bluuebunny/crossref_metadata_2025 huggingface dataset:
Behavioural stress feedback loops in benthic invertebrates caused by pH drop-induced metabolites
Authors: Feugere Lauric , Angell Lauren , Fagents James , Nightingale Rebecca , Rowland Kirsty , Skinner Saffiyah , Hardege Jorg , Bartels-Hardege Helga , Valero Katharina C. Wollenberg
Published: April 2021

Studies on pH stress in marine animals typically focus on direct or species-specific aspects. We here test the hypothesis that a drop to pH = 7.6 indirectly affects the intra- and interspecific interactions of benthic invertebrates by means of chemical communication. We recorded fitness-relevant behaviours of small hermit crabsDiogenes pugilator, green shore crabsCarcinus maenas, and harbour ragwormsHediste diversicolorin response to short-term pH drop, and to putative stress metabolites released by conspecifics or gilt-head sea breamSparus aurataduring 30 minutes of acute pH drop. Not only did acute pH drop itself impair time to find a food cue in small hermit crabs and burrowing in harbour ragworms, but similar effects were observed under exposure to pH drop-induced stress metabolites. Stress metabolites fromS. aurata,but not its regular control metabolites, also induced avoidance responses in all recipient species. Here, we confirm that a short-term abrupt pH drop, an abiotic stressor, has the capacity to trigger the release of metabolites which induce behavioural responses in conspecific and heterospecific individuals, which can be interpreted as a behavioural cost. Our findings that stress responses can be indirectly propagated through means of chemical communication warrant further research to confirm the effect size of the behavioural impairments caused by stress metabolites and to characterise their chemical nature.
Genomic Analysis of Hypoxia Inducible Factor Alpha Evolution in Ray-finned Fishes (Actinopterygii)
Authors: Townley Ian K. , Rees Bernard B.
Published: April 2021

Two rounds of genome duplication (GD) in the ancestor of vertebrates, followed by additional GD during the evolution of ray-finned fishes (Actinopterygii), expanded certain gene families, including those encoding the hypoxia inducible transcription factor (HIF). The present study analyzed Actinopterygian genomes for duplicates of HIFα, the subunit that confers oxygen-dependent gene regulation. In contrast to tetrapod vertebrates that retain three HIFα genes from the ancestral vertebrate GD, four HIFα forms were found in the genomes of primitive Actinopterygians (spotted gar and Asian arowana). All four forms have been retained in zebrafish and related species (Otocephala) and salmonids and their sister taxa (northern pike) but one of them (HIF4α) was lost during the evolution of more derived fishes (Neoteleostei). In addition, the current analyses confirm that Otocephala retain duplicates of HIF1α and HIF2α from the teleost-specific GD, provide new evidence of salmonid-specific duplicates of HIF1α, HIF2α, and HIF3α, and reveal a broad distribution of a truncated form of HIF2α in salmonids and Neoteleostei. This study delivers a comprehensive view of HIFα evolution in the ray-finned fishes, highlights the need for a consistent nomenclature, and suggests avenues for future research on this critical transcription factor.
Parallel introgression, not recurrent emergence, explains apparent elevational ecotypes of polyploid Himalayan snowtrout
Authors: Chafin Tyler K. , Regmi Binod , Douglas Marlis R. , Edds David R. , Wangchuk Karma , Dorji Sonam , Norbu Pema , Norbu Sangay , Changlu Changlu , Khanal Gopal Prasad , Tshering Singye , Douglas Michael E.
Published: April 2021

The recurrence of similar evolutionary patterns within different habitats often reflects parallel selective pressures acting upon either standing or independently occurring genetic variation to produce a convergence of phenotypes. This interpretation (i.e. parallel divergences within adjacent streams) has been hypothesized for drainage-specific morphological ‘ecotypes’ observed in polyploid snowtrout (Cyprinidae: Schizothorax). However, parallel patterns of differential introgression during secondary contact is a viable alternative hypothesis. Here, we utilized ddRADseq (N=35,319 de-novo and N=10,884 transcriptome-aligned SNPs), as derived from Nepali/Bhutanese samples (N=48 each), to test these competing hypotheses. We first employed genome-wide allelic depths to derive appropriate ploidy models, then a Bayesian approach to yield genotypes statistically consistent under the inferred expectations. Elevational ‘ecotypes’ were consistent in geometric-morphometric space, but with phylogenetic relationships at the drainage-level, sustaining an hypothesis of independent emergence. However, partitioned analyses of phylogeny and admixture identified subsets of loci under selection that retained genealogical concordance with morphology, suggesting instead that apparent patterns of morphological/phylogenetic discordance are driven by widespread genomic homogenization. Here, admixture occurring in secondary contact effectively ‘masks’ previous isolation. Our results underscore two salient factors:1) Morphological adaptations are retained despite hybridization; and 2) The degree of admixture varies across tributaries, presumably concomitant with underlying environmental or anthropogenic factors.
Stripenn detects architectural stripes from chromatin conformation data using computer vision
Authors: Yoon Sora , Vahedi Golnaz
Published: April 2021

Architectural stripes tend to form at genomic regions harboring genes with salient roles in cell identity and function. Therefore, the accurate identification and quantification of these features is essential for the understanding of lineage-specific gene regulation. Here, we present Stripenn, an algorithm rooted in computer vision to systematically detect and quantitate architectural stripes from chromatin conformation measurements of various technologies. We demonstrate that Stripenn outperforms existing methods, highlight its biological applications in the context of B and T lymphocytes, and examine the role of sequence variation on architectural stripes by studying the conservation of these features in inbred strains of mice. In summary, Stripenn is a computational method which borrows concepts from widely used image processing techniques for demarcation and quantification of architectural stripes.
Emergent vulnerability to intensive coastal anthropogenic disturbances in mangrove forests
Authors: Li Yangfan , Zhang Zhen , Yang Yi , Li Yi
Published: April 2021

Mangrove forests, as one of the most productive coastal ecosystems in tropical and subtropical areas, provide multiple valuable ecosystem services for human well-being. Mangrove coverage has been declining dramatically across much of developing regions due to extensive coastal anthropogenic disturbances such as reclamation, aquaculture, and seawall construction. As coastal human activities increase, there is urgent need to understand not only the direct loss, but also the vulnerability of mangroves to anthropogenic disturbances. In this study, we evaluated spatial pattern of mangrove vulnerability based on the conceptual framework of “Exposure-Sensitivity-Resilience” using geospatial datasets in mainland China. We find that within all 25,829 ha mangroves in five coastal provinces of mainland China in 2015, nearly 76% of mangroves was exposed or threatened by anthropogenic disturbances. Coastal reclamation and aquaculture were the key threats causing mangrove vulnerability. The overall distribution of high, medium and low vulnerability was following similar trend of aquaculture distribution, which suggests aquaculture was the greatest anthropogenic disturbance agent to mangroves. Hotspot regions for mangrove vulnerability are located at the developing provinces such as Guangxi and Hainan. This study provides the first spatially explicit evidence of the vulnerability of mangrove forests to intensive coastal anthropogenic disturbances at national scale, cloud serve as a benchmark for navigating coastal ecological redline management and coastal ecosystem restoration.
SARS-CoV-2 receptor binding domain fusion protein efficiently neutralizes virus infection
Authors: Chaouat Abigael , Achdout Hagit , Kol Inbal , Berhani Orit , Roi Gil , Vitner Einat B. , Melamed Sharon , Politi Boaz , Zahavy Eran , Brizic Ilija , Rovis Tihana Lenac , Alfi Or , Wolf Dana , Jonjic Stipan , Israely Tomer , Mandelboim Ofer
Published: April 2021

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the COVID-19 pandemic, causing health and economic problems. Currently, as dangerous mutations emerge there is an increased demand for specific treatments for SARS-CoV-2 infected patients. The spike glycoprotein on the virus membrane binds to the angiotensin converting enzyme 2 (ACE2) receptor on host cells through its receptor binding domain (RBD) to mediate virus entry. Thus, blocking this interaction may inhibit viral entry and consequently stop infection. Here, we generated fusion proteins composed of the extracellular portions of ACE2 and RBD fused to the Fc portion of human IgG1 (ACE2-Ig and RBD-Ig, respectively). We demonstrate that ACE2-Ig is enzymatically active and that it can be recognized by the SARS-CoV-2 RBD, independently of its enzymatic activity. We further show that RBD-Ig efficiently inhibits in vitro and in vivo SARS-CoV-2 infection, better than ACE2-Ig. Mechanistically we show that anti-spike antibodies generation, ACE2 enzymatic activity and ACE2 surface expression were not affected by RBD-Ig. Finally, we show that RBD-Ig is more efficient than ACE2-Ig at neutralizing high virus concentration infection. We thus propose that RBD-Ig physically blocks virus infection by binding to ACE2 and that RBD-Ig should be used for the treatment of SARS-CoV-2-infected patients.

Author Summary

SARS-CoV-2 infection caused serious socio-economic and health problems around the globe. As dangerous mutations emerge, there is an increased demand for specific treatments for SARS-CoV-2 infected patients. SARS-CoV-2 infection starts via binding of SARS-CoV-2 spike protein receptor binding domain (RBD) to its receptor, ACE2, on host cells. To intercept this binding, we generated Ig-fusion proteins. ACE2-Ig was generated to possibly block RBD by binding to it and RBD-Ig to block ACE2. We indeed showed that the fusion proteins bind to their respective target. We found that it is more efficient to inhibit SARS-CoV-2 infection by blocking ACE2 receptor with RBD-Ig. We also showed that RBD-Ig does not interfere with ACE2 activity or surface expression. Importantly, as our treatment does not target the virus directly, it may be efficient against any emerging variant. We propose here that RBD-Ig physically blocks virus infection by binding to ACE2 and thus it may be used for the treatment of SARS-CoV-2-infected patients.
The entorhinal cortex modulates trace fear memory formation and neuroplasticity in the lateral amygdala via cholecystokinin
Authors: Feng Hemin , Su Junfeng , Fang Wei , Chen Xi , He Jufang
Published: April 2021

Although the neural circuitry underlying fear memory formation is important in fear-related mental disorders, it is incompletely understood. Here, we utilized trace fear conditioning to study the formation of trace fear memory. We identified the entorhinal cortex (EC) as a critical component of sensory signaling to the amygdala. Moreover, we used the loss of function and rescue experiments to demonstrate that release of the neuropeptide cholecystokinin (CCK) from the EC is required for trace fear memory formation. We discovered that CCK-positive neurons extend from the EC to the lateral nuclei of the amygdala (LA), and inhibition of CCK-dependent signaling in the EC prevented long-term potentiation of sensory signals to the LA and formation of trace fear memory. Altogether, we suggest a model where sensory stimuli trigger the release of CCK from EC neurons, which potentiates sensory signals to the LA, ultimately influencing neural plasticity and trace fear memory formation.
Low dose inocula of SARS-CoV-2 B.1.1.7 variant initiate more robust infections in the upper respiratory tract of hamsters than earlier D614G variants
Authors: Mok Bobo Wing-Yee , Liu Honglian , Lau Siu-Ying , Deng Shaofeng , Liu Siwen , Tam Rachel Chun-Yee , Ng Timothy Ting-Leung , Leung Jake Siu-Lun , Wang Pui , To Kelvin Kai-Wang , Chan Jasper Fuk-Woo , Chan Kwok-Hung , Yuen Kwok-Yung , Siu Gilman Kit-Hang , Chen Honglin
Published: April 2021

There is a lack of experimental evidence to explain how the B.1.1.7 variant spreads more quickly than pre-existing variants in humans. We found that B.1.1.7 displays increased competitive fitness over earlier D614G lineages in anin-vitrosystem. Furthermore,, we demonstrated that B.1.1.7 variant is able to replicate and shed more efficiently in the nasal cavity than other variants with lower dose and shorter duration of exposure.
Identification and characterization of centromeric sequences in Xenopus laevis
Authors: Smith Owen K. , Limouse Charles , Fryer Kelsey A. , Teran Nicole A. , Sundararajan Kousik , Heald Rebecca , Straight Aaron F.
Published: April 2021

Centromeres play an essential function in cell division by specifying the site of kinetochore formation on each chromosome for mitotic spindle attachment. Centromeres are defined epigenetically by the histone H3 variant Centromere Protein A (Cenpa). Cenpa nucleosomes maintain the centromere by designating the site for new Cenpa assembly after dilution by replication. Vertebrate centromeres assemble on tandem arrays of repetitive sequences, but the function of repeat DNA in centromere formation has been challenging to dissect due to the difficulty in manipulating centromeres in cells. Xenopus laevis egg extracts assemble centromeres in vitro, providing a system for studying centromeric DNA functions. However, centromeric sequences in Xenopus laevis have not been extensively characterized. In this study, we combine Cenpa ChIP-seq with a k-mer based analysis approach to identify the Xenopus laevis centromere repeat sequences. By in situ hybridization, we show that Xenopus laevis centromeres contain diverse repeat sequences, and we map the centromere position on each Xenopus laevis chromosome using the distribution of centromere-enriched k-mers. Our identification of Xenopus laevis centromere sequences enables previously unapproachable centromere genomic studies. Our approach should be broadly applicable for the analysis of centromere and other repetitive sequences in any organism.
A microfluidic dosimetry cell to irradiate solutions with poorly penetrating radiations: a step towards online dosimetry for synchrotron beamlines
Authors: Huart Lucie , Nicolas Christophe , Hervé du Penhoat Marie-Anne , Guigner Jean-Michel , Gosse Charlie , Palaudoux Jérôme , Lefrançois Stephane , Mercere Pascal , Dasilva Paulo , Renault Jean-Philippe , Chevallard Corinne
Published: April 2021

Synchrotron radiation can induce sample damage, whether intended or not. In the case of sensitive samples, such as biological ones, modifications can be significant. To understand and predict the effects due to exposure, it is necessary to know the ionizing radiation dose deposited in the sample. In the case of aqueous samples, deleterious effects are mostly induced by the production of reactive oxygen species via water radiolysis. These species are therefore good indicators of the dose. Here the application of a microfluidic cell specifically optimized for low penetrating soft X-ray radiation is reported. Sodium benzoate was used as a fluorescent dosimeter thanks to its specific detection of hydroxyl radicals, a radiolytic product of water. Measurements at 1.28 keV led to the determination of a hydroxyl production yield, G(HO
.
), of 0.025 ± 0.004 µmol J−1. This result is in agreement with the literature and confirms the high linear energy transfer behavior of soft X-rays. An analysis of the important parameters of the microfluidic dosimetry cell, as well as their influences over dosimetry, is also reported.
Integrated sample-handling and mounting system for fixed-target serial synchrotron crystallography
Authors: Illava Gabrielle , Jayne Richard , Finke Aaron D. , Closs David , Zeng Wenjie , Milano Shawn K. , Huang Qingqiu , Kriksunov Irina , Sidorenko Pavel , Wise Frank W. , Zipfel Warren R. , Apker Benjamin A. , Thorne Robert E.
Published: April 2021

Serial synchrotron crystallography (SSX) is enabling the efficient use of small crystals for structure–function studies of biomolecules and for drug discovery. An integrated SSX system has been developed comprising ultralow background-scatter sample holders suitable for room and cryogenic temperature crystallographic data collection, a sample-loading station and a humid `gloveless' glovebox. The sample holders incorporate thin-film supports with a variety of designs optimized for different crystal-loading challenges. These holders facilitate the dispersion of crystals and the removal of excess liquid, can be cooled at extremely high rates, generate little background scatter, allow data collection over >90° of oscillation without obstruction or the risk of generating saturating Bragg peaks, are compatible with existing infrastructure for high-throughput cryocrystallography and are reusable. The sample-loading station allows sample preparation and loading onto the support film, the application of time-varying suction for optimal removal of excess liquid, crystal repositioning and cryoprotection, and the application of sealing films for room-temperature data collection, all in a controlled-humidity environment. The humid glovebox allows microscope observation of the sample-loading station and crystallization trays while maintaining near-saturating humidities that further minimize the risks of sample dehydration and damage, and maximize working times. This integrated system addresses common problems in obtaining properly dispersed, properly hydrated and isomorphous microcrystals for fixed-orientation and oscillation data collection. Its ease of use, flexibility and optimized performance make it attractive not just for SSX but also for single-crystal and few-crystal data collection. Fundamental concepts that are important in achieving desired crystal distributions on a sample holder via time-varying suction-induced liquid flows are also discussed.
On the suitability of using the diagonal Gaussian approximation in the calculation of the magnitude-based likelihood function
Authors: Lunin Vladimir Y.
Published: April 2021

Statistical likelihood maximization is currently one of the main tools in computational procedures in biological crystallography. In these procedures, the likelihood function is calculated, as a rule, within the framework of a diagonal Gaussian approximation (DGA) of the joint probability distribution of the real and imaginary parts of a set of structure factors. This approximation assumes pairwise uncorrelated values of various structure-factor components. In this paper, exact formulas are derived for pairwise correlations of structure factors, and conditions under which these correlations can be considered to be negligible are discussed. It is shown that in the case where the probability distribution of the atomic coordinates is related to the region of the molecule or its domains, the correlation of the structure factors of reflections s and w is determined mostly by the magnitudes of the Fourier transform of the probability distribution calculated at the points 2s, 2w, s − w and s + w. However, in the case where the probability distribution describes small corrections to the coordinates of the existing preliminary atomic model, the correlation is determined by the values of the structure factors of the preliminary model that correspond to the 2s, 2w, s − w and s + w reflections rather than by the Fourier transform of the probability distribution. Test cases demonstrate that the practice of using the DGA for calculation of the likelihood when based on sets containing neighbouring reflections may be unjustified in some crystallographic applications, especially in single-particle studies.
Range‐wide population viability analyses reveal high sensitivity to wildflower harvesting in extreme environments
Authors: Treurnicht Martina , Schurr Frank M. , Slingsby Jasper A. , Esler Karen J. , Pagel Jörn
Published: April 2021

The ecological effects of harvesting from wild populations are often uncertain, especially since the sensitivity of populations to harvesting can vary across species’ geographical ranges. In the Cape Floristic Region (CFR, South Africa) biodiversity hotspot, wildflower harvesting is widespread and economically important, providing an income to many rural communities. However, with very few species studied to date, and without considering range‐wide sensitivity to harvesting, there is limited information available to ensure the sustainability of wildflower harvesting.

We studied geographical variation in sensitivity to wildflower harvesting for 26 Proteaceae shrubs with fire‐driven life cycles using population viability analyses. We developed stochastic, density‐dependent population models that were parameterised from individual demographic rates (adult fecundity, seedling recruitment and adult fire survival) and local environmental conditions across the geographical ranges of the study species. We then simulated the effects of harvesting on populations in different environments across species ranges. Our model simulations predicted extinction risk per population, and we derived extinction probabilities over 100 years in response to different harvesting regimes. We used these population‐level extinction probabilities to quantify inter‐ and intraspecific variation in sensitivity to wildflower harvesting, and to explore how geographical variation in sensitivity depends on environmental conditions (climate, soil fertility and fire disturbance).

We detected considerable inter‐ and intraspecific variation in sensitivity to wildflower harvesting for the 26 study species. This held for both ‘nonsprouters’ and ‘resprouters’ (species with low and high fire persistence ability, respectively). Intraspecific variation in sensitivity to harvesting showed varying geographical patterns and associated with environmental variation. Notably, sensitivity was high towards range edges and at the climatic extremes of species ranges respectively.

Synthesis and applications. We show the importance of combining spatial demographic data, density‐dependent population dynamics and environmental variation when assessing sensitivity to harvesting across species' geographical ranges. Our findings caution against the application of general harvesting guidelines irrespective of species, geographical location or local environmental conditions. Our range‐wide population viability analyses provide insights for developing species‐specific, spatially nuanced guidelines for conservation management. Our approach also identifies species and areas to prioritise for monitoring to prevent the overexploitation of harvested species.
Accuracy of artificial intelligence‐assisted detection of esophageal cancer and neoplasms on endoscopic images: A systematic review and meta‐analysis
Authors: Zhang Si Min , Wang Yong Jun , Zhang Shu Tian
Published: April 2021

Objective

To investigate systematically previous studies on the accuracy of artificial intelligence (AI)‐assisted diagnostic models in detecting esophageal neoplasms on endoscopic images so as to provide scientific evidence for the effectiveness of these models.

Methods

A literature search was conducted on the PubMed, EMBASE and Cochrane Library databases for studies on the AI‐assisted detection of esophageal neoplasms on endoscopic images published up to December 2020. A bivariate mixed‐effects regression model was used to calculate the pooled diagnostic efficacy of AI‐assisted system. Subgroup analyses and meta‐regression analyses were performed to explore the sources of heterogeneity. The effectiveness of AI‐assisted models was also compared with that of the endoscopists.

Results

Sixteen studies were included in the systematic review and meta‐analysis. The pooled sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio and area under the summary receiver operating characteristic curve regarding AI‐assisted detection of esophageal neoplasms were 94% (95% confidence interval [CI] 92%‐96%), 85% (95% CI 73%‐92%), 6.40 (95% CI 3.38‐12.11), 0.06 (95% CI 0.04‐0.10), 98.88 (95% CI 39.45‐247.87) and 0.97 (95% CI 0.95‐0.98), respectively. AI‐based models performed better than endoscopists in terms of the pooled sensitivity (94% [95% CI 84%‐98%] vs 82% [95% CI 77%‐86%, P < 0.01).

Conclusions

The use of AI results in increased accuracy in detecting early esophageal cancer. However, most of the included studies have a retrospective study design, thus further validation with prospective trials is required.
Co‐producing a fire and seasons calendar to support renewed Indigenous cultural fire management
Authors: McKemey Michelle B. ,   Banbai Rangers, Ens Emilie J. , Hunter John T. , Ridges Malcolm , Costello Oliver , Reid Nick C. H.
Published: April 2021

Indigenous knowledge emphasises the importance of cultural connections between humans and the biophysical world. In the face of threats to the maintenance and transfer of Indigenous knowledge, novel approaches such as seasonal calendars are emerging as tools to share knowledge and guide management of natural and cultural resources. The renewal of Indigenous cultural fire management in southeast Australia provided an opportunity to explore whether the co‐production of a fire and seasons calendar, using Western and Indigenous knowledges, can support cultural fire management. We present a case study of cross‐cultural collaboration between scientists and the Banbai Aboriginal rangers at Wattleridge Indigenous Protected Area, New South Wales. We reviewed literature from various disciplines (archaeological, ethnohistorical, Indigenous and ecological) and undertook participatory action research and interviews to collate relevant information. This was synthesised in Winba = Fire, the Banbai Fire and Seasons Calendar, which is used by the Banbai rangers to guide cultural burning, share cross‐cultural knowledge and increase awareness of Indigenous cultural fire management. The process of co‐producing knowledge, revitalising culture, caring for Country, working together and supporting self‐determination is relevant for many Indigenous communities around the world.
Patient demographics and management landscape of metastatic colorectal cancer in the third‐line setting: Real‐world data in an australian population
Authors: Min Sandy Tun , Roohullah Aflah , Tognela Annette , Jalali Azim , Lee Margaret , Wong Rachel , Shapiro Jeremy , Burge Matthew , Yip Desmond , Nott Louise , Zimet Allan , Lee Belinda , Dean Andrew , Steel Simone , Wong Hui‐Li , Gibbs Peter , Lim Stephanie Hui‐Su
Published: April 2021

Background

Colorectal cancer is the third most common cancer and second leading cause of cancer mortality in Australia, thus carrying a significant disease burden.

Aims

This analysis aims to explore real‐world treatment landscape of metastatic colorectal cancer in the third‐line setting.

Methods

We retrospectively analysed treatment of recurrent and advanced colorectal cancer (TRACC) registry database from 2009 onwards. Patients treated with palliative intent who progressed after two lines of therapies were included. One treatment line was defined as any combination of systemic therapy given until progression.

Results

Out of 1820 patients treated palliatively, 32% (590 patients) met study criteria. Of these, 43% (254 patients) proceeded to third‐line therapy, equating to 14% of all metastatic patients. In KRAS mutant or unknown tumours (97 patients), fluoropyrimidine (FP)‐oxaliplatin combination was the most common choice (51%), followed by FP‐irinotecan (15%), trifluridine/tipiracil (11%), mono‐chemotherapy (10%), regorafenib (5%) and others (7%). Majority of FP‐doublet (83%) was given as rechallenge. In 157 patients with KRAS wildtype disease, monotherapy with EGFR inhibitor was most commonly used (41%), followed by EGFR inhibitor with chemotherapy (20%), FP‐doublet (18%), mono‐chemotherapy (6%), trifluridine/tipiracil (6%), regorafenib (1%) and others (8%). Median overall survival was 7.1 months (range 0.4‐41.2), and median time on third‐line treatment was 3 months (range 0.1‐40).

Conclusions

In real‐world Australian population, treatment choices differed based on KRAS status and will likely change with the availability of newer drugs on the pharmaceutical benefits scheme. Survival outcomes are comparable to newer agents in clinical trials for select patients.
Evaluation of palliative treatments in unresectable pancreatic cancer
Authors: Choi Colin Chan‐Min , Choi Julian , Houli Nezor , Smith Marty , Usatoff Val , Lipton Lara , Chan Steven
Published: April 2021

Background

Pancreatic ductal adenocarcinoma (PDAC) presents as unresectable disease in 80% of patients. Limited Australian data exists regarding management and outcome of palliative management for PDAC. This study aims to: (i) identify patients with PDAC being managed with palliative intent; (ii) assess the type of palliative management being used.

Methods

A prospectively maintained pancreatic database at Western Health (2015–2017) was used to identify patient demographics; stage and multidisciplinary decision regarding resectability and operative interventions; palliative care; use of chemotherapy, radiotherapy and; management of exocrine and endocrine insufficiency. Data on chemotherapy use, number of hospital admissions, emergency department attendances and intensive care unit admissions 30 days prior to death were recorded.

Results

One‐hundred and eleven patients had diagnosis of PDAC, 15% with locally advanced and 45% with metastatic PDAC. Among the locally advanced and metastatic PDAC, 48% received biliary stent insertions, 93% had palliative care referral, 45% received palliative chemotherapy and 10% received radiotherapy. Dietitian referral occurred in 79% and 36% were prescribed with a pancreatic enzyme replacement therapy. Diabetes mellitus was present in 52% of which 31% was new onset. Within 30 days prior to death, 11% patients received palliative chemotherapy, 32% were hospitalized and 11% visited an emergency department more than once. Sixty‐five percent died in hospital.

Conclusion

A high proportion of patients diagnosed with locally advanced and metastatic PDAC received palliative care referrals and appropriate level of end‐of‐life care. Further prospective studies are necessary, examining the management and impacts of pancreatic insufficiency in this group.
Impact of ultrasound on inguinal hernia repair rates in Australia: a population‐based analysis
Authors: Williams Michael L. , McCarthy Alexander S. E. , Lord Sally J. , Aczel Thomas , Brooke‐Cowden Geoffrey L.
Published: April 2021

Background

Inguinal hernias are a common pathology that often requires surgical management. The use of groin ultrasound (GU) to investigate inguinal hernias is a growing area of concern as an inefficient use of healthcare resources. Our aim was to assess changes in the rates of GU and the impact on surgical practice.

Methods

Medicare Item Reports and the Australian Institute of Health and Welfare Database were used to estimate annual GU and inguinal hernia repair (IHR) rates per 100 000 population for the period 2000/2001–2017/2018. Pearson's correlation coefficients and linear regression analyses were performed to assess associations between these variables.

Results

Over the 18‐year period, GU rates increased 13‐fold from 88 to 1174 per 100 000 population. Overall, total IHR rates decreased from 217 to 192 per 100 000. Overall, unilateral IHR rates have decreased (182–146 per 100 000), bilateral IHRs have increased (35–46 per 100 000), laparoscopic IHR has increased (30–86 per 100 000) and open surgery has declined (187–106 per 100 000). The increase in GU rates were strongly associated with the decrease in unilateral (r = −0.936, P = <0.001) and increase in bilateral IHR rates (r = 0.924, P = <0.001).

Conclusion

The use of GU has increased substantially, potentially representing an unnecessary cost to the healthcare system. Rising GU rates are not associated with an increase in IHR, however, may contribute to the increasing rates of bilateral IHRs. This study supports the opinion that more extensive clinical and health policy initiatives are needed in Australia to address this health issue.
Aeson—The Carmat total artificial heart is approved for enrollment in the United States
Authors: Han Jason J.
Published: April 2021

Aeson, the Carmat Total Artificial Heart has been recently approved by the FDA for beginning enrollment in the United States. This follows their recent attainment of CE marking in 2020.
3D human liver spheroids for translational pharmacology and toxicology
Authors: Ingelman‐Sundberg Magnus , Lauschke Volker M.
Published: April 2021

Drug development is a failure‐prone endeavour, and more than 85% of drugs fail during clinical development, showcasing that current preclinical systems for compound selection are clearly inadequate. Liver toxicity remains a major reason for safety failures. Furthermore, all efforts to develop pharmacological therapies for a variety of chronic liver diseases, such as non‐alcoholic steatohepatitis (NASH) and fibrosis, remain unsuccessful. Considering the time and expense of clinical trials, as well as the substantial burden on patients, new strategies are thus of paramount importance to increase clinical success rates. To this end, human liver spheroids are becoming increasingly utilized as they allow to preserve patient‐specific phenotypes and functions for multiple weeks in culture. We here review the recent application of such systems for i) predictive and mechanistic analyses of drug hepatotoxicity, ii) the evaluation of hepatic disposition and metabolite formation of low clearance drugs and iii) the development of drugs for metabolic and infectious liver diseases, including NASH, fibrosis, malaria and viral hepatitis. We envision that with increasing dissemination, liver spheroids might become the new gold standard for such applications in translational pharmacology and toxicology.
Utilisation of cytological samples for multiplex immunofluorescence assay
Authors: Tobar Laura Garcia , Villalba‐Esparza María , Abengozar‐Muela Marta , Alvarez Gigli Laura , Echeveste José I. , de Andrea Carlos E. , Lozano María D.
Published: April 2021

Objective

Understanding the immune environment of non‐small cell lung cancer (NSCLC) is important for designing effective anticancer immunotherapies. We describe the use of multiplex immunofluorescence (mIF) assays to enable characterisation of the tumour‐infiltrating immune cells and their interactions, both across and within immune subtypes.

Methods

Six cytological samples of NSCLC taken by transoesophageal ultrasound‐guided fine needle aspiration were tested with an mIF assay designed to detect the expression of key immune cell markers such as CD3, CD8, CD20, CD11b, and CD68. Pan‐cytokeratin was used to detect the NSCLC cells. Fluorescence images were acquired on a Vectra‐Polaris Automated Quantitative Pathology Imaging System (Akoya Biosciences).

Results

MIF assay was able to reliably detect and quantify the myeloid cell markers CD11b, CD68, CD3+ and CD8+ T cells, and CD20+ B lymphocytes on cytological samples of NSCLC. Whole‐tissue analysis and its correlation with the corresponding H&E stains allowed a better understanding of the tissue morphology and the relationship between tumour and stroma compartments. Additionally, a uniform, specific, and correct staining pattern was seen for every immune marker.

Conclusion

The implementation of mIF assay on cytological samples taken with minimally invasive methods seems feasible and can be used to explore the immune environment of NSCLC.
Sexual selection in a tropical toad: Do female toads choose brighter males in a species with rapid colour change?
Authors: Gardner Katrina M. , Mennill Daniel J. , Savi Lincoln M. , Shangi Nicole E. , Doucet Stéphanie M.
Published: April 2021

Conspicuous visual signals play an important role in animal communication, both within and between species. Bright, colourful signals allow animals to discriminate between individuals and can inform behavioural decisions and social interactions. In many instances, conspicuous colouration appears to have evolved through sexual selection via female mate choice or male–male competition. Male Neotropical yellow toads,Incilius luetkenii, display bright‐yellow colouration during their brief explosive mating events and then revert to a cryptic, female‐like, brown colour following amplexus and fertilization. Recent research has revealed that the yellow colouration of males may serve as a sex identification signal and that males remain yellow in the presence of both males and females but darken without conspecific stimulus. However, there is considerable variation in the brightness of yellow colouration in courting males, ranging from dull olive‐green to vibrant lemon‐yellow. The function of this variation remains unknown. In this study, we conducted two‐choice model presentation trials to test one mechanism of sexual selection that may drive this variation: intersexual selection. Specifically, we set out to determine whether females differentiate between males based on their colouration. We presented females with two hyper‐realistic robotic model toads, with one model painted to match a bright‐yellow male and the other a dull‐yellow male. Using several metrics of choice, we found that females did not show a preference for bright or dull colouration. Our research suggests that variation in the intensity of male breeding colouration is not driven by female choice in this species. Our study is consistent with the idea that there may be limited opportunity for female choice to influence male‐trait expression in explosive breeders. Future research will address whether intrasexual selection may influence colour variation in male yellow toads.
Compression‐induced crack initiation and growth in flawed rocks: A review
Authors: Zhou Xiao‐Ping , Zhang Jian‐Zhi , Yang Sheng‐Qi , Berto Filippo
Published: April 2021

The purpose of this review is to discuss the development and the contribution of the experiments and numerical simulations in compression‐induced failure characteristics of flawed rock specimens. Investigation is essential to understand the fundamental failures occurring in a rock bridge, for assessing anticipated and actual performances of the structures built on or in rock masses. The review begins by representing and discussing compression‐induced crack initiation and growth in flawed rocks and explaining the significance of studying these issues in Section 1. The crack initiation and growth behaviors in flawed rocks under uniaxial, biaxial, and triaxial compressions are described in depth in Section 2 where it is expected to distinguish 2‐D crack growth from 3‐D crack growth. After that, the failure characteristics of flawed rock specimens due to temperature treatments and hydraulic pressure are systematically reviewed. Numerical studies of the compression‐induced failure characteristics of flawed rock specimens based on different numerical theories and numerical models are comprehensively evaluated in Section 3. In Section 4, the new findings obtained recently from experimental and numerical studies are drawn. Finally, some aspects of prospective research and a brief summary are presented in Sections 5 and 6.
Behavioural effects of cage systems on theG93ASuperoxide Dismutase 1transgenic mouse model for amyotrophic lateral sclerosis
Authors: Guerra Stefan , Chung Roger , Yerbury Justin , Karl Tim
Published: April 2021

Environmental factors inherent to animal facilities can impact on the neuro‐behavioural phenotype of laboratory mice and genetic mouse models for human diseases. Many facilities have upgraded from traditional ‘open filter top’ cages (FT) to individually ventilated cage (IVC) systems, which have been shown to modify various behavioural responses of laboratory mice. Importantly, the impact of IVC housing on theG93A superoxide dismutase 1mouse model of amyotrophic lateral sclerosis (ALS) is currently unknown. Male and female wild type‐like (WT) and heterozygousSOD1G93Amice were group‐housed in FT or IVC systems from PND 30 ± 5 onwards. Body weight and motor function were assessed weekly from 15 weeks onward. Mice were also tested for cognitive abilities (i.e., fear conditioning and social recognition memory) and sensorimotor gating (i.e., prepulse inhibition: PPI).SOD1G93Amice lost body weight, and their motor function degenerated over time compared with control littermates. Motor impairments developed faster whenSOD1G93Afemales were housed in IVCs. Context and cuefreezingwere increased inSOD1G93Afemales compared with controls, whereas allSOD1G93Amice exhibited lower acoustic startle and PPI than WT mice. IVC housing led to an increase in cuefreezingin males and reduced the severity of PPI deficits inSOD1G93Afemales. Overall, IVC housing impacted moderately on theSOD1G93Aphenotype but central behavioural deficits were still evident across housing conditions. Nonetheless, our findings indicate the importance of assessing the effect of cage system in genetic mouse models as these systems can modulate the magnitude and onset of genotypic differences.
Study of melanocyte density and epidermal thickness in vulvar lichen sclerosus lesions
Authors: Fu Yu , Bao Yingqiu , Li Ziyuan , Gao Xiaoman , Chang Jianmin
Published: April 2021

Objective

This study aimed to analyze changes in melanocyte density and epidermal thickness in vulvar lichen sclerosus (VLS).

Methods

Vulvar skin tissues were collected from 15 VLS female patients in Beijing Hospital, classified into early (n = 7) and late VLS (n = 8) groups according to pathological manifestations. Melanocyte density and full epidermal and cell‐layer (from the bottom of the stratum corneum to that of the basal layer) thickness were calculated using an image analysis software. The control group was normal vulvar skin tissues from 15 females after plastic surgery.

Results

The early VLS (0.170 ± 0.071 µm) and late VLS (0.110 ± 0.035 µm) groups had significantly lower densities of epidermal melanocytes than the control group (0.275 ± 0.036) (F = 36.426, P < 0.001). The cell‐layer thickness did not differ between the early VLS (154.603 ± 121.984 µm) and control (176.974 ± 80.296 µm) groups (P = 0.899) but significantly decreased in the late VLS group (83.455 ± 37.129 µm) compared to the control group (P = 0.003).

Conclusions

Melanocyte density decreased in early and late VLS. The full epidermal and cell‐layer thickness did not significantly change in early VLS, but the cell‐layer thickness decreased in late VLS.
Do we need skin toxicity? Association of immune checkpoint inhibitor and tyrosine kinase inhibitor‐related cutaneous adverse events with outcomes in metastatic renal cell carcinoma
Authors: Corona‐Rodarte Eduardo , Olivas‐Martínez Antonio , Remolina‐Bonilla Yuly A. , Domínguez‐Cherit Judith G. , Lam Elaine T. , Bourlon Maria T.
Published: April 2021

Introduction

Skin toxicity is a common, expected side effect of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) used for metastatic renal cell carcinoma (mRCC). We evaluated the association between skin toxicity and clinical efficacy outcomes of these agents in mRCC patients.

Methods and Materials

Data were obtained from patients with mRCC treated with TKIs and/or ICIs from 2016–2019 at a referral hospital in Mexico City. Clinical outcomes were compared among patients who developed treatment‐related cutaneous adverse events (AEs) and those without skin toxicity.

Results

Thirty‐five patients with mRCC were identified who were treated with sunitinib (51.4%), nivolumab plus cabozantinib (28.6%), nivolumab monotherapy (17.1%), or ipilimumab plus nivolumab plus cabozantinib (2.9%). Any grade skin toxicity was seen in 65.7% of patients. With a median follow‐up of 14 months, radiological responses were as follows: 48.6% stable disease, 25.7% partial response, and 2.8% complete response. Compared to subjects without skin toxicity, patients who developed cutaneous AEs had higher disease control rate 91.3% vs. 50.0% (P = 0.019) and superior 12‐month overall survival rate 91% vs. 67% (P = 0.01), respectively. There was a trend toward improved median progression‐free survival (16 months vs. 5 months, P = 0.13). Grade 1–2 cutaneous toxicity was found to be predictive for disease control, with HR 2.72 (95% CI 1.1–6.71, P = 0.030), and all grade cutaneous toxicity was prognostic of overall survival, with HR 0.18 (95% CI 0.04–0.91, P = 0.039).

Conclusion

Cutaneous AEs are associated with improved overall survival and response in patients with mRCC treated with immunotherapy and/or TKIs.
Perceived social support in Chinese family caregivers of patients with dementia
Authors: Li Jufang , Gao Gexin , Zeng Yawei , Wu Yuping , Zhu Xiaoling , Xu Hongbo
Published: April 2021

Aim

This study aimed to describe levels of social support and explore the factors predictive of social support for Chinese family caregivers of patients with dementia.

Background

Social support levels and their predictive factors in Chinese dementia caregivers have not been well documented, which need to be further clarified to provide a basis for creating effective social support strategies.

Methods

This was a cross‐sectional study with 91 participants who completed a demographic questionnaire and the Social Support Rating Scale from 2015 to 2016.

Results

Chinese family caregivers of patients with dementia received moderate social support. Caregivers' subjective support domain scores and support utilization domain scores were significantly lower than those of the normal Chinese population, whereas caregivers' total social support scores were higher than those of the normal Chinese population. Family caregivers' monthly household income, educational level and place of residence were predictors of their own social support.

Conclusion

Social support in Chinese caregivers of patients with dementia needs to be improved, especially the subjective support and support utilization. Healthcare professionals should pay special attention to caregivers with a lower monthly household income and educational level and caregivers who lived in the suburban area.