bluuebunny/crossref_metadata_2025_split huggingface dataset:
Genotypic effects ofAPOE-ε4 on resting-state connectivity in cognitively intact individuals support functional brain compensation
Authors: Cacciaglia Raffaele , Operto Grégory , Falcón Carles , de Echavarri-Gómez José Maria González , Sánchez-Benavides Gonzalo , Brugulat-Serrat Anna , Milà-Alomà Marta , Blennow Kaj , Zetterberg Henrik , Molinuevo José Luis , Suárez-Calvet Marc , Gispert Juan Domingo ,   for the ALFA study, Akinci Müge , Beteta Annabella , Cañas Alba , Cumplido Irene , Deulofeu Carme , Dominguez Ruth , Emilio Maria , Fauria Karine , Fuentes Sherezade , Grau-Rivera Oriol , Hernandez Laura , Huesa Gema , Huguet Jordi , Arenaza-Urquijo Eider M , Palacios Eva M , Marne Paula , Menchón Tania , Minguillon Carolina , Palpatzis Eleni , Peña-Gómez Cleofé , Polo Albina , Pradas Sandra , Rodríguez-Fernández Blanca , Sala-Vila Aleix , Salvadó Gemma , Shekari Mahnaz , Soteras Anna , Stankeviciute Laura , Vilanova Marc , Vilor-Tejedor Natalia 
Published: June 2022

AbstractThe investigation of resting-state functional connectivity (rsFC) in asymptomatic individuals at genetic risk for Alzheimer’s disease (AD) enables discovering the earliest brain alterations in preclinical stages of the disease. The APOE-ε4 variant is the major genetic risk factor for AD, and previous studies have reported rsFC abnormalities in carriers of the ε4 allele. Yet, no study has assessed APOE-ε4 gene-dose effects on rsFC measures, and only a few studies included measures of cognitive performance to aid a clinical interpretation. We assessed the impact of APOE-ε4 on rsFC in a sample of 429 cognitively unimpaired individuals hosting a high number of ε4 homozygotes (n = 58), which enabled testing different models of genetic penetrance. We used independent component analysis and found a reduced rsFC as a function of the APOE-ε4 allelic load in the temporal default-mode and the medial temporal networks, while recessive effects were found in the extrastriate and limbic networks. Some of these results were replicated in a subsample with negative amyloid markers. Interaction with cognitive data suggests that such a network reorganization may support cognitive performance in the ε4-homozygotes. Our data indicate that APOE-ε4 shapes the functional architecture of the resting brain and favor the idea of a network-based functional compensation.
Mourning in a Pandemic: The Differential Impact of COVID-19 Widowhood on Mental Health
Authors: Wang Haowei , Smith-Greenaway Emily , Bauldry Shawn , Margolis Rachel , Verdery Ashton M 
Published: June 2022

Abstract

Objectives
The death of a spouse is an established predictor of mental health decline that foreshadows worsening physical health and elevated mortality. The millions widowed by COVID-19 worldwide may experience even worse health outcomes than comparable pre-pandemic widows given the particularities of dying, mourning, and grieving during a pandemic defined by protracted social isolation, economic precarity, and general uncertainty. If COVID-19 pandemic bereavement is more strongly associated with mental health challenges than pre-pandemic bereavement, the large new cohort of COVID-19 widow(er)s may be at substantial risk of downstream health problems long after the pandemic abates.

Methods
We pooled population-based Survey of Health, Ageing and Retirement in Europe data from 27 countries for two distinct periods: (1) pre-pandemic (Wave 8, fielded October 2019–March 2020; N = 46,266) and (2) early pandemic (COVID Supplement, fielded June–August 2020; N = 55,796). The analysis used a difference-in-difference design to assess whether a spouse dying from COVID-19 presents unique mental health risks (self-reported depression, loneliness, and trouble sleeping), compared with pre-pandemic recent spousal deaths.

Results
We find strong associations between recent spousal death and poor mental health before and during the pandemic. However, our difference-in-difference estimates indicate those whose spouses died of COVID-19 have higher risks of self-reported depression and loneliness, but not trouble sleeping, than expected based on pre-pandemic associations.

Discussion
These results highlight that the millions of COVID-19 widow(er)s face extreme mental health risks, eclipsing those experienced by surviving spouses pre-pandemic, furthering concerns about the pandemic’s lasting impacts on health.
Drug-induced adaptation along a resistance continuum in cancer cells
Authors: França Gustavo S. , Baron Maayan , Pour Maayan , King Benjamin R. , Rao Anjali , Misirlioglu Selim , Barkley Dalia , Dolgalev Igor , Ho-Tang Kwan , Avital Gal , Kuperwaser Felicia , Patel Ayushi , Levine Douglas A. , Lionnet Timothee , Yanai Itai 
Published: June 2022

AbstractAdvancements in rational drug design over the past decades have consistently produced new cancer therapies, but such treatments are inevitably countered through an adaptive process that fosters therapy resistance. Malignant cells achieve drug resistance through intrinsic and acquired mechanisms, rooted in genetic and non-genetic determinants. In particular, recent work has highlighted the role of intrinsic cellular heterogeneity in the emergence of transient drug-tolerant persister cells that survive drug treatment, as well as non-genetically driven cell plasticity toward stable resistance. However, these models do not account for the role of dose and treatment duration as extrinsic forces in eliciting cancer cell adaptation. Here, we show that these two components together drive the resistance of ovarian cancer cells to targeted therapy along a trajectory of cellular adaptation, that we denote the ‘resistance continuum’. We report that gradual dose exposure and prolonged treatment promote a continuous increase in fitness, and show that this process is mediated by evolving transcriptional, epigenetic and genetic changes that promote multiple cell state transitions. The resistance continuum is underpinned by the assembly of gene expression programs and epigenetically reinforced stress response regulation. Using both in vivo and in vitro models, we found that this process involves widespread reprogramming of cell survival pathways, including interferon response, lineage reprogramming, metabolic rewiring and oxidative stress regulation. Together, the resistance continuum reveals the dynamic nature of cellular adaptation, and carries implications for cancer therapies, as initial exposure to lower doses primes cells over time for increased resistance to higher doses. Beyond cancer, such continuous adaptation exposes a basic aspect of cellular plasticity, which may also be deployed in other biological systems such as development, immune response and host-pathogen interactions.
Evolutionary models predict potential mechanisms of escape from mutational meltdown
Authors: Bank Claudia , Schmitz Mark A. , Morales-Arce Ana Yansi 
Published: June 2022

ABSTRACTMutagenic drugs are promising candidates for the treatment of various RNA virus infections. Increasing the mutation rate of the virus leads to rapid accumulation of deleterious mutation load, which is proposed to ultimately result in extinction as described by the theoretical concepts of mutational meltdown and lethal mutagenesis. However, the conditions and potential mechanisms of viral escape from the effects of mutagenic drugs have not been conceptually explored. Here we apply a computational approach to quantify the population dynamics and genetics of a population under high mutation rates and discuss the likelihood of adaptation to a mutagenic drug by means of three proposed mechanisms: (1) a proportion of “traditional” beneficial mutations that increase growth/fitness, (2) a mutation rate modifier (i.e., evolution of resistance to the mutagenic drug) that reduces the mutation rate, and (3) a modifier of the distribution of fitness effects, which either decreases or increases deleterious effects of mutations (i.e., evolution of tolerance to the mutagenic drug). We track the population dynamics and genetics of evolving populations and find that successful adaptations have to appear early to override the increasing mutational load and rescue the population from its imminent extinction. We highlight that the observed stochasticity of adaptation, especially by means of modifiers of the distribution of fitness effects, is difficult to capture in experimental trials, which may leave potential dangers of the use of mutagenic treatments unexposed.
Role of polymetallic-nodule dependent fauna on carbon cycling in the eastern Clarion-Clip-perton Fracture Zone (Pacific)
Authors: Stratmann Tanja 
Published: June 2022

AbstractThe abyssal seafloor in the Clarion-Clipperton Fracture Zone (CCZ) in the central Pacific is covered with large densities of polymetallic nodules, i.e., metal concretions containing iron, manganese, nickel, cobalt, and copper. These nodules are of economic interested and considered potential future resources for said metals, but they also host a variety of deep-sea fauna. In a recent study it was estimated that the removal of these nodules would lead to a loss of up to 18% of all taxa in the CCZ. Here, I assess the impact of removing these nodule-dependent taxa on carbon cycling at two sites (B4S03, B6S02) of the Belgian exploration license area in the eastern CCZ. For this purpose, I developed two highly-resolved carbon-based food web models with 72 (B6S02) to 77 (B4S03) food-web compartments consisting of different detritus pools, bacteria, metazoan meiobenthos, macrobenthic isopods, polychaetes and other macrobenthos, megabenthic cnidarians, crustaceans, poriferans, holothurians and other invertebrate megabenthos, and fish. These compartments were connected with 304 (B6S02) to 338 (B4S03) links which were reduced by 5–6% when nodule-dependent faunal compartments were removed. The models estimated the total system throughput T‥, i.e., the sum of all carbon flows in the food webs, in intact food webs as 1.24 mmol C m−2 d−1 and 1.20 mmol C m−2 d−1 at B4S03 and B6S02, respectively, whereupon 67.7% (B4S03) to 69.8% (B6S02) of T‥ flowed through the microbial loop. A removal of the nodule-dependent fauna did not affect this microbial loop, but reduced the scavenger loop by 54.6% (B6S02) to 84.1% (B4S03). Overall, nodule-dependent fauna is responsible for only a small fraction of total carbon cycling at the eastern CCZ. Therefore, when the effect of prospective deep-seabed mining on carbon cycling is investigated, its impact on benthic prokaryotes and the microbial loop should be addressed specifically.
Blocking D2/D3 dopamine receptors increases volatility of beliefs when we learn to trust others
Authors: Mikus Nace , Eisenegger Christoph , Mathys Chris , Clark Luke , Müller Ulrich , Robbins Trevor W. , Lamm Claus , Naef Michael 
Published: June 2022

AbstractThe ability to flexibly adjust beliefs about other people is crucial for human social functioning. Dopamine has been proposed to regulate the precision of beliefs, but direct behavioural evidence of this is lacking. We investigated how a relatively high dose of the selective D2/D3 dopamine receptor antagonist sulpiride impacts learning about other people’s prosocial attitudes in a repeated trust game. Using a Bayesian model of belief updating, we show that sulpiride increased the volatility of beliefs, which led to higher precision-weights on prediction errors. This effect was entirely driven by participants with genetically conferring higher dopamine availability (Taq1a polymorphism). Higher precision weights were reflected in higher reciprocal behaviour in the repeated trust game but not in single-round trust games. This finding suggests that antipsychotic medication might acutely reduce rigidity of pathological beliefs.
Non-redundant odorant detection in a locust
Authors: Chang Hetan , Unni Anjana , Tom Megha Treesa , Cortés Llorca Lucas , Brase Sabine , Bucks Sascha , Weniger Kerstin , Bisch-Knaden Sonja , Hansson Bill S. , Knaden Markus 
Published: June 2022

SummaryOlfactory coding, from insects to humans, is canonically considered to involve considerable across-fiber coding already at the peripheral level, thereby allowing recognition of very large numbers of odor compounds. Here we show that the migratory locust, Locusta migratoria, has evolved an alternative strategy built on highly specific odorant receptors feeding into a complex primary processing center in the brain.By collecting odors from food and different life stages of the locust, we identified 208 ecologically relevant odorants, which we used to deorphanize 48 locust olfactory receptors via ectopic expression in Drosophila. Contrary to the often broadly tuned olfactory receptors of other insects, almost all locust receptors were found to be narrowly tuned to one ligand and most of these best ligands exclusively excited only one receptor. Knocking out a single receptor using CRISPR-Cas9 resulted in an abolished physiological and behavioral response to the corresponding ligand. We conclude that the locust olfactory system, with an apparent lack of redundancy among most olfactory receptors, differs from so-far described olfactory systems.
Tilt Aftereffect Spreads Across the Visual Field
Authors: Gurbuz Busra Tugce , Boyaci Huseyin 
Published: June 2022

AbstractThe tilt aftereffect (TAE) is observed when adaptation to a tilted contour alters the perceived tilt of a subsequently presented contour. Thus far, the TAE has been treated as a local aftereffect observed only at the location of the adapter. Whether and how TAE spreads to other locations in the visual field has not been systematically studied. Here we sought an answer to this question by measuring TAE magnitudes at locations including but not limited to the adapter location. The adapter was a tilted grating presented at the same peripheral location throughout an experimental session. In a single trial, participants indicated the perceived tilt of a test grating presented after the adapter at one of fifteen locations in the same hemifield as the adapter. We found non-zero TAE magnitudes in all locations tested, showing that the effect spreads across the tested visual hemifield. Next, to establish a link between neuronal activity and the behavioral results, and to predict possible origins of the spread, we built a model based on known characteristics of neuronal responses in the visual cortex. Simulation results showed that the model can successfully capture the pattern of the behavioral results. Furthermore, the pattern of the optimized receptive field sizes suggests that mid-level visual areas, for example V4, could be critically involved in TAE and its spread across the visual field.
A Phylogenomic Assessment of Processes Underpinning Convergent Evolution in Open-Habitat Chats
Authors: Kakhki Niloofar Alaei , Schweizer Manuel , Lutgen Dave , Bowie Rauri C. K. , Shirihai Hadoram , Suh Alexander , Schielzeth Holger , Burri Reto 
Published: June 2022

AbstractInsights into the processes underpinning convergent evolution advance our understanding of the contributions of ancestral, introgressed, and novel genetic variation to phenotypic evolution. Phylogenomic analyses characterizing genome-wide gene tree heterogeneity can provide first clues about the extent of ILS and of introgression and thereby into the potential of these processes or (in their absence) the need to invoke novel mutations to underpin convergent evolution. Here, we were interested in understanding the processes involved in convergent evolution in open-habitat chats (wheatears of the genusOenantheand their relatives). To this end, based on whole-genome resequencing data from 50 taxa of 44 species, we established the species tree, characterized gene tree heterogeneity, and investigated the footprints of ILS and introgression within the latter. The species tree corroborates the pattern of abundant convergent evolution, especially in wheatears. The high levels of gene tree heterogeneity in wheatears are explained by ILS alone only for 30% of internal branches. For multiple branches with high gene tree heterogeneity, D-statistics and phylogenetic networks identified footprints of introgression. Finally, long branches without extensive ILS between clades sporting similar phenotypes provide suggestive evidence for a role of novel mutations in the evolution of these phenotypes. Together, our results suggest that convergent evolution in open-habitat chats involved diverse processes and highlight that phenotypic diversification is often complex and best depicted as a network of interacting lineages.
Characterization of proteome-size scaling by integrative omics reveals mechanisms of proliferation control in cancer
Authors: Jones Ian , Dent Lucas , Higo Tomoaki , Roumeliotis Theo , Arias Garcia Mar , Shree Hansa , Choudhary Jyoti , Pedersen Malin , Bakal Chris 
Published: June 2022

AbstractAlmost all living cells maintain size uniformity through successive divisions. Proteins that sub- or super-scale with size act as rheostats which regulate cell progression. A comprehensive atlas of these proteins is lacking; particularly in cancer cells where both mitogen and growth signalling are dysregulated.Utilising a multi-omic strategy, that integrates quantitative single cell imaging, phosphoproteomic and transcriptomic datasets, we leverage the inherent size heterogeneity of melanoma cells to investigate how peptides, post-translational modifications, and mRNAs scale with cell size to regulate proliferation. We find melanoma cells have different mean sizes, but all retain uniformity. Across the proteome, we identify proteins and phosphorylation events that ‘sub’ and ‘super’ scale with cell size. In particular, G2/M, biosynthetic, and cytoskeletal regulators sub- and super-scale with size. In small cells growth and proliferation processes are tightly coupled by translation which promotes CCND1 accumulation and anabolic increases in mass. Counter intuitively, anabolic growth pathways and translational process are low in large cells, which throttles the expression of factors such as CCND1 and thereby coupling proliferation from anabolic growth. Strikingly, these cells exhibit increased growth and comparable proliferation rates. Mathematical modelling suggests that decoupling growth and proliferative signalling fosters proliferation under mitogenic inhibition. As factors which promote adhesion and actin reorganization super-scale with size or are enriched in large cells, we suggest that growth/proliferation in these cells may be decoupled by cell spreading and mechanics. This study provides one of the first demonstrations of size-scaling phenomena in cancer and how morphology determines the chemistry of the cell.
Mapping molecular determinants of CaV2.2 inhibition by RGK proteins and homologs in Xenopus oocytes
Authors: Sasson Yehezkel , Subramaniam Suraj , Buki Tal , Almagor Lior , Chomsky-Hecht Orna , Katz Moshe , Puhl Henry , Ikeda Stephen R. , Dascal Nathan , Hirsch Joel A. 
Published: June 2022

AbstractThe CaV1 and CaV2 families of voltage-dependent calcium channels play a crucial role in neurotransmitter release, excitation-contraction and many other cellular processes. Comprised of the membrane pore-forming α1, intracellular β and extracellular α2δ subunits, these channels have been targets for pharmacological intervention for decades. Physiological functions of CaV channels are attenuated by either constitutively or transiently bounds proteins in the cellular environment. The RGK (Rad, Gem, Rem, and Rem2) G-protein family potently inhibits CaV1 and CaV2 function in heterologous expression systems. RGK proteins bind to CaVβ and inhibit channel localization and activity by forming a ternary complex with CaVα1. Here, we evaluated the influence of RGK proteins on CaV2.2 channels heterologously expressed in Xenopus oocytes. Both Gem and Rad showed no nucleotide dependency on its inhibitory function on CaV2.2. The G-domain and C-terminus could inhibit the CaV2.2 channel independently when co-expressed with channel subunits. Our results demonstrated that structural determinants in Gem, crucial for channel inhibition, lie within the 222-296 amino acid region containing both the partial G-domain and C-terminus as determined from chimeric CaVβ-Gem constructs. We expanded our mapping efforts and prepared various chimeras of Drosophila melanogaster (Dm) RGK sequences fused to CaVβ and showed that 22 residues in RGK2t and RGK3L C-terminal imparted complete CaV2.2 inhibition. Point mutations in the DmRGK C-terminus, conserved in mammalian RGK proteins, abrogated the CaV2.2 inhibition to a significant extent, pointing to a hot region in the extreme C-terminus for inhibition of CaV channels. Since RGK homologs are now recognized as physiological modulators in β-adrenergic regulation of CaV channels, the relevance of this curious G-protein family deserves close examination.
A Photonic Biosensor-Integrated Tissue Chip Platform for Real-Time Sensing of Lung Epithelial Inflammatory Markers
Authors: Cognetti John S. , Moen Matthew T. , Brewer Matthew G. , Bryan Michael R. , Tice Joshua D. , McGrath James L. , Miller Benjamin L. 
Published: June 2022

AbstractTissue chip (TC) devices seek to mimic human physiology on a small scale. They are intended to improve upon animal models in terms of reproducibility and human relevance, at a lower monetary and ethical cost. Virtually all TC systems are analyzed at an endpoint, leading to widespread recognition that new methods are needed to enable sensing of specific biomolecules in real time, as they are being produced by the TC. To address this need, we incorporated photonic biosensors for inflammatory cytokines into a model TC. Human bronchial epithelial cells seeded in a microfluidic device were stimulated with lipopolysaccharide, and the cytokines secreted in response sensed in real time. Sensing analyte transport through the TC in response to disruption of tissue barrier was also demonstrated. This work demonstrates the first application of photonic sensors to a human TC device, and will enable new applications in drug development and disease modeling.
Compensatory aortic remodeling in Marfan syndrome protects against sexually dimorphic rupture during a BAPN challenge
Authors: Weiss D. , Rego B.V. , Cavinato C. , Li D.S. , Kawamura Y. , Emuna N. , Humphrey J.D. 
Published: June 2022

ABSTRACTTransmural rupture of the aorta is responsible for significant morbidity and mortality; it occurs when wall stress exceeds local wall strength. Amongst other conditions, the aortic root and ascending aorta become vulnerable to dissection and rupture in Marfan syndrome, a connective tissue disorder that results in a progressive fragmentation and degradation of the elastic fibers of the aortic wall. Whereas competent elastic fibers are critical for aortic functionality, cross-linked collagen fibers endow the aorta with its stiffness and strength. In this paper, we contrast progressive degeneration of the ascending aorta in male and female Marfan and wild-type mice, with and without chronic exposure to a potent inhibitor of lysyl oxidase (β-aminopropionitrile, or BAPN), to examine effects of extracellular matrix cross-linking in aortic dilatation and rupture. We found a strong sexual dimorphism in aortic dilatation in Marfan mice and aortic rupture in wild-type mice, but also a compensatory remodeling of the aorta that protected the Marfan aorta against lethal rupture despite a strong BAPN challenge. This compensation appears to be mediated via increased lysyl oxidase in the female and especially male Marfan aorta, resulting in improved collagen fiber stability and integrity, particularly of fibril bundles in the adventitia.