bluuebunny/crossref_metadata_2025 huggingface dataset:
Tweedle proteins form extracellular two-dimensional structures defining body and cell shape in
Drosophila melanogaster
Authors: Zuber Renata , Wang Yiwen , Gehring Nicole , Bartoszewski Slawomir , Moussian Bernard
Published: December 2020

Tissue function and shape rely on the organization of the extracellular matrix (ECM) produced by the respective cells. Our understanding of the underlying molecular mechanisms is limited. Here, we show that extracellular Tweedle (Twdl) proteins in the fruit fly
Drosophila melanogaster
form two adjacent two-dimensional sheets underneath the cuticle surface and above a distinct layer of dityrosinylated and probably elastic proteins enwrapping the whole body. Dominant mutations in
twdl
genes cause ectopic spherical aggregation of Twdl proteins that recruit dityrosinylated proteins at their periphery within lower cuticle regions. These aggregates perturb parallel ridges at the surface of epidermal cells that have been demonstrated to be crucial for body shaping. In one scenario, hence, this disorientation of epidermal ridges may explain the squatty phenotype of Twdl mutant larvae. In an alternative scenario, this phenotype may be due to the depletion of the dityrosinylated and elastic layer, and the consequent weakening of cuticle resistance against the internal hydrostatic pressure. According to Barlow's formula describing the distribution of internal pressure forces in pipes in dependence of pipe wall material properties, it follows that this reduction in turn causes lateral expansion at the expense of the antero-posterior elongation of the body.
Walking the tight wire between cell adhesion and WNT signalling: a balancing act for β-catenin
Authors: van der Wal Tanne , van Amerongen Renée
Published: December 2020

CTNNB1 (catenin β-1, also known as β-catenin) plays a dual role in the cell. It is the key effector of WNT/CTNNB1 signalling, acting as a transcriptional co-activator of TCF/LEF target genes. It is also crucial for cell adhesion and a critical component of cadherin-based adherens junctions. Two functional pools of CTNNB1, a transcriptionally active and an adhesive pool, can therefore be distinguished. Whether cells merely balance the distribution of available CTNNB1 between these functional pools or whether interplay occurs between them has long been studied and debated. While interplay has been indicated upon artificial modulation of cadherin expression levels and during epithelial–mesenchymal transition, it is unclear to what extent CTNNB1 exchange occurs under physiological conditions and in response to WNT stimulation. Here, we review the available evidence for both of these models, discuss how CTNNB1 binding to its many interaction partners is controlled and propose avenues for future studies.
Adipose tissue in health and disease
Authors: Harvey Innocence , Boudreau Anik , Stephens Jacqueline M.
Published: December 2020

Adipose, or fat, tissue (AT) was once considered an inert tissue that primarily existed to store lipids, and was not historically recognized as an important organ in the regulation and maintenance of health. With the rise of obesity and more rigorous research, AT is now recognized as a highly complex metabolic organ involved in a host of important physiological functions, including glucose homeostasis and a multitude of endocrine capabilities. AT dysfunction has been implicated in several disease states, most notably obesity, metabolic syndrome and type 2 diabetes. The study of AT has provided useful insight in developing strategies to combat these highly prevalent metabolic diseases. This review highlights the major functions of adipose tissue and the consequences that can occur when disruption of these functions leads to systemic metabolic dysfunction.
What determines eukaryotic translation elongation: recent molecular and quantitative analyses of protein synthesis
Authors: Neelagandan Nagammal , Lamberti Irene , Carvalho Hugo J. F. , Gobet Cédric , Naef Felix
Published: December 2020

Protein synthesis from mRNA is an energy-intensive and tightly controlled cellular process. Translation elongation is a well-coordinated, multifactorial step in translation that undergoes dynamic regulation owing to cellular state and environmental determinants. Recent studies involving genome-wide approaches have uncovered some crucial aspects of translation elongation including the mRNA itself and the nascent polypeptide chain. Additionally, these studies have fuelled quantitative and mathematical modelling of translation elongation. In this review, we provide a comprehensive overview of the key determinants of translation elongation. We discuss consequences of ribosome stalling or collision, and how the cells regulate translation in case of such events. Next, we review theoretical approaches and widely used mathematical models that have become an essential ingredient to interpret complex molecular datasets and study translation dynamics quantitatively. Finally, we review recent advances in live-cell reporter and related analysis techniques, to monitor the translation dynamics of single cells and single-mRNA molecules in real time.
Janus microdimer swimming in an oscillating magnetic field
Authors: Yang Jinyou
Published: December 2020

Artificial microswimmers powered by magnetic fields have numerous applications, such as drug delivery, biosensing for minimally invasive medicine and environmental remediation. Recently, a Janus microdimer surface walker that can be propelled by an oscillating magnetic field near a surface was reported by Li
et al.
(
Adv. Funct. Mater.
28
, 1706066. (
doi:10.1002/adfm.201706066
)). To clarify the mechanism for the surface walker, we numerically studied in detail a Janus microdimer swimming near a wall actuated by an oscillating magnetic field. The results showed that a Janus microdimer in an oscillating magnetic field can produce magnetic torque in the
y
-direction, which eventually propels the Janus microdimer along the
x
-direction near a wall. Furthermore, we found that the Janus microdimer can also move along a special direction in an oscillating magnetic field with two orientations without a wall. The knowledge obtained in this study is fundamental for understanding the interactions between a Janus microdimer and surfaces in an oscillating magnetic field and is useful for controlling Janus microdimer motion with or without a wall.
Event-related potentials reveal limited readiness to access phonetic details during word processing in dogs
Authors: Magyari L. , Huszár Zs. , Turzó A. , Andics A.
Published: December 2020

While dogs have remarkable abilities for social cognition and communication, the number of words they learn to recognize typically remains very low. The reason for this limited capacity is still unclear. We hypothesized that despite their human-like auditory abilities for analysing speech sounds, their word processing capacities might be less ready to access phonetic details. To test this, we developed procedures for non-invasive measurement of event-related potentials (ERPs) for language stimuli in awake dogs (n= 17). Dogs listened to familiar instruction words and phonetically similar and dissimilar nonsense words. We compared two different artefact cleaning procedures on the same data; they led to similar results. An early (200–300 ms; only after one of the cleaning procedures) and a late (650–800 ms; after both cleaning procedures) difference was present in the ERPs for known versus phonetically dissimilar nonsense words. There were no differences between the ERPs for known versus phonetically similar nonsense words. ERPs of dogs who heard the instructions more often also showed larger differences between instructions and dissimilar nonsense words. The study revealed not only dogs' sensitivity to known words, but also their limited capacity to access phonetic details. Future work should confirm the reported ERP correlates of word processing abilities in dogs.
A system for efficient egress scheduling during mass events and small-scale experimental demonstration
Authors: Murakami Hisashi , Feliciani Claudio , Shimura Kenichiro , Nishinari Katsuhiro
Published: December 2020

Improvements in the design of pedestrian facilities have reduced the frequency of crowd accidents, and safety is now generally ensured in well-planned crowd events. However, congestion and inefficient use of infrastructures still remain an issue. To guarantee comfort and reduce close contacts between people, there are circumstances when crowd density may have to be reduced well below safety limits. Although research has given a lot of attention to extreme scenarios, methods to improve non-critical conditions have been little explored. In addition, crowd sensing technology is still mostly used for data collection and direct use on crowd management is rare. In this work, we present a system aimed at computing optimal egress time for groups of people leaving a complex facility. We show that, if egress starting time is accurately computed for each group based on actual crowd conditions, density can be greatly reduced without having a large effect on the total egress time of the whole crowd. To show the efficacy of such a system, a small-scale experiment is conducted where all components are tested in a simple scenario. As a result, an increase in total egress time by only 5% allowed to reduce maximum density by 35%.
Polyphenol profile of buckwheat honey, nectar and pollen
Authors: Nešović Milica , Gašić Uroš , Tosti Tomislav , Horvacki Nikola , Šikoparija Branko , Nedić Nebojša , Blagojević Stevan , Ignjatović Ljubiša , Tešić Živoslav
Published: December 2020

A focus of research in recent years is the comparison of honey as the final product of bees with pollen and nectar of the plant from which the honey originates, as the main food source for bees. Buckwheat honey is recognized as a nutritionally valuable product, which provides a scientifically proven health benefit and is confirmed as a functional food. The quality of this type of honey is attributed to high levels of phytochemicals in buckwheat. The purpose of this study was the examination of similarity between buckwheat honey and buckwheat nectar and pollen, as well as simultaneous investigation of their chemical profiles and the origin of the honey. The phenolic profile of buckwheat pollen showed a lower number of flavonoids and phenolic acids than those of nectar and honey samples, but confirmed the presence of the most characteristic polyphenols derived from the buckwheat plant. The notable difference was found to be the presence of (epi)catechin units, its galloylated derivatives and procyanidin dimers, which were not present in honey. Honey polyphenols displayed a pronounced correlation with those of nectar, but not with those of pollen. Finally, by comparing the polyphenolic profiles of honey, nectar and pollen sharing the same geographical origin, new data could be provided for a potential assessment of the botanical origin of buckwheat honey.
Duplication of the bodily self: a perceptual illusion of dual full-body ownership and dual self-location
Authors: Guterstam Arvid , Larsson Dennis E. O. , Szczotka Joanna , Ehrsson H. Henrik
Published: December 2020

Previous research has shown that it is possible to use multisensory stimulation to induce the perceptual illusion of owning supernumerary limbs, such as two right arms. However, it remains unclear whether the coherent feeling of owning a full-body may be duplicated in the same manner and whether such a dual full-body illusion could be used to split the unitary sense of self-location into two. Here, we examined whether healthy human participants can experience simultaneous ownership of two full-bodies, located either close in parallel or in two separate spatial locations. A previously described full-body illusion, based on visuo-tactile stimulation of an artificial body viewed from the first-person perspective (1PP) via head-mounted displays, was adapted to a dual-body setting and quantified in five experiments using questionnaires, a behavioural self-location task and threat-evoked skin conductance responses. The results of experiments 1–3 showed that synchronous visuo-tactile stimulation of two bodies viewed from the 1PP lying in parallel next to each other induced a significant illusion of dual full-body ownership. In experiment 4, we failed to find support for our working hypothesis that splitting the visual scene into two, so that each of the two illusory bodies was placed in distinct spatial environments, would lead to dual self-location. In a final exploratory experiment (no. 5), we found preliminary support for an illusion of dual self-location and dual body ownership by using dynamic changes between the 1PPs of two artificial bodies and/or a common third-person perspective in the ceiling of the testing room. These findings suggest that healthy people, under certain conditions of multisensory perceptual ambiguity, may experience dual body ownership and dual self-location. These findings suggest that the coherent sense of the bodily self located at a single place in space is the result of an active and dynamic perceptual integration process.
How general is cognitive ability in non-human animals? A meta-analytical and multi-level reanalysis approach
Authors: Poirier Marc-Antoine , Kozlovsky Dovid Y. , Morand-Ferron Julie , Careau Vincent
Published: December 2020

General intelligence has been a topic of high interest for over a century. Traditionally, research on general intelligence was based on principal component analyses and other dimensionality reduction approaches. The advent of high-speed computing has provided alternative statistical tools that have been used to test predictions of human general intelligence. In comparison, research on general intelligence in non-human animals is in its infancy and still relies mostly on factor-analytical procedures. Here, we argue that dimensionality reduction, when incorrectly applied, can lead to spurious results and limit our understanding of ecological and evolutionary causes of variation in animal cognition. Using a meta-analytical approach, we show, based on 555 bivariate correlations, that the average correlation among cognitive abilities is low (
r
= 0.185; 95% CI: 0.087–0.287), suggesting relatively weak support for general intelligence in animals. We then use a case study with relatedness (genetic) data to demonstrate how analysing traits using mixed models, without dimensionality reduction, provides new insights into the structure of phenotypic variance among cognitive traits, and uncovers genetic associations that would be hidden otherwise. We hope this article will stimulate the use of alternative tools in the study of cognition and its evolution in animals.
Personality-specific carry-over effects on breeding
Authors: Harris Stephanie M. , Descamps Sébastien , Sneddon Lynne U. , Cairo Milena , Bertrand Philip , Patrick Samantha C.
Published: December 2020

Carry-over effects describe the phenomenon whereby an animal's previous conditions influence its subsequent performance. Carry-over effects are unlikely to affect individuals uniformly, but the factors modulating their strength are poorly known. Variation in the strength of carry-over effects may reflect individual differences in pace-of-life: slow-paced, shyly behaved individuals are thought to favour an allocation to self-maintenance over current reproduction, compared to their fast-paced, boldly behaved conspecifics (the pace-of-life syndrome hypothesis). Therefore, detectable carry-over effects on breeding should be weaker in bolder individuals, as they should maintain an allocation to reproduction irrespective of previous conditions, while shy individuals should experience stronger carry-over effects. We tested this prediction in black-legged kittiwakes breeding in Svalbard. Using miniature biologging devices, we measured non-breeding activity of kittiwakes and monitored their subsequent breeding performance. We report a number of negative carry-over effects of non-breeding activity on breeding, which were generally stronger in shyer individuals: more active winters were followed by later breeding phenology and poorer breeding performance in shy birds, but these effects were weaker or undetected in bolder individuals. Our study quantifies individual variability in the strength of carry-over effects on breeding and provides a mechanism explaining widespread differences in individual reproductive success.
A single heat-stress bout induces rapid and prolonged heat acclimation in the California mussel,Mytilus californianus
Authors: Moyen Nicole E. , Crane Rachel L. , Somero George N. , Denny Mark W.
Published: December 2020

Climate change is not only causing steady increases in average global temperatures but also increasing the frequency with which extreme heating events occur. These extreme events may be pivotal in determining the ability of organisms to persist in their current habitats. Thus, it is important to understand how quickly an organism's heat tolerance can be gained and lost relative to the frequency with which extreme heating events occur in the field. We show that the California mussel,Mytilus californianus—a sessile intertidal species that experiences extreme temperature fluctuations and cannot behaviourally thermoregulate—can quickly (in 24–48 h) acquire improved heat tolerance after exposure to a single sublethal heat-stress bout (2 h at 30 or 35°C) and then maintain this improved tolerance for up to three weeks without further exposure to elevated temperatures. This adaptive response improved survival rates by approximately 75% under extreme heat-stress bouts (2 h at 40°C). To interpret these laboratory findings in an ecological context, we evaluated 4 years of mussel body temperatures recorded in the field. The majority (approx. 64%) of consecutive heat-stress bouts were separated by 24–48 h, but several consecutive heat bouts were separated by as much as 22 days. Thus, the ability ofM. californianusto maintain improved heat tolerance for up to three weeks after a single sublethal heat-stress bout significantly improves their probability of survival, as approximately 33% of consecutive heat events are separated by 3–22 days. As a sessile animal, mussels likely evolved the capability to rapidly gain and slowly lose heat tolerance to survive the intermittent, and often unpredictable, heat events in the intertidal zone. This adaptive strategy will likely prove beneficial under the extreme heat events predicted with climate change.
Genomic analysis reveals G3P[13] porcine rotavirus A interspecific transmission to human from pigs in a swine farm with diarrhoea outbreak
Authors: Yan Nan , Yue Hua , Wang Yuanwei , Zhang Bin , Tang Cheng
Published: December 2020

Rotavirus A (RVA) is a major diarrhoea-causing pathogen in young animals and children. The zoonotic potential of RVA has received extensive attention in recent years. In May 2018, an outbreak of diarrhoea among piglets occurred on a swine farm in Sichuan province, PR China. RVA was detected in 95.7 % (22/23) of piglet samples, 60 % (9/15) of sow samples and 100 % (3/3) of pig-breeder faecal samples. The predominant RVA genotype on this swine farm was G3P[13], and G3P[13] RVA was also detected in the three breeder faecal samples. Three G3P[13] RVA strains were isolated from a piglet faecal sample, a sow faecal sample and a pig-breeder faecal sample, and were named SCLS-X1, SCLS-3 and SCLS-R3, respectively. The complete sequences of 11 gene segments of these three isolates were derived. Phylogenetic analysis showed that ten gene segments (VP7, VP4, VP1–VP3 and NSP1–NSP5) of pig-breeder isolate SCLS-R3 were closely related to pig isolates SCLS-X1 and SCLS-3 from this farm. Only the VP6 gene shared higher homology with human RVA strain I321. Therefore, a G3P[13] porcine RVA strain most likely infected pig breeders. These results provided the first complete epidemiological link demonstrating interspecies transmission of G3P[13] RVA from pigs to human. Our data contribute to an improved understanding of the genetic evolution and interspecies transmission of RVA.
Understanding the microbial components of periodontal diseases and periodontal treatment-induced microbiological shifts
Authors: Fragkioudakis Ioannis , Riggio Marcello P. , Apatzidou Danae Anastasia
Published: December 2020

In the mid-1960s the microbial aetiology of periodontal diseases was introduced based on classical experimental gingivitis studies . Since then, numerous studies have addressed the fundamental role that oral microbiota plays in the initiation and progression of periodontal diseases. Recent advances in laboratory identification techniques have contributed to a better understanding of the complexity of the oral microbiome in both health and disease. Modern culture-independent methods such as human oral microbial identification microarray and next-generation sequencing have been used to identify a wide variety of microbial taxa residing in the gingival sulcus and the periodontal pocket. The first theory of the ‘non-specific plaque’ hypothesis gave rise to the ‘ecological plaque’ hypothesis and more recently to the ‘polymicrobial synergy and dysbiosis hypothesis’. Periodontitis is now considered to be a multimicrobial inflammatory disease in which the various bacterial species within the dental biofilm are in a dysbiotic state and this imbalance favours the establishment of chronic inflammatory conditions and ultimately the destruction of tooth-supporting tissues. Apart from the known putative periodontal pathogens, the whole biofilm community is now considered to play a role in the establishment of inflammation and the initiation and progression of periodontitis in a susceptible host. Treatment is unlikely to eliminate putative pathogens but, when it is thoroughly performed it has the potential to establish a healthy ecosystem by altering the microbial community in numbers and composition and also contribute to the maturation of the host immune response.
Genomic epidemiology of Escherichia coli isolates from a tertiary referral center in Lilongwe, Malawi
Authors: Tegha Gerald , Ciccone Emily J. , Krysiak Robert , Kaphatika James , Chikaonda Tarsizio , Ndhlovu Isaac , van Duin David , Hoffman Irving , Juliano Jonathan J. , Wang Jeremy
Published: December 2020

Antimicrobial resistance (AMR) is a global threat, including in sub-Saharan Africa. However, little is known about the genetics of resistant bacteria in the region. In Malawi, there is growing concern about increasing rates of antimicrobial resistance to most empirically used antimicrobials. The highly drug resistant

Escherichia coli

sequence type (ST) 131, which is associated with the extended spectrum β-lactamase blaCTX-M-15
, has been increasing in prevalence globally. Previous data from isolates collected between 2006 and 2013 in southern Malawi have revealed the presence of ST131 and the blaCTX-M-15
gene in the country. We performed whole genome sequencing (WGS) of 58 clinical

E. coli

isolates at Kamuzu Central Hospital, a tertiary care centre in central Malawi, collected from 2012 to 2018. We used Oxford Nanopore Technologies (ONT) sequencing, which was performed in Malawi. We show that ST131 is observed more often (14.9% increasing to 32.8%) and that the blaCTX-M-15
gene is occurring at a higher frequency (21.3% increasing to 44.8%). Phylogenetics indicates that isolates are highly related between the central and southern geographic regions and confirms that ST131 isolates are contained in a single group. All AMR genes, including blaCTX-M-15
, were widely distributed across sequence types. We also identified an increased number of ST410 isolates, which in this study tend to carry a plasmid-located copy of blaCTX-M-15
gene at a higher frequency than blaCTX-M-15
occurs in ST131. This study confirms the expanding nature of ST131 and the wide distribution of the blaCTX-M-15
gene in Malawi. We also highlight the feasibility of conducting longitudinal genomic epidemiology studies of important bacteria with the sequencing done on site using a nanopore platform that requires minimal infrastructure.
CpxR regulates the Rcs phosphorelay system in controlling the Ysc-Yop type III secretion system in Yersinia pseudotuberculosis
Authors: Fei Keke , Chao Hong-Jun , Hu Yangbo , Francis Matthew S. , Chen Shiyun
Published: December 2020

The CpxRA two-component regulatory system and the Rcs phosphorelay system are both employed by theEnterobacteriaceaefamily to preserve bacterial envelope integrity and function when growing under stress. Although both systems regulate several overlapping physiological processes, evidence demonstrating a molecular connection between Cpx and Rcs signalling outputs is scarce. Here, we show that CpxR negatively regulates the transcription of thercsBgene in the Rcs phosphorelay system inYersinia pseudotuberculosis. Interestingly, transcription ofrcsBis under the control of three promoters, which were all repressed by CpxR. Critically, synthetic activation of Cpx signalling through mislocalization of the NlpE lipoprotein to the inner membrane resulted in an active form of CpxR that repressed activity ofrcsBpromoters. On the other hand, a site-directed mutation of the phosphorylation site at residue 51 in CpxR generated an inactive non-phosphorylated variant that was unable to regulate output from thesercsBpromoters. Importantly, CpxR-mediated inhibition ofrcsBtranscription in turn restricted activation of the Ysc-Yop type III secretion system (T3SS). Moreover, active CpxR blocks zinc-mediated activation of Rcs signalling and the subsequent activation oflcrFtranscription. Our results demonstrate a novel regulatory cascade linking CpxR-RcsB-LcrF to control production of the Ysc-Yop T3SS.
Breast cancer: Emerging principles of metastasis, adjuvant and neoadjuvant treatment from cancer registry data
Authors: Engel Jutta , Eckel Renate , Schrodi Simone , Halfter Kathrin , Schubert-Fritschle Gabriele , Hölzel Dieter
Published: December 2020

Background

Growing primary breast cancers (PT) can initiate local (LR), regional (pLN), and distant metastases (MET). Characteristics of these progressions such as initiation, frequency, growth duration and treatment success describe principles of these processes. They are bottlenecks through which scientific and molecular biological concepts and hypotheses must fit.

Methods

Population-based data from the Munich Cancer Registry over 4 time periods since 1978 with the most important prognostic factors and an up to date follow-up are analyzed. With 66.818 patients, reliable data are obtained on initiation on METs, growth time und survival even in small subgroups. Together with results of clinical trials on prevention and adjuvant treatment (AT) principles for tumor growth, MET process and AT are derived.

Results

The median growth periods for PT/ MET/LR/pLN result in 12.5/8.8/5/3.5 years. Even if 30% of METs only appear after 10 years of MET-free time, a delayed initiation or cascade like initiation of METs, e.g. from pLNs cannot be derived from the data. That is an immediate MET initiation principle by PT. The growth rate of the PT can vary by a factor of 10 or more and can be transferred to the MET. Nevertheless, the relation of the growth times PT/MET results in a less varying value of 1.4. Principles of AT are the 50% eradication of 1st and 2ndPTs, the selective and partial eradication of bone and lung METs with successful ATs, which cannot be improved by extending the duration of ATs. These principles reveal, among other things, that there is no rationale for the accepted for long-term endocrine ATs, breast cancer risk by hormone replacement therapies, or cascading initiation of METs.

Conclusion

A paradigm with ten principles for the MET process and ATs can be derived from real world data and clinical trials. The principles show limits and opportunities for innovation also through alternative interpretations of well-known studies. The outlined MET process should be generalizable to all solid tumors.
Comparable specimen collection from both ends of at-home mid-turbinate swabs
Authors: Truong Melissa , Pfau Brian , McDermot Evan , Han Peter D. , Brandstetter Elisabeth , Richardson Matthew , Kim Ashley E. , Rieder Mark J. , Chu Helen Y. , Englund Janet A. , Nickerson Deborah A. , Shendure Jay , Lockwood Christina M. , Konnick Eric Q. , Starita Lea M.
Published: December 2020

Unsupervised upper respiratory specimen collection is a key factor in the ability to massively scale SARS-CoV-2 testing. But there is concern that unsupervised specimen collection may produce inferior samples. Across two studies that included unsupervised at-home mid-turbinate specimen collection, ∼1% of participants used the wrong end of the swab. We found that molecular detection of respiratory pathogens and a human biomarker were comparable between specimens collected from the handle of the swab and those collected correctly. Older participants were more likely to use the swab backwards. Our results suggest that errors made during home-collection of nasal specimens do not preclude molecular detection of pathogens and specialized swabs may be an unnecessary luxury during a pandemic.
Epigenetic Signatures of Human Myocardium and Brown Adipose Tissue Revealed with Simultaneous Positron Emission Tomography and Magnetic Resonance of Class I Histone Deacetylases
Authors: Izquierdo-Garcia David , Hooker Jacob M. , Schroeder Frederick A. , Mekkaoui Choukri , Gilbert Tonya M. , Panagia Marcello , Cero Cheryl , Rogers Lindsey , Bhanot Anisha , Wang Changning , Cypess Aaron M. , Catana Ciprian , Sosnovik David E.
Published: December 2020

Rationale

Histone deacetylases (HDACs) play a central role in cardiac hypertrophy and fibrosis in preclinical models. However, their impact in the human heart remains unknown.

Objective

We aimed to image HDAC expression in the human heartin vivowith PET-MR (positron emission tomography and magnetic resonance) using [11C]Martinostat, a novel radiotracer targeted to class I HDACs. We further aimed to compare HDAC expression in the heart with its expression in skeletal muscle and brown/white adipose tissue (BAT/WAT).

Methods and Results

The specificity and selectivity of [11C]Martinostat binding in the heart was assessed in non-human primates (n=2) byin vivoblocking studies and with anex vivocellular thermal shift assay (CETSA) of HDAC paralog stabilization by Martinostat. PET-MR imaging of [11C]Martinostat was performed in healthy volunteers (n=6) for 60 minutes to obtain time-activity curves of probe uptake and kinetics. qPCR of class I HDACs was performed in specimens of BAT obtained from patients (n=7) undergoing abdominal surgery and in specimens of human subcutaneous WAT (n=7). CETSA and the blocking studies demonstrated that Martinostat was specific for class I HDACs in the heart. HDAC density, measured by standardized uptake values of [11C]Martinostat, was 8 times higher in the myocardium than skeletal muscle (4.4 ± 0.6 vs. 0.54 ± 0.29, p<0.05) and also significantly higher in BAT than WAT (0.96 ± 0.29 vs. 0.17 ± 0.08, p<0.05). qPCR confirmed higher class I HDAC expression in BAT, particularly HDAC2 and HDAC3 (2.6 and 2.7-fold higher than WAT respectively, p<0.01).

Conclusions

Class I HDAC expression in the human heart can be imagedin vivoand is dramatically higher than any other peripheral tissue, including skeletal muscle. The high levels of HDAC in the myocardium and BAT suggest that epigenetic regulation plays an important role in tissues with high energetic demands and metabolic plasticity.
The anti-vaccination infodemic on social media: a behavioral analysis
Authors: Germani Federico , Biller-Andorno Nikola
Published: December 2020

Vaccinations are without doubt one of the greatest achievements of modern medicine, and there is hope that they can constitute a solution to halt the ongoing COVID-19 pandemic. However, the anti-vaccination movement is currently on the rise, spreading online misinformation about vaccine safety and causing a worrying reduction in vaccination rates worldwide. In this historical time, it is imperative to understand the reasons of vaccine hesitancy, and to find effective strategies to dismantle the rhetoric of anti-vaccination supporters. For this reason, we analyzed the behavior of anti-vaccination supporters on the platform Twitter. Here we identify that anti-vaccination supporters, in comparison to pro-vaccination supporters, share conspiracy theories and make use of emotional language. We demonstrate that anti-vaccination supporters are more engaged in discussions on Twitter and share their contents from a pull of strong influencers. We show that the movement’s success relies on a strong sense of community, based on the contents produced by a small fraction of profiles, with the community at large serving as a sounding board for anti-vaccination discourse to circulate online. Surprisingly, our data demonstrate that Donald Trump, together with members of his entourage and his closest supporters, are the main drivers of vaccine misinformation on Twitter. Based on these results, we propose to strategically target the anti-vaccination community online through policies that aim at halting the circulation of false information about vaccines. Based on our data, we also propose solutions to improve the communication strategy of health organizations and build a community of engaged influencers that support the dissemination of scientific insights, including issues related to vaccines and their safety.
Hawkmoths use wingstroke-to-wingstroke frequency modulation for aerial recovery to vortex ring perturbations
Authors: Gau Jeff , Gemilere Ryan ,   LDS-VIP (FM subteam), Lynch James , Gravish Nick , Sponberg Simon
Published: December 2020

Centimeter-scale fliers that combine wings with springy elements must contend with the high power requirements and mechanical constraints of flapping wing flight. Insects utilize elastic energy exchange to reduce the inertial costs of flapping wing flight and potentially match wingbeat frequencies to a mechanical resonance. Flying at resonance may be energetically favorable under steady conditions, but it is difficult to modulate the frequency of a resonant system. Evidence suggests that insects utilize frequency modulation over long time scales to adjust aerodynamic forces, but it remains an open question the extent to which insects can modulate frequency on the wingstroke-to-wingstroke timescale. If wingbeat frequencies deviate from resonance, the musculature must work against the elastic flight system, thereby potentially increasing energetic costs. To assess how insects address the simultaneous needs for power and control, we tested the capacity for wingstroke-to-wingstroke wingbeat frequency modulation by perturbing free hoveringManduca sextawith vortex rings while recording high-speed video at 2000 fps. Because hawkmoth flight muscles are synchronous, there is at least the potential for the nervous system to modulate frequency on each wingstroke. We observed±16% wingbeat frequency modulation in just a few wing strokes. Via instantaneous phase analysis of wing kinematics, we found that over 85% of perturbation responses required active changes in motor input frequency. Unlike their robotic counterparts that explicitly abdicate frequency modulation in favor of energy efficiency, we find that wingstroke-to-wingstroke frequency modulation is an underappreciated control strategies that complements other strategies for maneuverability and stability in insect flight.
Haplotype divergence supports ancient asexuality in the oribatid miteOppiella nova
Authors: Brandt A. , Van P. Tran , Bluhm C. , Anselmetti Y. , Dumas Z. , Figuet E. , François C. M. , Galtier N. , Heimburger B. , Jaron K. S. , Labédan M. , Maraun M. , Parker D. J. , Robinson-Rechavi M. , Schaefer I. , Simion P. , Scheu S. , Schwander T. , Bast J. ,   2020
Published: December 2020

Sex strongly impacts genome evolution via recombination and segregation. In the absence of these processes, haplotypes within lineages of diploid organisms are predicted to accumulate mutations independently of each other and diverge over time. This so-called ‘Meselson effect’ is regarded as a strong indicator of the long-term evolution under obligate asexuality. Here, we present genomic and transcriptomic data of three populations of the asexual oribatid mite speciesOppiella novaand its sexual relativeOppiella subpectinata. We document strikingly different patterns of haplotype divergence between the two species, strongly supporting Meselson effect like evolution and ancient asexuality inO. nova: (I) Variation within individuals exceeds variation between populations inO. novabutvice versainO. subpectinata. (II) TwoO. novasub-lineages feature a high proportion of heterozygous genotypes and lineage-specific haplotypes, indicating that haplotypes diverged independently within the two lineages after their split. (III) The deepest split in gene trees generally separates haplotypes inO. nova, but populations inO. subpectinata. (IV) Tree topologies of the two haplotypes match each other. Our findings provide positive evidence for the absence of sex over evolutionary time inO. novaand suggest that asexual oribatid mites can escape the dead-end fate usually associated with asexual lineages.
The human odorant receptor OR10A6 is tuned to the pheromone of the commensal fruit fly Drosophila melanogaster
Authors: Frey Tim , Kwadha Charles A. , Wallin Erika A. , Holgersson Elsa , Hedenström Erik , Bohman Björn , Bengtsson Marie , Becher Paul G. , Krautwurst Dietmar , Witzgall Peter
Published: December 2020

Background

All living things speak chemical. The challenge is to discover the vocabulary, the volatile odorant chemicals that enable communication across phylogenies and to translate them to physiological, behavioural and ecological function. Olfactory receptors (ORs) interface animals with airborne odorants. Expression of single ORs in human embryonic kidney cells (HEK-293) makes it possible to interrogate ORs with synthetic chemicals and to identify cognate ligands that convey olfactory information.

Results

The cosmopolitan strain of the vinegar fly Drosophila melanogaster has accompanied the human expansion out of Africa, more than ten thousand years ago. These flies are strictly anthropophilic and depend on human resources and housing for survival, particularly in colder climate zones. Curiously, humans sense the scent of a single fly, and more precisely the female pheromone (Z)-4 undecenal (Z4-11Al), at 10 ng/mL (0.06 µmol/L). A screening of all functional human ORs in a HEK-293 assay provides an explanation for this astounding sensitivity, as it shows that OR10A6, one of the most highly expressed human ORs, is specifically tuned to Z4-11Al. Chemical analysis of fly effluvia confirms that cosmopolitan D. melanogaster females release Z4-11Al, while females of an African fly strain from Zimbabwe release a 1:3-blend of Z4-11Al and (Z)-4 nonenal (Z4-9Al). Interestingly, a blend of Z4-9Al and Z4-11Al produces a different aroma than the the single compounds, which is why we readily differentiate cosmopolitan and Zimbabwe flies by nose.

Conclusion

That we sensitively and specifically perceive the fly pheromone Z4-11Al suggests that it is a component of human odour scenes. This may have afforded a sensory drive during adaptation of commensal flies to human habitats and selected for a role of Z4-11Al in fly aggregation and premating communication. Screening ORs for key ligands leads to the discovery of messenger chemicals that enable chemical communication among and betwen vertebrate and invertebrate animals.
Reducing interaural tonotopic mismatch preserves binaural unmasking in cochlear implant simulations of single-sided deafness
Authors: Sagi Elad , Azadpour Mahan , Neukam Jonathan , Capach Nicole Hope , Svirsky Mario A.
Published: December 2020

Binaural unmasking, a key feature of normal binaural hearing, refers to the improved intelligibility of masked speech by adding masking noise that facilities perceived spatial separation of target and masker. A question particularly relevant for cochlear implant users with single-sided deafness (SSD-CI) is whether binaural unmasking can still be achieved if the additional masking is distorted. Adding the CI restores some aspects of binaural hearing to these listeners, although binaural unmasking remains limited. Notably, these listeners may experience a mismatch between the frequency information perceived through the CI and that perceived by their normal hearing ear. Employing acoustic simulations of SSD-CI with normal hearing listeners, the present study confirms a previous simulation study that binaural unmasking is severely limited when interaural frequency mismatch between the input frequency range and simulated place of stimulation exceeds 1-2 mm. The present study also shows that binaural unmasking is largely retained when the input frequency range is adjusted to match simulated place of stimulation, even at the expense of removing low-frequency information. This result bears implication for the mechanisms driving the type of binaural unmasking of the present study, as well as for mapping the frequency range of the CI speech processor in SSD-CI users.
Neonatal Thyroxine Activation Modifies Epigenetic Programming of The Liver
Authors: Fonseca Tatiana L. , Garcia Tzintzuni , Fernandes Gustavo W. , Nair T. Murlidharan , Bianco Antonio C.
Published: December 2020

In the neonatal liver, a peak of type 2 deiodinase (D2) activity accelerates local T3 production and the expression of thyroid hormone (TH)-responsive genes. Here we show that this acute increase in T3 signaling permanently modifies hepatic gene expression. Liver-specific Dio2 inactivation (Alb-D2KO) transiently increased H3K9me3 levels during post-natal days 1-5 (P1-P5) in discrete chromatin areas, and methylation of 1,508 DNA sites (H-sites) that remained in the adult mouse liver. These sites were associated with 1,551 areas of reduced chromatin accessibility (RCA; Atac-seq) within core promoters and 2,426 within intergenic regions, with reduction in the expression of 1,525 genes (RNA-seq). There was strong correlation between H-sites and RCA sites (r=0.85; p<0.0002), suggesting a cause-effect relationship. The analysis of chromosome conformation capture (Hi-C) data revealed a set of 57 repressed genes that have a promoter RCA in close contact with an intergenic RCA ~300 Kbp apart, including Foxa2 that plays an important role during development. Thus, the post-natal surge in hepatic D2 activity and TH-signaling prevents discrete DNA methylation and modifies the transcriptome of the adult mouse. This explains how the systemic T3 hormone acts locally during development to define future chromatin accessibility and expression of critically relevant hepatic genes.
Can we conjointly record direct interactions between neuronsin vivoin anatomically-connected brain areas? Probabilistic analyses and further implications
Authors: Martin Sean K. , Aggleton John P. , O’Mara Shane M.
Published: December 2020

Large-scale simultaneousin vivorecordings of neurons in multiple brain regions raises the question of the probability of recording direct interactions of neurons within, and between, multiple brain regions. In turn, identifying inter-regional communication rules between neurons during behavioural tasks might be possible, assuming conjoint activity between neurons in connected brain regions can be detected. Using the hypergeometric distribution, and employing anatomically-tractable connection mapping between regions, we derive a method to calculate the probability distribution of ‘recordable’ connections between groups of neurons. This mathematically-derived distribution is validated by Monte Carlo simulations of directed graphs representing the underlying anatomical connectivity structure. We apply this method to simulated graphs with multiple neurons, based on counts in rat brain regions, and to connection matrices from the Blue Brain model of the mouse neocortex connectome. Overall, we find low probabilities of simultaneously-recording directly interacting neuronsin vivoin anatomically-connected regions with standard (tetrode-based) approaches. We suggest alternative approaches, including new recording technologies and summing neuronal activity over larger scales, offer promise for testing hypothesised interregional communication and source transformation rules.
Engineered receptor binding domain immunogens elicit pan-sarbecovirus neutralizing antibodies outside the receptor binding motif
Authors: Hauser Blake M. , Sangesland Maya , Lam Evan C. , Denis Kerri J. St. , Feldman Jared , Yousif Ashraf S. , Caradonna Timothy M. , Kannegieter Ty , Balazs Alejandro B. , Lingwood Daniel , Schmidt Aaron G.
Published: December 2020

Effective countermeasures are needed against emerging coronaviruses of pandemic potential, similar to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Designing immunogens that elicit broadly neutralizing antibodies to conserved viral epitopes on the major surface glycoprotein, spike, such as the receptor binding domain (RBD) is one potential approach. Here, we report the generation of homotrimeric RBD immunogens from different sarbecoviruses using a stabilized, immune-silent trimerization tag. In mice, we find that a cocktail of these homotrimeric sarbecovirus RBDs elicits antibodies to conserved viral epitopes outside of the ACE2 receptor binding motif (RBM). Importantly, these responses neutralize all sarbecovirus components even in context of prior SARS-CoV-2 imprinting. We further show that a substantial fraction of the neutralizing antibodies elicited after vaccination in humans also engages non-RBM epitopes on the RBD. Collectively, our results suggest a strategy for eliciting broadly neutralizing responses leading to a pan-sarbecovirus vaccine.

Author summary

Immunity to SARS-CoV-2 in the human population will be widespread due to natural infection and vaccination. However, another novel coronavirus will likely emerge in the future and may cause a subsequent pandemic. Humoral responses induced by SARS-CoV-2 infection and vaccination provide limited protection against even closely related coronaviruses. We show immunization with a cocktail of trimeric coronavirus receptor binding domains induces a neutralizing antibody response that is broadened to related coronaviruses with pandemic potential. Importantly, this broadening occurs in context of an initial imprinted SARS-CoV-2 spike immunization showing that preexisting immunity can be expanded to recognize other related coronaviruses. Our immunogens focused the serum antibody response to conserved epitopes on the receptor binding domain outside of the ACE2 receptor binding motif; this contrasts with current SARS-CoV-2 therapeutic antibodies, which predominantly target the receptor binding motif.