bluuebunny/crossref_metadata_2025 huggingface dataset:
Type construction in qualitative health research and its relevance in complementary and integrative medicine. Two studies about patients’ experiences with herbal medicine preparations
Authors: Canella Claudia , Wolfensberger Balz , Witt Claudia M.
Published: June 2022

In this article, we explore the method of type construction in qualitative health research in the field of complementary and integrative medicine. We applied type construction to research questions in phytotherapy about the everyday life experiences of patients using two specific herbal medicine preparations. In total, 21 patients participated in two consecutive qualitative studies. The collected data incorporated patient diaries, face-to-face interviews and pre- and posttreatment questionnaires. A type construction approach was applied for data analysis. In the Passiflora-study, three distinct biographical narrative types attributed to different experiences when using a specific ethanolic extract of Passiflora incarnata were identified. In the Angelica-study, four types of thematic dimensions of experiences with a specific ethanolic extract of Angelica archangelica were identified. Type construction in qualitative health research can contribute to evidence-based phytotherapy and complementary and integrative medicine in general by supporting shared decision making and individualized treatment approaches.
DIVE: a reference-free statistical approach to diversity-generating & mobile genetic element discovery
Authors: Abante J. , Wang P.L. , Salzman J.
Published: June 2022

Diversity-generating and mobile genetic elements are paramount to microbial and viral evolution and result in evolutionary leaps conferring novel phenotypes, such as antimicrobial resistance. State-of-the-art algorithms to detect these elements have many limitations, including reliance on reference genomes, assemblers, and heuristics, resulting in computational bottlenecks and limiting the scope of biological discoveries. Here we introduce DIVE, a new reference-free approach to overcome these limitations using information contained in sequencing reads alone. We show that DIVE has improved detection power compared to existing reference-based methods using simulations and real data. We use DIVE to rediscover and characterize the activity of known and novel elements and generate new biological hypotheses about the mobilome. Using DIVE we rediscover CRISPR and identify novel repeats, and we discover unannotated genetic hyper-variability hotspots inEscherichia coliandVibrio cholerae. Building on DIVE, we develop a reference-free framework capable ofde novodiscovery of mobile genetic elements, not currently available to our knowledge, and we use it to rediscover the known transposons inMycobacterium tuberculosis, the causative agent oftuberculosis.
Coordination Between Embryo Growth and Trophoblast Migration Upon Implantation Delineates Mouse Embryogenesis
Authors: Bondarenko V. , Nikolaev M. , Kromm D. , Belousov R. , Wolny A. , Rezakhani S. , Hugger J. , Uhlmann V. , Hufnagel L. , Kreshuk A. , Ellenberg J. , Erzberger A. , Lutolf M. , Hiiragi T.
Published: June 2022

Implantation marks a key transition in mammalian development. The role of embryo-uterus interaction in periimplantation development is however poorly understood due to inaccessibility in utero. Here, we develop an engineered uterus-like microenvironment to recapitulate mouse development ex vivo up to E5.25 and discover an essential role of integrin-mediated trophoblast adhesion to the uterine matrix. Light-sheet microscopy shows that trophoblast cells undergo Rac1-dependent collective migration upon implantation, displacing Reichert’s membrane and generating space for egg cylinder growth. The key role of coordination between trophoblast migration and embryo growth is verified by experimentally manipulating the migration velocity and geometry of the engineered uterus. Modeling the implanting embryo as a wetting droplet links the tissue shape dynamics to underlying changes in trophoblast adhesion and suggests that the corresponding tension release facilitates egg cylinder formation. Together, this study provides mechanisms by which dynamic embryo-uterus interactions play an essential role in peri-implantation development.
Decoding Imagined Musical Pitch from Human Scalp Electroencephalograms
Authors: Chung Miyoung , Kim Taehyung , Jeong Eunju , Chung Chun-Kee , Kim June-Sic , Kwon Oh-Sang , Kim Sung-Phil
Published: June 2022

Brain-computer interfaces (BCIs) can restore the functions of communication and control in people with paralysis. In addition to the currently proven functions restored by BCIs, it would enrich life if one could regain a function of musical activity. However, it remains largely unknown whether it is feasible to decode imagined musical information directly from neural activity. Among various musical information, this study aimed to decode pitch information directly from scalp electroencephalography (EEG). Twenty healthy participants performed a task to imagine one of the seven musical pitches (C4 – B4) randomly. To find EEG features for pitch imagination, we took two approaches: exploring multi-band spectral power at individual channels (IC); and exploring power differences between bilaterally symmetric channels (DC). We classified these features into the seven pitch classes using various types of classifiers. The selected spectral power features revealed marked contrasts between left and right hemispheres, between low-, (<13 Hz) and high-frequency (> 13 Hz) bands, and between frontal and parietal areas. The best classification performance for seven pitches was obtained using the IC feature and SVM with the average accuracy of 35.68±7.47% (max. 50%) and the average information transfer rate (ITR) of 0.37±0.22 bits/sec. Yet, when we decoded a different number of classes (K = 2 ∼ 6) by grouping adjacent pitches, ITR was similar across K as well as between IC and DC features, suggesting efficiency of DC features. This study would be the first to demonstrate the feasibility of decoding imagined musical pitch directly from human EEG.
Tolerant crops increase growers’ yields but promote selfishness: how the epidemiology of disease resistant and tolerant varieties affect grower behaviour
Authors: Murray-Watson Rachel E. , Cunniffe Nik J.
Published: June 2022

1

Disease management often involves genetically improved crops. Resistant varieties are less susceptible, and so less likely to act as reservoirs of inoculum. Tolerant varieties can be highly susceptible, but limit yield loss for those who grow them. Population-scale effects of deploying resistant or tolerant varieties have received little consideration from epidemiologists.

We examined how tolerant and resistant crop have opposing consequences upon the uptake of control using a behavioural model based on strategic-adaptive expectations. Growers compared last season’s profit with an estimate of what could be expected from the alternative crop type, thereby assessing whether to alter their strategy for the next season.

Tolerant crop only benefited growers using it, decreasing yields for others. This incentivises widespread use via a negative feedback loop. Resistant crop was more widely beneficial, with reduced population-scale disease pressure leading to increased yields for all. However, this positive externality allows growers who do not deploy resistant crop to “free-ride” upon the management of others.

This work highlights how a community of growers responds to the contrasting incentives caused by tolerant and resistant crop varieties, and how this leads to very distinct effects on yields and population-scale deployment.
Exploration of DPP-IV inhibitory peptide design rules assisted by deep learning pipeline that identifies restriction enzyme cutting site
Authors: Guan Changge , Luo Jiawei , Li Shucheng , Tan Zheng Lin , Wang Yi , Chen Haihong , Yamamoto Naoyuki , Zhang Chong , Lu Yuan , Chen Junjie , Xing Xin-Hui
Published: June 2022

Mining of anti-diabetic dipeptidyl peptidase IV (DPP-IV) inhibitory peptides (DPP-IV-IPs) is currently a costly and laborious process. Due to the absence of rational peptide design rules, it relies on cumbersome screening of unknown enzyme hydrolysates. Here, we present an enhanced deep learning (DL) model called BERT-DPPIV, specifically designed to classify DPP-IV-IPs and exploring their design rules to discover potent candidates. The end-to-end model utilizes a fine-tuned bidirectional encoder representations (BERT) architecture to extract structural/functional information from input peptides and accurately identify DPP-IV-Ips from input peptides. Experimental results in benchmark dataset showed BERT-DPPIV yielded state-of-the-art accuracy of 0.894, surpassing the 0.797 obtained by sequence-feature model. Furthermore, we leverage the attention mechanism to uncover that our model could recognize restriction enzyme cutting site and specific residues that contribute to the inhibition of DPP-IV. Moreover, guided by BERT-DPPIV, proposed design rules of DPP-IV inhibitory tripeptides and pentapeptides were validated and they can be used to screen potent DPP-IV-IPs.
The regional distribution of resident immune cells shapes distinct immunological environments along the murine epididymis
Authors: Pleuger Christiane , Ai Dingding , Hoppe Minea , Winter Laura , Bohnert Daniel , Karl Dominik , Guenther Stefan , Epelman Slava , Kantores Crystal , Fijak Monika , Ravens Sarina , Middendorff Ralf , Mayer Johannes U. , Loveland Kate L. , Hedger Mark P. , Bhushan Sudhanshu , Meinhardt Andreas
Published: June 2022

Summary/ Abstract

The epididymis constitutes an important transition zone for post-testicular sperm maturation and storage. As the organ consists of a single convoluted duct, inflammation-associated tissue damage has a severe impact on fertility. In order to clarify the reasons for region-specific differences in the intensity of immune responses observed in a mouse model of acute bacterial epididymitis, we investigated the heterogeneity of resident immune cell populations within the epididymis under physiological conditions by scRNASeq analysis of extravascular CD45+ cells. 12 distinct immune cell subsets were identified, displaying substantial differences in distribution along the epididymis. Several distinct subsets of macrophages constituted the majority of these cells. Crucially, the proximal and distal regions showed striking differences in their immunological landscapes. These findings indicate that resident immune cells are strategically positioned along the epididymal duct, potentially providing different immunological environments required for sperm maturations and elimination of pathogens ascending the urogenital tract.
Inhibition of the TPL2-MKK1/2-ERK1/2 pathway has cytostatic effect on B-Cell Lymphoma
Authors: Asslan Mariana , Martel Guy , Rousseau Simon
Published: June 2022

1)

Diffuse Large B-Cell Lymphoma (DLBCL) are the most common form of non-Hodgkin lymphoma. Their molecular origin is heterogeneous and therefore treatments aimed at DLBCL must be adapted in function of the underlying molecular mechanisms driving cellular transformation. Constitutive activation of the protein kinases ERK1/2 is a hallmark of many B-cell malignancies. ERK1/2 activation which can occur downstream of the classical MAPK cascade via RAF or, in response to TLR stimulation, via the Tumor Promoting Locus 2 (TPL2) protein kinase. This pathway also relays signals from the MYD88 oncogenic mutant L265P, frequently found in hematologic malignancies. We report here that TPL2 participate to ERK1/2 activation downstream of BCR in a DLBCL cell line (OCI-Ly2). Moreover, we showed that a ERK2[Y316F] mutant increased c-Myc-luciferase reporter expression. We then investigated the impact of ERK1/2 inhibition on the proliferation of OCI-Ly2 cells. We found that blocking ERK1/2 MAPK signaling cascade using either MKK1/2 inhibitors (PD184352 and MEK162) or TPL2 inhibitor (Compound 1) was mainly cytostatic. Finally, we showed that while TPL2-MKK1/2 inhibition leads to cytostatic effect, Compound 1 has cytocidal effect at high concentrations, that is mediated via additional targets. Taken together, this study demonstrates the involvement of TPL2 in oncogenic signaling of DLBCL and supports the idea that combination therapy targeting multiple molecular pathways linked to cellular transformation is a superior avenue for future therapies.
Trem2 deficiency does not worsen metabolic function in diet-induced obese mice
Authors: Winn Nathan C. , Wolf Elysa M. , Garcia Jamie N. , Hasty Alyssa H.
Published: June 2022

Triggering receptor expressed on myeloid cells 2 (Trem2) is highly expressed on myeloid cells and is involved in cellular lipid homeostasis and inflammatory processes. Trem2 deletion in mice (Trem2-/-) has been implicated in evoking adipose tissue dysfunction, but its role in worsening obesity-induced metabolic dysfunction is not resolved. Here we aimed to determine the causal role of Trem2 in regulating glucose homeostasis and insulin sensitivity in mice. Nine-week-old male and female littermate WT and Trem2-/- mice were fed low fat or high fat diet for 18 weeks and phenotyped for metabolic function. Diet-induced weight gain was similar between genotypes, irrespective of sex. Consistent with prior reports, we find that loss of Trem2 causes massive adipocyte hypertrophy and an attenuation in the lipid associated macrophage transcriptional response to obesity. In contrast to published data, we find that loss of Trem2 does not worsen metabolic function in obese mice. No differences in intraperitoneal glucose tolerance (ipGTT), oral GTT, or mixed meal substrate control, including postprandial glucose, non-esterified fatty acids, insulin, or triglycerides were found between WT and Trem2-/- animals. Similarly, no phenotypic differences existed when animals were challenged with stressors on metabolic demand (i.e., acute exercise or environmental temperature modulation) or when animals were challenged with a non-lethal dose of endotoxin. Collectively, we report a disassociation between adipose tissue remodeling caused by loss of Trem2 and whole-body metabolic homeostasis in obese mice. The complementary nature of experiments conducted gives credence to the conclusion that loss of Trem2 is unlikely to worsen glucose homeostasis in mice.
SERCA2 regulates proinsulin processing and processing enzyme maturation in the pancreatic β cell
Authors: Iida Hitoshi , Kono Tatsuyoshi , Lee Chih-Chun , Krishnan Preethi , Arvin Matthew C. , Weaver Staci A. , Jarvela Timothy S. , Bone Robert N. , Tong Xin , Arvan Peter , Lindberg Iris , Evans-Molina Carmella
Published: June 2022

Increased circulating levels of incompletely processed insulin (i.e. proinsulin) are observed clinically in both type 1 and type 2 diabetes; however, the mechanisms underlying impaired proinsulin processing remain incompletely understood. Here, we identify the sarcoendoplasmic reticulum Ca2+ ATPase-2 (SERCA2) pump and β cell ER Ca2+ as key regulators of systemic glucose tolerance and proinsulin processing. We generated mice with a β cell-specific SERCA2 deletion (βS2KO) and SERCA2 deficient INS-1 cells to show that SERCA2 loss increases systemic and pancreatic levels of proinsulin protein and leads to aberrant localization of proinsulin within the proximal β cell secretory pathway. These defects in proinsulin processing were linked to reduced maturation of the proinsulin processing enzymes PC1/3 and PC2, suggesting a model whereby chronic ER Ca2+ depletion in the β cell, which is observed in many pathological conditions, impairs the spatial regulation of prohormone trafficking, processing, and maturation within the β cell secretory pathway.
DriverSEAT: A spatially-explicit stochastic modelling framework for the evaluation of gene drives in novel target species
Authors: Legros Mathieu , Barrett Luke G.
Published: June 2022

Gene drives represent a potentially ground breaking technology for the control of undesirable species or the introduction of desirable traits in wild population, and there is strong interest in applying these technologies to a wide range of species across many domains including agriculture, health, conservation and biosecurity. There remains however considerable uncertainty regarding the feasibility and efficacy of gene drives in various species, based in particular on biological and ecological specificities of each target. In this paper we introduce DriverSEAT, a new spatial, modular modelling framework designed to assess the outcome of gene drives in a range of target species based on their specific ecological dynamics and genetics. In addition to the main structure and characteristics of the model, we present an example of its application on scenarios of genetic control of weeds, a potential candidate for gene drive control that presents significant challenges associated with plant population dynamics. We illustrate here how the results from DriverSEAT can inform on the potential value of gene drives in this specific context, and generally provide ecologically informed guidance for the development and feasibility of gene drives as a control method in new target species.
Simple Human Response Times are Governed by Dual Anticipatory Processes with Distinct and Distributed Neural Signatures
Authors: Ramayya Ashwin G. , Buch Vivek , Richardson Andrew , Lucas Timothy , Gold Joshua I.
Published: June 2022

Human behavior can be highly sensitive to anticipation, but the mechanisms underlying this sensitivity are poorly understood. We obtained intracranial electrocephalography (iEEG) measurements in neurosurgical patients as they performed a simple sensory-motor task with variable (short or long) foreperiod delays that affected anticipation of the cue to respond. Participants showed two forms of anticipatory response biases, distinguished by more premature false alarms (FAs) or faster response times (RTs) on long-delay trials. These biases had distinct neural signatures in prestimulus neural activity modulations that were distributed and intermixed across the brain: the FA bias was most evident in preparatory motor activity immediately prior to response-cue presentation, whereas the RT bias was most evident in visuospatial activity at the beginning of the foreperiod. These results suggest that human anticipatory behavior emerges from a combination of motor-preparatory and attention-like modulations of neural activity, implemented by anatomically widespread and intermixed, but functionally identifiable, brain networks.

Graphical Abstract
Factors associated with COVID-19 vaccine uptake in people with kidney disease: an OpenSAFELY cohort study
Authors:   The OpenSAFELY Collaborative, Parker Edward PK , Tazare John , Hulme William J , Bates Christopher , Beale Rupert , Carr Edward J , Cockburn Jonathan , Curtis Helen J , Fisher Louis , Green Amelia CA , Harper Sam , Hester Frank , Horne Elsie MF , Loud Fiona , Lyon Susan , Mahalingasivam Viyaasan , Mehrkar Amir , Nab Linda , Parry John , Santhakumaran Shalini , Steenkamp Retha , Sterne Jonathan AC , Walker Alex J , Williamson Elizabeth J , Willicombe Michelle , Zheng Bang , Goldacre Ben , Nitsch Dorothea , Tomlinson Laurie A
Published: June 2022

Background

Kidney disease is a significant risk factor for COVID-19-related mortality. Achieving high COVID-19 vaccine coverage among people with kidney disease is therefore a public health priority.

Methods

With the approval of NHS England, we performed a retrospective cohort study using the OpenSAFELY-TPP platform. Individual-level routine clinical data from 24 million people in England were included. A cohort of individuals with stage 3–5 chronic kidney disease (CKD) or receiving renal replacement therapy (RRT) at the start of the COVID-19 vaccine roll-out was identified based on evidence of reduced estimated glomerular filtration rate or inclusion in the UK Renal Registry. Individual-level factors associated with vaccine uptake were explored via Cox proportional hazards models.

Results

948,845 people with stage 3–5 CKD or receiving RRT were included. Cumulative vaccine coverage as of 11th May 2022 was 97.5%, 97.0%, and 93.5% for doses 1, 2, and 3, respectively, and 61.1% among individuals with one or more indications for receipt of a fourth dose. Delayed 3-dose vaccine uptake was associated with non-White ethnicity, social deprivation, and severe mental illness – associations that were consistent across CKD stages and in RRT recipients. Similar associations were observed for 4-dose uptake, which was also delayed among care home residents.

Conclusion

Although high primary and booster dose coverage has been achieved among people with kidney disease in England, key disparities in vaccine uptake remain across demographic groups. Identifying how to address these disparities remains a priority to reduce the risk of severe disease in this vulnerable patient group.
Association of lithocholic acid with skeletal muscle hypertrophy through TGR5-IGF-1 and skeletal muscle mass in chronic liver disease rats and humans
Authors: Tamai Yasuyuki , Eguchi Akiko , Shigefuku Ryuta , Kitamura Hiroshi , Tempaku Mina , Sugimoto Ryosuke , Kobayashi Yoshinao , Iwasa Motoh , Takei Yoshiyuki , Nakagawa Hayato
Published: June 2022

[Background & aims] Hepatic sarcopenia is one of many complications associated with chronic liver disease (CLD) and has a high mortality rate, however, the liver-muscle axis is not fully understood. Therefore, few effective treatments exist for hepatic sarcopenia, the best of which being branched-amino acid (BCAA) supplementation to help increase muscle mass. Our aim was to investigate the molecular mechanism(s) of hepatic sarcopenia focused on bile acid (BA) composition. [Methods] Gastrocnemius muscle phenotype and serum BA levels were assessed in CLD rats treated with BCAA. Mouse skeletal muscle cells (C2C12) were incubated with lithocholic acid (LCA), G-protein-coupled receptor 5 (TGR5) agonist or TGR5 antagonist to assess skeletal muscle hypertrophy. The correlation between serum BA levels and psoas muscle area index (PMI) was examined in 73 CLD patients. [Results] Gastrocnemius muscle weight significantly increased in CLD rats treated with BCAA via suppression of protein degradation pathways, coupled with a significant increase in serum LCA levels. LCA treated C2C12 hypertrophy occurred in a concentration-dependent manner linked with TGR5-Akt pathways based upon inhibition results via a TGR5 antagonist. In human CLD, serum LCA levels were the sole factor positively correlated with PMI and were significantly decreased in both the low muscle mass group and the deceased group. Serum LCA levels were also shown to predict patient survival. [Conclusion] Our results indicate LCA-mediated skeletal muscle hypertrophy via activation of TGR5-IGF1-Akt signaling pathways. In addition, serum LCA levels were associated with skeletal muscle mass in cirrhotic rats, as well as CLD patients, and predicted overall patient survival. [Funding] This research was supported by JSPS KAKENHI Grant Number 22K08011 and 21H02892, and AMED under Grant Number JP21fk0210090 and JP22fk0210115.
Changes in basal insulin secretion capacity after pancreatectomy: a retrospective study
Authors: Kihara Yasuhiro , Murotani Kenta , Yokomizo Hiroshi
Published: June 2022

This study evaluated the changes in basal insulin secretion capacity (BISC) after pancreatectomy across two surgical procedures. We also investigated the association between decreased BISC and the introduction of postoperative insulin therapy. The data on 110 patients who underwent pancreatectomy during October 2018–February 2022 at our hospital were analyzed retrospectively. We focused on the C-peptide index (CPI) as an index for BISC. A decreased postoperative BISC was defined as a postoperative CPI (post-CPI) <1.0, which was in turn defined as the event occurrence in our study. The receiver operating characteristic curve for the event occurrence was plotted for factors related to preoperative glucose tolerance. Of the preoperative non-diabetic 73 patients, 44 and 29 who underwent pancreaticoduodenectomy (PD) and distal pancreatectomy (DP), respectively, were examined. A post-CPI of <1.0 was observed in 29 patients (39%). Although the proportion of remnant pancreatic volume was significantly smaller in patients with PD than in patients with DP (38% vs. 68%, p <0.0001), no significant difference was observed in the event rates (39% vs. 41%). In patients with PD, preoperative CPI (area under the curve: 0.75) was used for predicting post-CPI <1.0. Multivariate analysis revealed that preoperative CPI <1.65 (odds ratio: 7.69, 95% confidence interval: 1.87–31.5) was an independent predictor of decreased postoperative BISC. However, in patients with DP, no significant predictors were identified. Induction of insulin therapy was significantly lower in preoperative non-diabetic patients (n=73) after undergoing a pancreatectomy (1.4% vs. 37.5%, p<0.0001) than in preoperative medically treated patients (n=16); there was no significant difference in event (post-CPI <1.0) rates (39.7% vs. 56.2%, p=0.23). Although pancreatectomy reduces BISC after surgery, the coexistence of insulin resistance, which is a pathophysiology of type 2 diabetes mellitus, may play a role in whether postoperative glucose tolerance is reduced to the point where insulin therapy is necessary.
The relationship between response dynamics and the formation of confidence varies across the lifespan
Authors: Overhoff Helen , Ko Yiu Hong , Fink Gereon R. , Stahl Jutta , Weiss Peter H. , Bode Stefan , Niessen Eva
Published: June 2022

Accurate metacognitive judgements, such as forming a confidence judgement, are crucial for goaldirected behaviour but decline with older age. Besides changes in the sensory processing of stimulus features, there might also be changes in the motoric aspects of giving responses that account for age-related changes in confidence. In order to assess the association between confidence and response parameters across the adult lifespan, we measured response times and peak forces in a four-choice flanker task with subsequent confidence judgements. In 65 healthy adults from 20 to 76 years of age, we showed divergent associations of each measure with confidence, depending on decision accuracy. Participants indicated higher confidence after faster responses in correct but not incorrect trials. They also indicated higher confidence after less forceful responses in errors but not in correct trials. Notably, these associations were age-dependent as the relationship between confidence and response time was more pronounced in older participants, while the relationship between confidence and response force decayed with age. Our results add to the notion that confidence is related to response parameters and demonstrate noteworthy changes in the observed associations across the adult lifespan. These changes potentially constitute an expression of general age-related deficits in performance monitoring or, alternatively, index a failing mechanism in the computation of confidence in older adults.
CellScape: Protein structure visualization with vector graphics cartoons
Authors: Silvestre-Ryan Jordi , Fletcher Daniel A. , Holmes Ian
Published: June 2022

Motivation

Illustrative renderings of proteins are useful aids for scientific communication and education. Nevertheless, few software packages exist to automate the generation of these visualizations.

Results

We introduce CellScape, a tool designed to generate 2D molecular cartoons from atomic coordinates and combine them into larger cellular scenes. These illustrations can outline protein regions in different levels of detail. Unlike most molecular visualization tools which use raster image formats, these illustrations are represented as vector graphics, making them easily editable and composable with other graphics.

Availability and Implementation

CellScape is implemented in Python 3 and freely available at https://github.com/jordisr/cellscape. It can be run as a command-line tool or interactively in a Jupyter notebook.

Contact

jordisr@berkeley.edu
Evolving copy number gains promote tumor expansion and bolster mutational diversification
Authors: Wang Zicheng , Xia Yunong , Mills Lauren , Nikolakopoulos Athanasios N. , Maeser Nicole , Sheltzer Jason M. , Sun Ruping
Published: June 2022

Charting the evolutionary history of rampant somatic copy number alterations (SCNA) is an indispensable step toward a deeper understanding of their roles in tumor development. However, the existing SCNA timing analysis is limited to low copy number states and initiating gains, which are not necessarily close to the onset of the malignant proliferation. Moreover, it remains a critical question if the timing of an SCNA reveals the corresponding variant’s fitness effect. Here we propose a framework to estimate the arrival time of a clonal SCNA, i.e., the time delay from its last alteration to the start of population expansion, in addition to its initiation time when the first alteration occurs. Our method leverages the bias that a genomic segment, when resting on a copy number (CN) state, accumulates somatic single nucleotide variants (SSNV) at a rate proportional to its CN. From the whole genome sequencing data of 184 samples from 75 patients across five tumor types, we commonly observed late clonal CN gains following early initiating events, which appear right before the expansion leading to the observed tumor sample(s). Genome doubling (GD) can be late, but post-GD CN evolution is prevalent in the genealogy of the most recent common ancestor of patient tumors. Notably, mathematical modeling suggests that late evolving events could contain rate-limiting drivers. The advantage of evolving gains could arise from the dosage increase of cancer genes in proliferative signaling and amplification of early functional variants. In addition, evolving SCNAs bolster the diversification of SSNVs between sub-populations, exacerbating the vicious circle between malignant growth and accumulation of genomic heterogeneity. Our findings have broad implications for resolving the trajectory of SCNAs, discerning the CN markers of malignant growth in vivo, and properly quantifying tumor heterogeneity in aneuploid tumors.
Skull allometries in three species of Didelphis (Didelphimorphia, Didelphidae)
Authors: Parés-Casanova Pere M.
Published: June 2022

As biological shape is usually complex and evolves on different constraints, it can be assessed using integrative methods such as geometric morphometrics. Allometric changes were analysed in three species of Didelphis genus (D. albiventris n=20, D. marsupialis n=82, D. pernigra n=35) by means of geometric morphometric techniques. A significant correlation between shape and size was found, suggesting an allometric change pattern for all three species studied. However, allometries appeared to be different between D. marsupialis and D. pernigra, both of which belong to different groups (the so-called black-eared group and the white-eared group, respectively). Results are consistent with taxonomic recognition at the group level and can help to elucidate phylogenetic relationships between these three Didelphis species.
Validation of a new coil array tailored for dog functional magnetic resonance imaging (fMRI) studies
Authors: Alexandrina Guran C.-N. , Sladky Ronald , Karl Sabrina , Boch Magdalena , Laistler Elmar , Windischberger Christian , Huber Ludwig , Lamm Claus
Published: June 2022

Comparative neuroimaging allows for the identification of similarities and differences between species. It provides an important and promising avenue, to answer questions about the evolutionary origins of the brain’s organization, in terms of both structure and function. Dog fMRI has recently become one particularly promising and increasingly used approach to study brain function and coevolution. In dog neuroimaging, image acquisition has so far been mostly performed with coils originally developed for use in human MRI. Since such coils have been tailored to human anatomy, their sensitivity and data quality is likely not optimal for dog MRI. Therefore, we developed a multi-channel receive coil (K9 coil) tailored for high-resolution functional imaging in canines, optimized for dog cranial anatomy. In this paper we report structural (n = 9) as well as functional imaging data (resting-state, n = 6; simple visual paradigm, n = 9) collected with the K9 coil in comparison to reference data collected with a human knee coil. Our results show that the K9 coil significantly outperforms the human knee coil, improving the signal-to-noise ratio across the imaging modalities. We noted increases of roughly 45% signal-to-noise in the structural and functional domain. In terms of translation to functional fMRI data collected in a visual flickering checkerboard paradigm, group-level analyses show that the K9 coil performs better than the knee coil as well. These findings demonstrate how hardware improvements may be instrumental in driving data quality, and thus, quality of imaging results, for dog-human comparative neuroimaging.

Significance Statement

Comparative neuroimaging is a powerful avenue to discover evolutionary mechanisms at the brain level. However, data quality is a major constraint in non-human functional magnetic resonance imaging. We describe a novel canine head coil for magnetic resonance imaging, designed specifically for dog cranial anatomy. Data quality performance and improvements over previously used human knee coils are described quantitatively. In brief, the canine coil improved signal quality substantially across both structural and functional imaging domains, with strongest improvements noted on the cortical surface.
Timbral effects on consonance illuminate psychoacoustics of music evolution
Authors: Marjieh Raja , Harrison Peter M. C. , Lee Harin , Deligiannaki Fotini , Jacoby Nori
Published: June 2022

The phenomenon of musical ‘consonance’ is an essential feature in diverse musical styles. The traditional belief, supported by centuries of Western music theory and psychological studies, is that consonance derives from simple (‘harmonic’) frequency ratios between tones. Here we show through massive large-scale behavioral experiments (235,440 judgments) that harmonic consonance preferences can be deeply reshaped by timbral manipulations, even as far as to induce preferences for inharmonic intervals. We show how such effects may have shaped the cultural evolution of diverse scale systems ranging from the gamelan’s ‘slendro’ scale to the tuning of Western ‘mean-tone’ and ‘equal-tempered’ scales. Through computational modeling we show that these timbral manipulations elegantly dissociate competing psychoacoustic mechanisms underlying consonance, and we derive an updated computational model combining liking of harmonicity, disliking of fast beats (roughness), and liking of slow beats. Altogether, this work showcases how large-scale behavioral experiments can inform classical questions in auditory perception.

Author summary

“We reveal effects of timbre on consonance perception that motivate a new understanding of the evolution of musical scales.”
Engineered model of t(7;12)(q36;p13) AML recapitulates patient-specific features and gene expression profiles
Authors: Ragusa Denise , Cicirò Ylenia , Federico Concetta , Saccone Salvatore , Bruno Francesca , Saeedi Reza , Sisu Cristina , Pina Cristina , Sala Arturo , Tosi Sabrina
Published: June 2022

Acute myeloid leukaemia carrying the translocation t(7;12)(q36;p13) is an adverse-risk leukaemia uniquely observed in infants. Despite constituting up to 30% of cases in under 2-year-olds, it remains poorly understood. Known molecular features are ectopic overexpression of the MNX1 gene and generation of a fusion transcript in 50% of patients. Lack of research models has hindered understanding of t(7;12) biology, which has historically focused on MNX1 overexpression rather than the cytogenetic entity itself. Here, we employed CRISPR/Cas9 to generate t(7;12) in the human K562 cell line, and in healthy CD34+ haematopoietic progenitors where the translocation was not sustained in long-term cultures or through serial replating. In contrast, in K562 cells, t(7;12) was propagated in self-renewing clonogenic assays, with sustained myeloid bias in colony formation and baseline depletion of erythroid signatures. Nuclear localisation analysis revealed repositioning of the translocated MNX1 locus to the interior of t(7;12)-harbouring K562 nuclei - a known phenomenon in t(7;12) patients which associates with ectopic overexpression of MNX1. Crucially, the K562-t(7;12) model successfully recapitulated the transcriptional landscape of t(7;12) patient leukaemia. In summary, we engineered a clinically-relevant model of t(7;12) acute myeloid leukaemia with the potential to unravel targetable molecular mechanisms of disease.
Astrocyte Autophagy Response Upon Neuronal Cilia Loss in the Aging Brain
Authors: de las Heras-García Laura , Pampliega Olatz
Published: June 2022

Primary cilia are microtubule-based signaling organelles present in the plasma membrane of most cell types, including mature astrocytes and neurons. However, little is known about the role of this organelle in the mature brain. Data from our lab show that neuronal primary cilia (nPC) is required for soluble amyloid beta oligomer signaling and modulation of autophagy, and that these events are age dependent. Here, we hypothesize that astrocytes react to the loss of nPC and that aging might impact these events. For that purpose, we have characterized morphological changes in astrocytes as well as in the cilium and autophagy of these cells in brain tissue from young and old mice with impaired PC in neurons. Our results show that upon loss of PC in neurons astrocytes become reactive and reduce their lysosomal capacity, an effect that is reinforced with aging. Moreover, aging reduced the pool of ciliated astrocytes, which might impact their ability to react to extracellular events. Overall, our data suggest that the PC might act an intermediary in the communication between astrocytes and neurons.

Highlights of the paper

Astrocytes become reactive upon loss of primary cilia in neurons, which is reinforced during aging.

Astrocytes in the old brain are less ciliated.

Loss of neuronal primary cilia decreases lysosomal capacity in astrocytes in age-dependent manner.
Gray matter cortical thickness predicts individual pain sensitivity: a multi-center machine learning approach
Authors: Kotikalapudi Raviteja , Kincses Balint , Zunhammer Matthias , Schlitt Frederik , Schmidt-Wilcke Tobias , Kincses Zsigmond T. , Asan Livia , Bingel Ulrike , Spisak Tamas
Published: June 2022

Pain sensitivity is known to considerably vary across individuals. While the variability in pain has been linked to structural neural correlates, it is still unclear how well these findings replicate in independent data and whether they are powerful enough to provide reliable pain sensitivity predictions on the individual level. In this study, we constructed a predictive model of pain sensitivity utilising structural MRI-based cortical thickness data from a multi-center dataset (3 centers, 131 healthy participants). Cross-validated estimates revealed a statistically significant and clinically relevant predictive performance (Pearson’s r = 0.36, p < 0.0005). The predictions were found to be specific to pain sensitivity and not biased towards potential confounding effects (e.g., anxiety, stress, depression, center-effects). Analysis of model coefficients suggests that the most robust cortical thickness predictors of pain sensitivity are the right rostral anterior cingulate gyrus, left parahippocampal gyrus and left temporal pole. Cortical thickness in these regions was negatively correlated to pain sensitivity. Our results can be considered as a proof-of-concept for the capacity of brain morphology to predict pain sensitivity, paving the way towards future multimodal brain-based biomarkers of pain.

Highlights

We present a robust, brain structure-based multi-center predictive model for pain sensitivity.

Our model based on gray matter cortical thickness explains 13% of the variance in pain sensitivity and generalizes to out-of-center data.

The predictions are specific to pain sensitivity and not driven by potential confounders such as stress, depression, anxiety, and center-effects.

The most important predictors were rostral anterior cingulate cortex, parahippocampal gyrus and temporal pole, all negatively correlated with pain sensitivity.
Changes in neural readout of response magnitude during auditory streaming do not correlate with behavioral choice in the auditory cortex
Authors: Banno Taku , Shirley Harry , Fishman Yonatan I. , Cohen Yale E.
Published: June 2022

Although previous studies have identified neural mechanisms that may underlie auditory scene analysis, the relationship between these mechanisms and behavior remains elusive. To fill these gaps, we recorded multiunit activity (MUA) from the posterior and anterior auditory fields while monkeys participated in an auditory streaming task. We found that MUA magnitude was reduced as the streaming stimulus unfolded over time, and this reduction depended on the frequency difference between the tone bursts comprising the streaming stimulus. We then examined whether this frequency-dependent reduction in activity could be utilized by downstream neurons to read out “one stream” versus “two streams” and found that, as the frequency difference increased, an ideal observer consistently classified neural activity as “two streams”. However, because this classification was not modulated by the monkeys’ choices, it suggests that this activity may not reflect the segregation of stimuli into perceptually distinct auditory streams but may simply reflect bottom-up processes.
Product inhibition can accelerate evolution
Authors: Ruth Beatrice , Dittrich Peter
Published: June 2022

Molecular replicators studied in-vitro exhibit product inhibition, typically caused by the hybridization of products into dimer complex that are not able to replicate. As a result, the replication rate and the selection pressure is reduced, potentially allowing the “survival of everyone”. Here, we introduce a stochastic evolution model of replicating and hybridizing RNA strands to study the effect of product inhibition on evolution. We found that hybridization, though reducing the rate of replication, can increase the rate of evolution, measured as fitness gain within a period of time. The positive effect has been observed for a mutation error smaller than half of the error threshold. In this situation, frequency-dependent competition causes an increased diversity that spreads not only within a neutral network but also over various neutral networks through a dynamical modulation of the fitness landscape, resulting in a more effective search for better replicators. The underlying model is inspired by RNA virus replication and the RNA world hypothesis. Further investigations are needed to validate the actual effect of accelerated evolution through product inhibition in those systems.

Significance Statement

In this paper we present a novel evolutionary phenomenon, where product inhibition, though reducing the effective replication rate, can accelerate the rate of evolution. We show this phenomenon in a model of simulated single-stranded RNA (sRNA) sequence evolution extended by hybridization of sRNA, causing product inhibition. The evolutionary phenomenon could be relevant in (a) prebiotic evolution, where replicating polymers hypothetically emerged and where very likely subject to product inhibition, (b) biotic evolution, e.g., where RNA strands of viruses replicate within a biological cell, or (c) artificial molecular or chemical evolution, where product inhibition might be used to evolve molecules with desired properties more efficiently.
A wireless, user-friendly, and unattended robotic flower system to assess pollinator foraging behaviour
Authors: Debeuckelaere Kamiel , Janssens Dirk , Asensio Estefanía Serral , Wenseleers Tom , Jacquemyn Hans , Pozo María I.
Published: June 2022

Understanding the complex interactions between external and internal factors that influence pollinator foraging behaviour is essential for developing effective conservation strategies. However, collecting large datasets that incorporate data from various sources has been challenging.

To address this issue, we present a wireless and cost-effective robotic flower equipped with Internet of Things (IoT) technology that automatically offers nectar to visiting insects while monitoring visitation time and duration. The robotic flower is easy to manipulate and settings such as nectar refill rates can be remotely altered, making it ideal for field settings. The system transmits data completely wirelessly and autonomously, is mobile and easy to clean.

The prototype settings allow for approximately two weeks of uninterrupted data collection for each battery charge. As a proof-of-concept application, a foraging-preference dual choice experiment with bumblebees was performed. On average, more than 14 000 flower visits were registered daily with a setup consisting of 16 robotic flowers. The data show a gradual preference shift from the pre-trained, lower quality food source towards the higher quality source.

The robotic flower provides accurate and reliable data on insect behaviour, dramatically reducing the price and/or labour costs. Although primarily designed for (bumble)bees, the system could be easily adapted for other flower-visiting insects. The robotic flower is user-friendly and can be easily adapted to address a wide range of research questions in pollination ecology, conservation biology, biocontrol and ecotoxicology, and allows for detailed studies on how nectar traits, flower colour and shape and pollutants would affect foraging behaviour.
The Impact of Storage Condition and Duration on Function of Native and Cargo-Loaded Mesenchymal Stromal Cell Extracellular Vesicles
Authors: Levy Daniel , Jeyaram Anjana , Born Louis J. , Chang Kai-Hua , Abadchi Sanaz Nourmohammadi , Wei Hsu Angela Ting , Solomon Talia , Aranda Amaya , Stewart Samantha , He Xiaoming , Harmon John W. , Jay Steven M.
Published: June 2022

As evidenced by ongoing clinical trials and increased activity in the commercial sector, extracellular vesicle (EV)-based therapies have begun the transition from bench to bedside. As this progression continues, one critical aspect to EV clinical translation is understanding the effects of storage and transport conditions. Several studies have assessed the impact of storage on EV characteristics such as morphology, uptake, and component content, but effects of storage duration and temperature on EV functional bioactivity and, especially, loaded cargo are scarcely reported. Here, EV outcomes following storage at different temperatures (room temperature, 4°C, -20°C, -80°C) for various durations as well as after lyophilization were assessed. Mesenchymal stem/stromal cell (MSC) EVs were observed to retain key aspects of their bioactivity (pro-vascularization, anti-inflammation) for up to 4-6 weeks at -20°C, -80°C, and after lyophilization. Furthermore, via in vitro assays and an in vivo wound healing model respectively, these same storage conditions were also demonstrated to enable preservation of the functionality of loaded microRNA (miRNA) as well as long non-coding RNA (lncRNA) cargo in MSC EVs. These findings extend the current understanding of how EV therapeutic potential is impacted by storage conditions and may inform best practices for handling and storage of MSC EVs for both basic research and translational purposes.