval reburns in the boreal forest alter soil bacterial communities, reflecting increased pH and poor conifer seedling establishment
Authors: Woolet Jamie , Whitman Ellen , Parisien Marc-André , Thompson Dan K. , Flannigan Mike D. , Whitman Thea
Published: April 2021

Increasing burn rates (percentage area burned annually) in some biomes are leading to fires burning in close succession, triggering rapid vegetation change as well as altering soil properties. Despite the importance of soil microbes for nutrient cycling and as plant symbionts, the effects of increased fire frequency on belowground microbial communities remain largely unknown. We present a study of the effects of short interval reburns (defined here as <20 years between fires) on soil bacterial communities in the boreal forest of northwestern Canada, using a paired site design that spans wetlands and uplands, with 50 sites total. We asked whether short interval reburns significantly alter soil bacterial community composition and richness, and which bacterial taxa are associated with greater or lower fire frequency. We found that, while short interval reburns had no significant effect on bacterial richness, there were significant changes in overall community composition. We did not find correlations between understory vegetation community dissimilarities and bacterial community dissimilarities, suggesting the primary drivers of changes induced by short interval reburns may differ between plants and microbes. We identified an abundantBlastococcus sp. that was consistently enriched in short interval reburns, in both wetlands and uplands, indicating its role as a strongly “pyrophilous” bacterium. We also identified an abundantCallaberonia sordidicolataxon as being consistently depleted in short interval reburns. This endophytic diazotrophic organism is a robust colonizer of pine and spruce seedlings and has the ability to increase seedling growth, due in part to large contributions of fixed nitrogen. Its depletion in short-interval reburn sites raises questions about whether this is contributing to – or merely reflects – poor conifer seedling recolonization post-fire at short-interval reburns.
To knot or not to knot: Multiple conformations of the SARS-CoV-2 frameshifting RNA element
Authors: Schlick Tamar , Zhu Qiyao , Dey Abhishek , Jain Swati , Yan Shuting , Laederach Alain
Published: April 2021

The SARS-CoV-2 frameshifting RNA element (FSE) is an excellent target for therapeutic intervention against Covid-19. This small gene element employs a shifting mechanism to pause and backtrack the ribosome during translation between Open Reading Frames 1a and 1b, which code for viral polyproteins. Any interference with this process has profound effect on viral replication and propagation. Pinpointing the structures adapted by the FSE and associated structural transformations involved in frameshifting has been a challenge. Using our graph-theory-based modeling tools for representing RNA secondary structures, “RAG” (RNA-As-Graphs), and chemical structure probing experiments, we show that the 3-stem H-type pseudoknot (3_6 dual graph), long assumed to be the dominant structure has a viable alternative, an HL-type 3-stem pseudoknot (3_3) for longer constructs. In addition, an unknotted 3-way junction RNA (3_5) emerges as a minor conformation. These three conformations share Stems 1 and 3, while the different Stem 2 may be involved in a conformational switch and possibly associations with the ribo-some during translation. For full-length genomes, a stem-loop motif (2_2) may compete with these forms. These structural and mechanistic insights advance our understanding of the SARS-CoV-2 frameshifting process and concomitant virus life cycle, and point to three avenues of therapeutic intervention.
Decreased adaptation at human disease genes as a possible consequence of interference between advantageous and deleterious variants
Authors: Di Chenlu , Tortosa Diego Salazar , Lauterbur M. Elise , Enard David
Published: April 2021

Advances in genome sequencing have dramatically improved our understanding of the genetic basis of human diseases, and thousands of human genes have been associated with different diseases. Despite our expanding knowledge of gene-disease associations, and despite the medical importance of disease genes, their evolution has not been thoroughly studied across diverse human populations. In particular, recent genomic adaptation at disease genes has not been well characterized, even though multiple evolutionary processes are expected to connect disease and adaptation at the gene level. Understanding the relationship between disease and adaptation at the gene level in the human genome is severely hampered by the fact that we don’t even know whether disease genes have experienced more, less, or as much adaptation as non-disease genes during recent human evolution. Here, we compare the rate of strong recent adaptation in the form of selective sweeps between disease genes and non-disease genes across 26 distinct human populations from the 1,000 Genomes Project. We find that disease genes have experienced far less selective sweeps compared to non-disease genes during recent human evolution. This sweep deficit at disease genes is particularly visible in Africa, and less visible in East Asia or Europe, likely due to more intense genetic drift in the latter populations creating more spurious selective sweeps signals. Investigating further the possible causes of the sweep deficit at disease genes, we find that this deficit is very strong at disease genes with both low recombination rates and with high numbers of associated disease variants, but is inexistant at disease genes with higher recombination rates or lower numbers of associated disease variants. Because recessive deleterious variants have the ability to interfere with adaptive ones, these observations strongly suggest that adaptation has been slowed down by the presence of interfering recessive deleterious variants at disease genes. These results clarify the evolutionary relationship between disease genes and recent genomic adaptation, and suggest that disease genes suffer not only from a higher load of segregating deleterious mutations, but also an inability to adapt as much, and/or as fast as the rest of the genome.
Two timescales control the creation of large protein aggregates in
cells
Authors: Miangolarra A. Movilla , Duperray-Susini A. , Coppey M. , Castellana M.
Published: April 2021

Protein aggregation is of particular interest due to its connection with
many diseases and disorders. Many factors can alter the dynamics and result of
this process, one of them being the diffusivity of the monomers and aggregates
in the system. Here, we study experimentally and theoretically an aggregation
process in cells, and we identify two distinct physical timescales that set the
number and size of aggregates. The first timescale involves fast aggregation of
small clusters freely diffusing in the cytoplasm, while, in the second one, the
aggregates are larger than the pore size of the cytoplasm and thus barely
diffuse, and the aggregation process is slowed down. However, the process is not
entirely halted, potentially reflecting a myriad of active but random forces
forces that stir the aggregates. Such slow timescale is essential to account for
the experimental results of the aggregation process. These results could also
have implications in other processes of spatial organization in cell biology,
such as phase-separated droplets.

SIGNIFICANCE

Protein aggregation is a physico-chemical process that underlies
many diseases and disorders, such as Alzheimer’s or Huntington’s
disease. Here, we study experimental and theoretically the effect of
a sharp decrease of diffusivity in the aggregation dynamics, such as
the one that could happen in the cell due to the presence of
obstacles. We find that two different timescales are important in
setting the size of large aggregates and we give an estimate of the
size of the aggregate at which this dramatic change in behaviour
occurs, which could not be exclusive of protein aggregation but
affect many other intracellular processes.
A HIT-trapping strategy for rapid generation of reversible and conditional alleles using a universal donor
Authors: Lu Hengxing , Liu Jun , Feng Tao , Guo Zihang , Yin Yunjun , Gao Fei , Cao Gengsheng , Du Xuguang , Wu Sen
Published: April 2021

Targeted mutagenesis in model organisms is key for gene functional annotation and biomedical research. Despite technological advances in gene editing by the CRISPR-Cas9 systems, rapid and efficient introduction of site-directed mutations remains a challenge in large animal models. Here, we developed a robust and flexible insertional mutagenesis strategy, homology-independent targeted trapping (HIT-trapping), which is generic and can efficiently target-trap an endogenous gene of interest independent of homology arm and embryonic stem cells. Further optimization and equipping the HIT-trap donor with a site-specific DNA inversion mechanism enabled one-step generation of reversible and conditional alleles in a single experiment. As a proof of concept, we successfully created mutant alleles for 21 disease-related genes in primary porcine fibroblasts with an average knock-in frequency of 53.2%, a great improvement over previous approaches. The versatile HIT-trapping strategy presented here is expected to simplify the targeted generation of mutant alleles and facilitate large-scale mutagenesis in large mammals such as pigs.
Live Imaging of Cytoskeletal Dynamics in Embryonic Xenopus laevis Growth Cones and Neural Crest Cells
Authors: Erdogan Burcu , Bearce Elizabeth A. , Lowery Laura Anne
Published: April 2021

The cytoskeleton is a dynamic, fundamental network that not only provides mechanical strength to maintain a cell's shape but also controls critical events like cell division, polarity, and movement. Thus, how the cytoskeleton is organized and dynamically regulated is critical to our understanding of countless processes. Live imaging of fluorophore-tagged cytoskeletal proteins allows us to monitor the dynamic nature of cytoskeleton components in embryonic cells. Here, we describe a protocol to monitor and analyze cytoskeletal dynamics in primary embryonic neuronal growth cones and neural crest cells obtained from Xenopus laevis embryos.
Patients' perceptions of quality in Swedish primary care – a study of differences between private and public ownership
Authors: Andersson Thomas , Eriksson Nomie , Müllern Tomas
Published: April 2021

Purpose

The purpose of the paper is to describe and analyze differences in patients' quality perceptions of private and public primary care centers in Sweden.

Design/methodology/approach

The article explores the differences in quality perceptions between patients of public and private primary care centers based on data from a large patient survey in Sweden. The survey covers seven dimensions, and in this paper the measure Overall impression was used for the comparison. With more than 80,000 valid responses, the survey covers all primary care centers in Sweden which allowed for a detailed analysis of differences in quality perceptions among patients from the different categories of owners.

Findings

The article contributes with a detailed description of different types of private owners: not-for-profit and for profit, as well as corporate groups and independent care centers. The results show a higher quality perception for independent centers compared to both public and corporate groups.

Research limitations/implications

The small number of not-for-profit centers (21 out of 1,117 centers) does not allow for clear conclusions for this group. The results, however, indicate an even higher patient quality perception for not-for-profit centers. The study focus on describing differences in quality perceptions between the owner categories. Future research can contribute with explanations to why independent care centers receive higher patient satisfaction.

Social implications

The results from the study have policy implications both in a Swedish as well as international perspective. The differentiation between different types of private owners made in this paper opens up for interesting discussions on privatization of healthcare and how it affects patient satisfaction.

Originality/value

The main contribution of the paper is the detailed comparison of different categories of private owners and the public owners.
Fine‐scale environmental heterogeneity and conservation management: Beach‐cast wrack creates microhabitats for thermoregulation in shorebirds
Authors: Davis Timothy John , Keppel Gunnar
Published: April 2021

Conservation management to protect coastal ecosystems sometimes overlooks site‐specific fine‐scale heterogeneity. For example, while habitat loss is a known key driver of population declines in many shorebirds, these birds are also dependent on high‐quality habitats to maximize energy stores. Here we describe the microhabitats provided by beach‐cast wrack (washed up macroalgae and seagrasses), a resource threatened by harvesting and beach cleaning, and how shorebirds utilize these.

We measured the temperature and absolute humidity at 10 cm above three substrates (fresh wrack, aged wrack and sand) and then related bird behaviour (roosting vs. foraging) to climatic and environmental data.

Freshly beach‐cast wrack mostly provided cooler and less humid habitats, but warmer temperatures than aged wrack or sand in the early mornings. Microtopography created by shelter from prevailing winds and wrack depth modified these general trends.

Generally, temperature predicted where shorebirds overall and the two most common species, the double‐banded plover Charadrius bicinctus and red‐necked stint Calidris ruficollis, were observed. During most of the day, foraging and roosting were more likely to occur on the warmer aged wrack. In the early morning, when fresh wrack provided the warmer temperatures, birds tended to roost and forage on fresh wrack.

Synthesis and Applications. Beach‐cast wrack creates a complex mosaic of unique microclimates varying in space and time, which allows shorebirds to minimize energy expenditure by selecting the thermally most favourable habitats for roosting and foraging. Removal of beach‐cast wrack for commercial and aesthetic reasons thus reduces habitat quality and increases energy expenditure in shorebirds. Associated declines in energy stores may be contributing to declines in shorebird populations. Management of coastal ecosystems and shorebirds therefore needs to consider and maintain fine‐scale environmental heterogeneity at local scales.
Large predators can mitigate nutrient losses associated with off‐site removal of animals from a wildlife reserve
Authors: Abraham Andrew J. , Webster Andrea B. , Prys‐Jones Tomos O. , le Roux Elizabeth , Smith Dylan , McFayden Duncan , de Jager Pieter C. , Clauss Marcus , Doughty Christopher E.
Published: April 2021

Animals concentrate key nutrients in their bodies. In fenced wildlife reserves where nutrient input and/or retention is low, the off‐site removal of animals may constitute a significant loss of nutrients for the ecosystem.

Here we add wildlife capture and removal into the phosphorus (P) and calcium (Ca) budget for a 121,700 ha fenced game reserve located in the southern Kalahari. We then use faecal P concentrations from 11 mammal herbivores >10 kg as an indicator of potential nutrient stress in this system to investigate whether the implications of nutrient loss via off‐site wildlife removal may be cause for concern. Finally, we assess the role of natural predation as a mechanism to minimise the need for wildlife removal and concomitant nutrient loss.

During the period 2009–2018, mean loss of P and Ca via wildlife removal was 2.9 and 6.2 kg km−2 year−1, respectively. This compares to 1.0 and 2.1 kg km−2 year−1 of P and Ca added via the provision of mineral licks. If it is assumed that natural fluxes of these elements are in steady state, then anthropogenic activities have resulted in a net deficit of 18.5 kg/km2 of P and 40.6 kg/km2 of Ca over the decade.

We found that dry season herbivore faecal P concentrations are close to or below a widely cited minimum threshold of 2,000 mg/kg, below which most vertebrates begin suffering growth and reproductive issues. Large animals were more likely to be under this threshold. Prolonged continuation of off‐site wildlife removal may result in nutrient losses that can lead to long‐term ecological degradation. Natural predation levels were, however, found sufficient to mitigate the need for wildlife removal and present a management strategy whereby herbivore populations can be regulated without a loss of nutrients.

Synthesis and applications. We find that the capture and permanent removal of large‐bodied animals from wildlife reserves can be a significant cause of nutrient loss. Over time, in sites where nutrient input and/or retention is low, this may contribute to nutritional stress for remaining resident animals. Where possible, holistic management strategies that promote the retention of animals and carcasses within the reserve—such as the reintroduction of large carnivores—should be preferred.
A meta‐analysis of the influence of anthropogenic noise on terrestrial wildlife communication strategies
Authors: Duquette Cameron Albert , Loss Scott R. , Hovick Torre J.
Published: April 2021

Human‐caused noise pollution dominates the soundscape of modern ecosystems, from urban centres to national parks. Although wildlife can generally alter their communication to accommodate many types of natural noise (e.g. wind, wave action, heterospecific communication), noise pollution from anthropogenic sources pushes the limits of wildlife communication flexibility by causing loud, low‐pitched and near‐continuous interference. Because responses to noise pollution are variable and taxa specific, multi‐species risk assessments and mitigation are not currently possible.

We conducted a meta‐analysis to synthesize noise pollution effects on terrestrial wildlife communication. Specifically, we assessed: (a) the impacts of noise pollution on modulation of call rate, duration, amplitude and frequency (including peak, minimum and maximum frequency); and (b) the literature on anthropogenic noise pollution by region, taxa, study design and disturbance type.

Terrestrial wildlife (results driven by avian studies) generally respond to noise pollution by calling with higher minimum frequencies, while they generally do not alter the amplitude, maximum frequency, peak frequency, duration and rate of calling.

The literature on noise pollution research is biased towards birds, population‐level studies, urban noise sources and study systems in North America.

Synthesis and applications. Our study reveals the ways in which wildlife can alter their signals to contend with anthropogenic noise, and discusses the potential fitness and management consequences of these signal alterations. This information, combined with an identification of current research needs, will allow researchers and managers to better develop noise pollution risk assessment protocols and prioritize mitigation efforts to reduce anthropogenic noise.
EVERYTHING POSSIBLE AND NOTHING TRUE: NOTES ON THE CAPITOL INSURRECTION
Authors: Dalsheim Joyce , Starrett Gregory
Published: April 2021

On 6 January 2021, an overwhelmingly white, Christian mob stormed the US Capitol building in Washington DC as part of a rally to ‘Save America’. Moving beyond media reports and the analyses of popular pundits, the authors provide an ethnographic outline of some of the complexities and contradictions on display that day. Thinking with Hannah Arendt, Emmanuel Ladurie, Ursula LeGuin and others, these notes frame the rally preceding the attack on the Capitol in terms of historical narrative, carnival aesthetics and Christian symbolisms of salvation. The rally and attempted insurrection displayed multiple social and symbolic inversions, combining yearnings for order and stability with parody, playful optimism and violent threat. Unlike many other pre‐Lenten carnivals, here it was never entirely clear which social order was being overturned and which was being reinstated, one result of the deeply divided world views that currently characterize much of the US population.
Precarity's reach: intersections of history, life, and labour in the Australian horticultural industry
Authors: Stead Victoria
Published: April 2021

The temporary labour migrations of Pacific Islanders to work in the orchards and packing sheds of the Australian horticultural industry feed the demands for flexible labour that are marks of the precarious present. At the same time, their labour experiences call attention to the diverse, historically situated, and racialized configurations of power and risk that converge in the present moment within particular places and within the intersecting lives and bodies of differently positioned others. Focused on a fruit packing shed in north‐central Victoria, and on the ni‐Vanuatu workers, farmers, managers, and mediating agents who meet there, this article seeks to develop an ethnography of precarity's intersections. Here, the insecurities and fraying reciprocities widely theorized in the context of post‐Fordist, neoliberal precarity articulate with the hierarchies and imaginaries of development regimes, the colonial co‐production of Global North and South, and the always‐precarious rhythms of horticultural production. Precarity, I argue, is neither particular to the post‐Fordist relations of Western Europe, nor an all‐consuming leveller of historical, cultural, and place‐based difference. Rather, it emerges out of the situated convergences of diverse people and histories, and practices of both mobility and containment, producing intersecting but ultimately unequal distributions of risk.
Determination of gelation properties and bio‐therapeutic potential of black carrot fibre‐enriched functional yoghurt produced using pectin and gum arabic as prebiotic
Authors: Karaman Saliha , Ozcan Tulay
Published: April 2021

In this study, bacterial viability, changes in gel matrix properties of functional yoghurts produced with the addition of black carrot (Daucus carota ssp. sativus var. atrorubens Alef variety) fibre, pectin and gum arabic during storage, was investigated with consumer preference and bio‐therapeutic potential. Streptococcus thermophilus, Lactobacillus delbrueckii subsp. bulgaricus, Lactobacillus acidophilus and Bifidobacterium animalis subsp. lactis cultures were used in the production of probiotic yoghurts. It was found that the addition of pectin, gum arabic and black carrot fibre to probiotic yoghurt stimulated the growth of probiotic bacteria and gel development during storage. The viability of the probiotic bacteria was determined within the bio‐therapeutic level (>7 log10 cfu/g) with potential prebiotic effects. It was determined that black carrot, pectin and gum arabic addition increased the total phenolic content and antioxidant activity of probiotic yoghurts, as well as improved the textural properties. Sensorial attributes increased throughout storage with yoghurts containing gum arabic and black carrot displayed higher scores for sensorial qualifications.
YALI0C22088g from Yarrowia lipolytica catalyses the conversion of l‐methionine into volatile organic sulfur‐containing compounds
Authors: Zhao Quan‐Lu , Wang Zhu‐Lin , Yang Lan , Zhang Sai , Jia Kai‐Zhi
Published: April 2021

The enzymatic conversion of l‐methionine (l‐Met) into volatile organic sulfur‐containing compounds (VOSCs) plays an important role in developing the characteristic aroma of foods. However, the mechanism for the direct conversion of l‐Met into VOSCs is still unclear in yeast cells used to make food products. Here, we show that the transcription profile of YALI0C22088g from Yarrowia lipolytica correlates positively with l‐Met addition. YALI0C22088g catalyses the γ‐elimination of l‐Met, directly converting l‐Met into VOSCs. YALI0C22088g also exhibits strong C‐S lysis activities towards l‐cystathionine and the other sulfur‐containing compounds and forms a distinct cystathionine‐γ‐lyase subgroup. We identified eight key amino acid residues in YALI0C22088g, and we inferred that the size of the tunnel and the charges carried by the entrance amino acid residue are the determinants for the enzymatic conversion of l‐Met into VOSCs. These findings reveal the formation mechanism of VOSCs produced directly from l‐Met via the demethiolation pathway in Yarrowia lipolytica, which provides a rationale for engineering the enzymatic conversion of l‐Met into VOSCs and thus stimulates the enzymatic production of aroma compounds.
Is denosumab associated with an increased risk for infection in patients with low bone mineral density? A systematic review and meta‐analysis of randomized controlled trials
Authors: Catton Brett , Surangiwala Salman , Towheed Tanveer
Published: April 2021

Aim

Denosumab increases bone mineral density through inhibition of the receptor activator of nuclear factor κ‐Β ligand (RANKL). RANKL has known immunomodulatory effect. The largest study to date that reviewed denosumab efficacy in osteoporosis demonstrated an increased incidence of serious adverse events of infection (SAEI). We aimed to further evaluate risk of infection and SAEI in denosumab‐treated patients.

Method

PubMed, Embase, Cochrane Central Register of Controlled Trials, and Web of Science were searched for randomized controlled trials. Studies comparing denosumab 60 mg every 6 months with placebo or bisphosphonate for treatment of low bone mineral density were included. Trials were excluded for use of denosumab in cancer patients treated for skeletal‐related events, immunosuppressed patient populations, or for comparison to teriparatide. Risk ratios (RR) with a 95% confidence interval (CI) were pooled using a fixed effects model, or a random effects model if heterogeneity occurred.

Results

Twenty‐four randomized controlled trials (20 470 patients) were analyzed. An increased incidence of any infection (RR 1.11; 95% CI 1.02‐1.20; P = 0.02) was observed in denosumab‐treated patients compared with bisphosphonates, but not when compared with placebo. In contrast, a higher incidence of SAEI (RR 1.21; 95% CI 1.03‐1.43; P = 0.02) was seen with denosumab when compared with placebo, but not compared with bisphosphonates.

Conclusion

Denosumab‐treated patients with low bone mineral density have slightly increased incidence of SAEI compared with placebo, but not when compared with bisphosphonates. Application of these results requires consideration of the entire body of data available regarding denosumab safety.
The effects of climate change on Australia’s only endemic Pokémon: Measuring bias in species distribution models
Authors: Warren Dan L. , Dornburg Alex , Zapfe Katerina , Iglesias Teresa L.
Published: April 2021

Species distribution models (SDMs) are frequently used to predict the effects of climate change on species of conservation concern. Biases inherent in the process of constructing SDMs and transferring them to new climate scenarios may result in undesirable conservation outcomes. We explore these issues and demonstrate new methods to estimate biases induced by the design of SDM studies. We present these methods in the context of estimating the effects of climate change on Australia's only endemic Pokémon.

Using a citizen science dataset, we build species distribution models for Garura kangaskhani to predict the effects of climate change on the suitability of habitat for the species. We demonstrate a novel Monte Carlo procedure for estimating the biases implicit in a given study design, and compare the results seen for Pokémon to those seen from our Monte Carlo tests as well as previous studies in the same region using both simulated and real data.

Our models suggest that climate change will impact the suitability of habitat for G. kangaskhani, which may compound the effects of threats such as habitat loss and their use in blood sport. However, we also find that using SDMs to estimate the effects of climate change can be accompanied by biases so strong that the data themselves have minimal impact on modelling outcomes.

We show that the direction and magnitude of bias in estimates of climate change impacts are affected by every aspect of the modelling process, and suggest that bias estimates should be included in future studies of this type. Given the widespread use of SDMs, systemic biases could have substantial financial and opportunity costs. By demonstrating these biases and presenting a novel statistical tool to estimate them, we hope to provide a more secure future for G. kangaskhani and the rest of the world's biodiversity.
Manic morbidity and executive function impairment as determinants of long‐term psychosocial dysfunction in bipolar disorder
Authors: Lomastro María Julieta , Valerio Marina P. , Szmulewicz Alejandro G. , Martino Diego J.
Published: April 2021

Objective

In this study, we aimed to evaluate the role of cognitive performance and measures of clinical course—including both syndromal and subsyndromal symptomatology—as determinants of the functional outcome of patients with Bipolar Disorder (BD) during a mean follow‐up period of more than 4 years.

Methods

Seventy patients with euthymic BD completed a neurocognitive battery at study entry. Clinical course was assessed prospectively for a period longer than 48 months by two measures: time spent ill (documented using a modified life charting technique) and density of affective episodes (defined as the number of depressive and hypo/manic episodes per year of follow‐up). Psychosocial functioning was assessed during euthymia using the Functioning Assessment Short Test (FAST) total score at the end of follow‐up period.

Results

Baseline deficits in phonological fluency, a measure of executive functions (β = −2.49; 95% CI = −3.98, −0.99), and density of hypo/manic episodes during follow‐up (β = 6.54; 95% CI = 0.43, 12.65) were independently associated with FAST total score at the end of study.

Conclusions

Although interrelated, manic morbidity and executive function impairments independently contribute to long‐term psychosocial dysfunction in BD and could be potential targets of intervention.
Effect of rurality and socioeconomic deprivation on presentation stage and long‐term outcomes in patients undergoing surgery for colorectal cancer
Authors: Pasch James A. , MacDermid Ewan , Velovski Susan
Published: April 2021

Background

Geographical remoteness and socioeconomic status (SES) are important factors affecting presentation stage and survival for colorectal cancer. A series of patients from a single institution in northern New South Wales was studied to determine if rural isolation or SES affected presentation and survival in patients undergoing resection.

Methods

Consecutive colorectal cancer resections performed at Lismore Base Hospital from 2011 to 2019 were identified. Patient residential addresses were categorized by the Modified Monash Model (MMM), an Australian Government definition of rural isolation, and Socioeconomic Index for Areas (SEIFA) quintiles, an Australian Bureau of Statistics index of socioeconomic deprivation. Univariate and Cox regression survival analysis was performed on data from histopathology and clinical notes matched with survival data.

Results

A total of 405 patients were included in MMM categories 3 (n = 207, 51.1%), 4 (n = 69, 17%) and 5 (n = 129, 31.9) corresponding to large, medium and small rural towns. MMM 3 was associated with emergency cases (25.6% versus 18.7%, P < 0.001), nodal disease (44.4% versus 38.4%, P = 0.018) and T3/4 tumours (82.1% versus 73.7%, P < 0.001) compared with isolated patients without difference in 5‐year survival (P = 0.370). Disadvantaged SEIFA quintiles 1/2 demonstrated increased poor differentiation (23.0% versus 15.4%, P < 0.001) and vascular invasion (15.8% versus 9.1%, P < 0.001) with reduced 5‐year survival (57.0% versus 70.4%, P = 0.039). Independent predictors of survival included age, emergency cases, group stage, lymphatic invasion and low lymph node yield.

Conclusion

A ‘rural reversal’ may be present for patients in northern New South Wales; however, SES and established clinicopathological factors are the strongest predictors of survival in our population.
Lateral versus cross pinning in paediatric supracondylar humerus fractures: a meta‐analysis of randomized control trials
Authors: Kwok Samuel M. , Clayworth Catriona , Nara Naveen
Published: April 2021

Background

Supracondylar humerus fractures are common in children. Percutaneous pinning remains the mainstay in treatment; however, there is lack of consensus on the optimal configuration: lateral‐only pinning or cross pinning. This study aims to investigate the differences in clinical and surgical outcomes between lateral‐only and cross‐pinning paediatric supracondylar humerus fractures.

Methods

A systematic search was performed using Medline Ovid, Embase and Cochrane databases for relevant randomized control trials comparing lateral and cross pinning of paediatric supracondylar humerus fractures, reporting at least one of the following: rate of iatrogenic ulnar nerve injury, loss of reduction, infection, loss of Baumann's angle and loss of carrying angle. Statistical analysis was performed using STATA 13.0.

Results

Eleven suitable randomized control trials involving 900 patients were reviewed. Loss of reduction was more common with lateral pinning (relative risk 1.44, 95% confidence interval 1.04–2.00, P = 0.027). Iatrogenic ulnar nerve injury was less common in lateral pinning with treatment‐based analysis (relative risk 0.36, 95% confidence interval 0.14–0.92, P = 0.032). There was no statistically significant difference in loss of carrying angle, loss of Baumann angle or rate of infection.

Conclusion

Cross pinning provides superior stability in the treatment of supracondylar humerus fractures in children; however, it carries greater risk of iatrogenic ulnar nerve injury.
Restricted function‐on‐function linear regression model
Authors: Luo Ruiyan , Qi Xin
Published: April 2021

The usual function‐on‐function linear regression model depicts the association between functional variables in the whole rectangular region and the value of response curve at any point is influenced by the entire trajectory of the predictor curve. But in addition to this, there are cases where the value of the response curve at a point is only influenced by the value of the predictor curve in a subregion, such as the historical relationship and the short‐term association. We will consider the restricted function‐on‐function regression model, where the value of response curve at any point is influenced by a subtrajectory of the predictor. We have two major purposes. First, we propose a novel estimation procedure that is more accurate and computational efficient for the restricted function‐on‐function model with a given subregion. Second, as the subregion is seldom specified in practice, we propose a subregion selection procedure that can lead to models with better interpretation and predictive performance. Algorithms are developed for both model estimation and subregion selection.
Should patients with low‐risk renal cell carcinoma be followed differently after nephron‐sparing surgery vs radical nephrectomy?
Authors: Abu‐Ghanem Yasmin , Powles Thomas , Capitanio Umberto , Beisland Christian , Järvinen Petrus , Stewart Grant D. , Gudmundsson Eirikur , Lam Thomas B.L. , Marconi Lorenzo , Fernandéz‐Pello Sergio , Nisen Harry , Meijer Richard P. , Volpe Alessandro , Ljungberg Börje , Klatte Tobias , Bensalah Karim , Dabestani Saeed , Bex Axel
Published: April 2021

Objective

To investigate whether pT1 renal cell carcinoma (RCC) should be followed differently after partial (PN) or radical nephrectomy (RN) based on a retrospective analysis of a multicentre database (RECUR).

Subjects

A retrospective study was conducted in 3380 patients treated for nonmetastatic RCC between January 2006 and December 2011 across 15 centres from 10 countries, as part of the RECUR database project. For patients with pT1 clear‐cell RCC, patterns of recurrence were compared between RN and PN according to recurrence site. Univariate and multivariate models were used to evaluate the association between surgical approach and recurrence‐free survival (RFS) and cancer‐specific mortality (CSM).

Results

From the database 1995 patients were identified as low‐risk patients (pT1, pN0, pNx), of whom 1055 (52.9%) underwent PN. On multivariate analysis, features associated with worse RFS included tumour size (hazard ratio [HR] 1.32, 95% confidence interval [CI] 1.14–1.39; P < 0.001), nuclear grade (HR 2.31, 95% CI 1.73–3.08; P < 0.001), tumour necrosis (HR 1.5, 95% CI 1.03–2.3; P = 0.037), vascular invasion (HR 2.4, 95% CI 1.3–4.4; P = 0.005) and positive surgical margins (HR 4.4, 95% CI 2.3–8.5; P < 0.001). Kaplan–Meier analysis of CSM revealed that the survival of patients with recurrence after PN was significantly better than those with recurrence after RN (P = 0.02). While the above‐mentioned risk factors were associated with prognosis, type of surgery alone was not an independent prognostic variable for RFS nor CSM. Limitations include the retrospective nature of the study.

Conclusion

Our results showed that follow‐up protocols should not rely solely on stage and type of primary surgery. An optimized regimen should also include validated risk factors rather than type of surgery alone to select the best imaging method and to avoid unnecessary imaging. A follow‐up of more than 3 years should be considered in patients with pT1 tumours after RN. A novel follow‐up strategy is proposed.
Longitudinal follow‐up and performance validation of an mRNA‐based urine test (Xpert® Bladder Cancer Monitor ) for surveillance in patients with non‐muscle‐invasive bladder cancer
Authors: Cowan Barrett , Klein Eric , Jansz Ken , Westenfelder Karl , Bradford Timothy , Peterson Chad , Scherr Douglas , Karsh Lawrence I. , Egerdie Blair , Witjes Alfred , Trainer Andrew , Harris Richard , Goldfarb Bernard , Flax Stanley , Kroeger Robert , Boyd Buffi , Liao Joseph , Patel Sanjay , Bridge Julia , Reuter Victor , Quigley Neil , Brown Sarah , Zhao Suling , Satya Malini , Bates Michael , Simon Iris M. , Campbell Scott , Lotan Yair
Published: April 2021

Objective

To evaluate the performance of the Xpert Bladder Cancer Monitor (Xpert; Cepheid, Sunnyvale, CA, USA) test as a predictor of tumour recurrence in patients with non‐muscle‐invasive bladder cancer (NMIBC).

Patients and Methods

Patients (n = 429) undergoing surveillance for NMIBC underwent Xpert, cytology, and UroVysion testing. Patients with a positive Xpert and a negative cystoscopy result (positive‐negative [PN] group, n = 66) and a control group of double negative patients (negative Xpert and cystoscopy results [NN] group) were followed for 12 months (±90 days).

Results

Histology‐confirmed recurrences were detected in 58 patients (13.5%). Xpert had an overall sensitivity of 60.3% and a specificity of 76.5%. The sensitivity for high‐grade (HG) cancer was 87% with a negative predictive value (NPV) of 99%. Urine cytology showed an overall sensitivity of 23.2% (47.6% sensitivity for HG tumours) and a specificity of 88.3%. In the PN group, 32% (n = 21) developed a recurrence within 12 months, 11 of which were HG tumours. In the NN control group, 14% (n = 9) developed a recurrence and only two were HG tumours. The hazard ratio for developing recurrence in the PN group was 2.68 for all tumours and 6.84 for HG cancer.

Conclusions

The Xpert test has a high sensitivity for detecting the recurrence of cancer and a high NPV for excluding HG cancer. In addition, the data suggest that patients with a positive Xpert assay in the setting of negative cystoscopy are at high risk for recurrence and need close surveillance.