bluuebunny/crossref_metadata_2025 huggingface dataset:
An optimal control strategy to design passive thermal cloaks of arbitrary shape
Authors: Saporiti Riccardo , Sinigaglia Carlo , Manzoni Andrea , Braghin Francesco
Published: July 2024

In this paper, we describe a numerical framework for achieving passive thermal cloaking of arbitrary shapes in both static and transient regimes. The design strategy is cast as the solution of an optimal control problem (OCP) for the heat equation where the coefficients of the thermal diffusivity matrix take the role of control functions, and the distance between the uncloaked and the cloaked field is minimized in a suitable observation domain. The control actions enter bilinearly in the heat equation, thus making the resulting OCP nonlinear, and its analysis non-trivial. We show that optimal diffusivity coefficients exist both for the static and the transient case; we derive a system of first-order necessary optimality conditions; finally, we carry out their numerical approximation using the finite-element method. A series of numerical test cases assess the capability of our strategy to tackle passive thermal cloaking of arbitrarily complex two-dimensional objects.
Some reef-building corals only disperse metres per generation
Authors: Prata Katharine E. , Bongaerts Pim , Dwyer John M. , Ishida Hisatake , Howitt Samantha M. , Hereward James P. , Crandall Eric D. , Riginos Cynthia
Published: July 2024

Understanding the dispersal potential of different species is essential for predicting recovery trajectories following local disturbances and the potential for adaptive loci to spread to populations facing extreme environmental changes. However, dispersal distances have been notoriously difficult to estimate for scleractinian corals, where sexually (as gametes or larvae) or asexually (as fragments or larvae) derived propagules disperse through vast oceans. Here, we demonstrate that generational dispersal distances for sexually produced propagules can be indirectly inferred for corals using individual-based isolation-by-distance (IbD) analyses by combining reduced-representation genomic sequencing with photogrammetric spatial mapping. Colonies from the genus
Agaricia
were densely sampled across plots at four locations and three depths in Curaçao. Seven cryptic taxa were found among the three nominal species (
Agaricia agaricites
,
Agaricia humilis
and
Agaricia lamarcki
), with four taxa showing generational dispersal distances within metres (two taxa within
A. agaricites
and two within
A. humilis
). However, no signals of IbD were found in
A. lamarcki
taxa and thus these taxa probably disperse relatively longer distances. The short distances estimated here imply that
A. agaricites
and
A. humilis
populations are reliant on highly localized replenishment and demonstrate the need to estimate dispersal distances quantitatively for more coral species.
Optix
and
cortex/ivory/mir-193
again: the repeated use of two mimicry hotspot loci
Authors: Orteu Anna , Hornett Emily A. , Reynolds Louise A. , Kemp Darrell J. , Gloder Gabriele , Warren Ian A. , Hurst Gregory D. D. , Martin Simon H. , Jiggins Chris D.
Published: July 2024

The extent to which evolution is repeatable has been a debated topic among evolutionary biologists. Although rewinding the tape of life perhaps would not lead to the same outcome every time, repeated evolution of analogous genes for similar functions has been extensively reported. Wing phenotypes of butterflies and moths have provided a wealth of examples of gene re-use, with certain ‘hotspot loci’ controlling wing patterns across diverse taxa. Here, we present an example of convergent evolution in the molecular genetic basis of Batesian wing mimicry in two
Hypolimnas
butterfly species. We show that mimicry is controlled by variation near
cortex/ivory/mir-193
, a known butterfly hotspot locus. By dissecting the genetic architecture of mimicry in
Hypolimnas misippus
and
Hypolimnas bolina
, we present evidence that distinct non-coding regions control the development of white pattern elements in the forewing and hindwing of the two species, suggesting independent evolution, and that no structural variation is found at the locus. Finally, we also show that orange coloration in
H. bolina
is associated with
optix,
a well-known patterning gene. Overall, our study once again implicates variation near the hotspot loci
cortex/ivory/mir-193
and
optix
in butterfly wing mimicry and thereby highlights the repeatability of adaptive evolution.
Improve animal health to reduce livestock emissions: quantifying an open goal
Authors: Kyriazakis Ilias , Arndt Claudia , Aubry Aurelie , Charlier Johannes , Ezenwa Vanessa O. , Godber Olivia F. , Krogh Mogens , Mostert Pim F. , Orsel Karin , Robinson Mark W. , Ryan Frances S , Skuce Philip J. , Takahashi Taro , van Middelaar Corina E. , Vigors Stafford , Morgan Eric R.
Published: July 2024

Greenhouse gas (GHG) emissions from livestock production must be urgently tackled to substantially reduce their contribution to global warming. Simply reducing livestock numbers to this end risks impacting negatively on food security, rural livelihoods and climate change adaptation. We argue that significant mitigation of livestock emissions can be delivered immediately by improving animal health and hence production efficiency, but this route is not prioritized because its benefits, although intuitive, are poorly quantified. Rigorous methodology must be developed to estimate emissions from animal disease and hence achievable benefits from improved health through interventions. If, as expected, climate change is to affect the distribution and severity of health conditions, such quantification becomes of even greater importance. We have therefore developed a framework and identified data sources for robust quantification of the relationship between animal health and greenhouse gas emissions, which could be applied to drive and account for positive action. This will not only help mitigate climate change but at the same time promote cost-effective food production and enhanced animal welfare, a rare win–win in the search for a sustainable planetary future.
Novel fluorescence-based methods to determine infarct and scar size in murine models of reperfused myocardial infarction
Authors: Duplessis Ashley , Elster Christin , Becher Stefanie , Engel Christina , Lang Alexander , Kaldirim Madlen , Jung Christian , Grandoch Maria , Kelm Malte , Pfeiler Susanne , Gerdes Norbert
Published: July 2024

Background

Determination of infarct area and scar size following myocardial infarction (MI) is commonly used to evaluate the efficacy of potential cardioprotective treatments in mice and other animal models.

Methods

For both, early and late time points following MI, we compared classical histochemical approaches with fluorescence staining methods. Reperfused MI was induced in male C57BL/6J mice and hearts were extracted 24 hours, 7-, 21-, or 28-days following MI and stained with 2,3,5-Triphenyltetrazolium chloride (TTC) and Evans Blue, Hoechst, phalloidin, Sirius Red, Masson’s or Gomorís Trichrome or Wheat Germ Agglutinin (WGA).

Results

Fluorescent staining combining Hoechst and phalloidin constitutes an alternative for TTC and Evans Blue, enabling a clear visualization of infarct area, area at risk, as well as remote area unaffected by MI. Infarct size early after reperfusion determined with TTC staining correlates strongly with that demarcated by phalloidin while combination of Hoechst and phalloidin staining can emulate classical TTC/Evans Blue staining 24 h post-MI. Moreover, WGA is equally accurate as the classical Sirius Red, Masson’s and Gomorís Trichrome stainings in identifying scar size in later phases (>7d) post-MI. Finally, we demonstrate feasibility of combining conventional fluorescence staining by localizing CD45+leukocytes to specific regions of the infarcted myocardium.

Conclusion

We established staining procedure is not inferior to classical TTC staining while providing substantial benefits including the option for unbiased software-assisted analysis while sparing ample residual tissue for additional analyses. Overall, this enhances the data quality and reduces the required animal numbers consistent with the 3R concept of animal experimentation.

Graphical abstract
Lead Exposure and Alzheimer’s Disease Mortality Among US Adults: NHANES Analysis from 1988-2008
Authors: Grossman Aaron
Published: July 2024

Objective

To investigate the association between blood lead level (BLL) and Alzheimer’s disease (AD) mortality.

Design

Prospective cohort study.

Setting

US National Health and Nutrition Examination Survey (NHANES) 1988-94 and 1999-2008.

Participants

21,308 subjects aged 40 years and over with a BLL ≥1.0 µg/dL.

Main outcome measures

AD mortality from baseline until December 2019.

Results

AD was the underlying cause of death for 350 participants. In the fully adjusted model with a calendar effect variable, log-transformed BLL was inversely associated with AD mortality among all subjects (HR: 0.57 [95% CI, 0.46, 0.70]). A similar finding was evident when BLL was modeled as a categorical variable, with hazard ratios of 0.69 (95% CI: 0.54, 0.88), 0.56 (0.39, 0.80), 0.36 (0.19, 0.70), and 0.31 (0.14, 0.72) for 2.5-4.9 µg/dL, 5.0-7.4 µg/dL, 7.5-9.9 µg/dL, and ≥10 µg/dL, when compared to 1-2.4 µg/dL (p-trend < 0.0001). Restricted cubic spline analysis confirmed an inverse dose-response relationship between BLL and AD mortality.

Conclusions

Our study suggests an inverse association between lead exposure and AD mortality among US adults; however, the results should be interpreted with caution due to the observational nature of the study.

What is already known on this topic

Studies investigating the association of blood lead and Alzheimer’s disease are rare.

Prior publications reported increased risk of Alzheimer’s disease mortality with exposure to lead, however, due to potential biases in these prior studies, it was critical to reassess the association between blood lead and Alzheimer’s disease mortality.

What this study adds

In contrast to much of the existing literature on dementia, the findings from this study suggest that lead exposure reduces the risk of Alzheimer’s disease mortality and likely mitigates the development of Alzheimer’s disease itself.

Prospective studies focused on blood lead and its association with the development or progression of Alzheimer’s disease are necessary to confirm the results.
The Impact of Preprints on the Citations of Journal Articles Related to COVID-19
Authors: Tsunoda Hiroyuki , Sun Yuan , Nishizawa Masaki , Liu Xiaomin , Amano Kou , Kominami Rie
Published: July 2024

To investigate the impact of preprints on the citation counts of COVID-19-related papers, this study compares the number of citations received by drafts initially distributed as preprints and later published in journals with those received by papers directly submitted to journals. The difference in the median number of citations between COVID-19 preprint-distributed papers and COVID-19 directly submitted papers published in 184 journals was tested using the Mann-Whitney U test. The results showed that 129 journals had a statistically significant higher median citation count for COVID-19 preprint-distributed papers compared to directly submitted papers, with a p-value of less than 0.05. In contrast, no journals had a statistically significant higher median citation count for COVID-19 directly submitted papers. This indicates that 70.11% of the journals that published preprint-distributed papers experienced a significant increase in citations. We also identified that among the 184 journals, 13 journals garnered a substantial number of citations. Among the 74,037 COVID-19 papers, preprint-distributed papers (9,028) accounted for only 12.19%. However, among the 2,015,997 citations received by COVID-19 papers, preprint-distributed papers garnered 542,715 citations, representing a substantial 26.92%. These results suggest that distributing preprints prior to formal publication may help COVID-19 research reach a wider audience, potentially leading to increased readership and citations.
The Unity/Diversity Framework of Executive Functions in Older Adults
Authors: Guo Sheng-Ju , Wang Ping , Cao Lizhi , Li Hui-Jie
Published: July 2024

Executive functions (EFs), encompassing inhibition, shifting, and updating as three fundamental subdomains, are typically characterized by a unity/diversity construct. However, given the dedifferentiation trend observed in aging, it remains controversial whether the construct of EFs in older adults becomes unidimensional or maintains unity/diversity. This study aims to explore and validate the construct of EFs in older adults. At the behavioral level, we conducted confirmatory factor analysis on data from 222 older adults who completed six tasks specifically targeting inhibition, shifting, and updating. One unidimensional model and six unity/diversity models of EFs were evaluated. Our results indicated that the EFs of older adults demonstrated greater congruence with the unity/diversity construct. At neural level, thirty older adults completed three thematically consistent fMRI tasks, targeting three subdomains of EFs respectively. Multivariate pattern analysis showed that rostromedia prefrontal cortex robustly showed similar neural representation across different tasks (unity). Meanwhile, the three EF domains were encoded by distinct global neural representation and the lateral prefrontal cortex play a crucial role in classification (diversity). These findings underscore the unity/diversity framework of EFs in older adults and offer important insights for designing interventions aimed at improving EFs in this population.
A Hypothalamic Circuit that Modulates Feeding and Parenting Behaviors
Authors: Alcantara Ivan C. , Li Chia , Mickelsen Laura E. , Mazzone Christopher M. , de Araujo Salgado Isabel , Gao Claire , Papas Brian N. , Xiao Cuiying , Karolczak Eva O. , Goldschmidt Abigail I. , Rodriguez Gonzalez Shakira , Piñol Ramón A. , Li Jian-Liang , Cui Guohong , Reitman Marc L. , Krashes Michael J.
Published: July 2024

Across mammalian species, new mothers undergo considerable behavioral changes to nurture their offspring and meet the caloric demands of milk production1-5. While many neural circuits underlying feeding and parenting behaviors are well characterized6-9, it is unclear how these different circuits interact and adapt during lactation. Here, we characterized the transcriptomic changes in the arcuate nucleus (ARC) and the medial preoptic area (MPOA) of the mouse hypothalamus in response to lactation and hunger. Furthermore, we showed that heightened appetite in lactating mice was accompanied by increased activity of hunger-promoting agouti-related peptide (AgRP) neurons in the ARC. To assess the strength of hunger versus maternal drives, we designed a conflict assay where female mice chose between a food source or a chamber containing pups and nesting material. Although food-deprived lactating mothers prioritized parenting over feeding, hunger reduced the duration and disrupted the sequences of parenting behaviors in both lactating and virgin females. We discovered that ARCAgRPneurons directly inhibit bombesin receptor subtype-3 (BRS3) neurons in the MPOA, a population that governs both parenting and satiety. Selective activation of this ARCAgRPto MPOABRS3circuit shifted behaviors from parenting to food-seeking. Thus, hypothalamic networks are modulated by physiological states and work antagonistically during the prioritization of competing motivated behaviors.
Population genetic structure of the aphid pestMyzus persicaein organic and conventional greenhouses
Authors: Beekman Mariska M. , van den Heuvel Joost , Donner S. Helena , Litjens Jordy J. H. , Dicke Marcel , Zwaan Bas J. , Verhulst Eveline C. , Pannebakker Bart A.
Published: July 2024

Aphids display remarkable adaptability to pest control strategies and their partheno-genetic reproduction results in rapid numerical increase of higher-fitness clones. Con-sequently, a high prevalence of only a few clonal lines could indicate positive selection for these genotypes, potentially reflecting adaptation to pest control methods. Here, we investigated the clonal diversity and population genetic structure of the green peach aphidMyzus persicaeusing microsatellite markers, in both organic and conventionally managed Dutch sweet pepper greenhouses over four consecutive years. In total, 26 distinct multilocus genotypes (MLG) were detected, with higher clonal diversity in organic than in conventional greenhouses. Strikingly, a single MLG dominated conventional greenhouses in 2019, only to be completely replaced by a new dominant MLG by 2022. Whole-genome sequencing of 15 sampled lines — seven sharing the same MLG and eighth with unique MLGs — revealed that all aphids with the dominant MLG of 2019, collected from various locations and over multiple years, originated from a single parthenogenetic ancestor. Our findings indicate that the population genetic structure ofM. persicaediffers between organically and conventionally managed sweet pepper greenhouses. The presence of dominant MLGs in conventional crop systems may suggest positive selection or evolutionary forces such as a founder effect. Understanding the forces driving these differences in population genetic structure and their impact on the efficacy of biocontrol agents will further help us improve control strategies forM. persicaein greenhouse crops.
Bayesian Prior Uncertainty and Surprisal Elicit Distinct Neural Patterns During Sound Localization in Dynamic Environments
Authors: Bayram Burcu , Meijer David , Barumerli Roberto , Spierings Michelle , Baumgartner Robert , Pomper Ulrich
Published: July 2024

Estimating the location of a stimulus is a key function in sensory processing, and widely considered to result from the integration of prior information and sensory input according to Bayesian principles. A deviation of sensory input from the prior elicits surprisal, depending on the uncertainty of the prior.

While this mechanism is increasingly understood in the visual domain, much less is known about its implementation in audition, especially regarding spatial localization. Here, we combined human EEG with computational modeling to study auditory spatial inference in a noisy, volatile environment and analyzed behavioral and neural patterns associated with prior uncertainty and surprisal.

First, our results demonstrate that participants indeed used prior information during periods of stable environmental statistics, but showed evidence of surprisal and discarded prior information following environmental changes. Second, we observed distinct EEG activity patterns associated with prior uncertainty and surprisal in both the time- and time-frequency domain, which are in line with previous studies using visual tasks. Third, these EEG activity patterns were predictive of our participants’ sound localization error, response uncertainty, and prior bias on a trial-by-trial basis.

In summary, our work provides novel behavioral and neural evidence for Bayesian inference during dynamic auditory localization.
Evidence for homing behaviour consistent with path integration inDascyllus trimaculatus
Authors: Murley Freddie , Sibeaux Adelaide , Burt de Perera Theresa
Published: July 2024

Path integration is a strategy that allows animals to monitor their movement relative to a starting point using directional and distance cues. It has been observed in a wide range of terrestrial species, but evidence of this behaviour in fish is still lacking. In contrast to most animals shown to navigate via path integration, fish are not surface bound but exist within a three-dimensional medium. This may present additional challenges when monitoring their position relative to a specific point. We developed a novel experimental paradigm to test whether the coral reef-dwelling domino damselfishDascyllus trimaculatuscould use path integration to navigate back to a shelter location. This consisted of a circular pool with a shelter and landmarks near the edge and a trap containing food in the centre. Our results show that these fish follow homing trajectories back to the previous location of the removed shelter without using landmarks after a foraging trip into the central trap. Error in homing trajectory increased with outward path length, consistent with the use of path integration. These results addD. trimaculatusto the growing list of path-integrating species, opening new avenues for investigating the evolution and neural underpinnings of this navigational strategy.
dsRNAEngineer: a web-based tool of comprehensive dsRNA design for pest control
Authors: Chen Yang , Shi Yufei , Wang Ziguo , An Xin , Wei Siyu , Andronis Christos , Vontas John , Wang Jin-jun , Niu Jinzhi
Published: July 2024

RNA interference (RNAi) is a form of gene silencing triggered by double-stranded RNA (dsRNA) that operates in all eukaryotic organisms, including insects, mites, nematodes and fungi. In the last two decades, many dsRNAs have been synthesized to silence the target genes for exploration of the underlying function in these pests. Some of them are lethal to pests or inhibit the growth of the pest population, leading to a new concept of pesticides. The generation of these environment-friendly pesticides requires precisein silicodesign of dsRNA molecules that are specific to target pests but do not target non-pest organisms. Current efforts for dsRNA design are mostly focused on gene sequence level, lacking comprehensive analysis of RNAi-based mode-of-action at the whole transcriptome level of given species, causing low efficiency and imprecise dsRNA target exploration. To address these limitations, we have created dsRNAEngineer, a publicly available online tool that allows a comprehensive and rational dsRNA design, incorporating hundreds of pests and non-pests transcriptomes. Developed functionalities include screen-target (screen conserved genes for co-targets of various pest species), on-target, off-target, and multi-target to generate optimal dsRNA for precise pest control. dsRNAEngineer is available athttps://dsrna-engineer.cn/.

Graphical abstract
STK19 positions TFIIH for cell-free transcription-coupled DNA repair
Authors: Mevissen Tycho E.T. , Kümmecke Maximilian , Schmid Ernst W. , Farnung Lucas , Walter Johannes C.
Published: July 2024

In transcription-coupled repair, stalled RNA polymerase II (Pol II) is recognized by CSB and CRL4CSA, which co-operate with UVSSSA and ELOF1 to recruit TFIIH for nucleotide excision repair (TC-NER). To explore the mechanism of TC-NER, we recapitulated this reactionin vitro. When a plasmid containing a site-specific lesion is transcribed in frog egg extract, error-free repair is observed that depends on CSB, CRL4CSA, UVSSA, and ELOF1. Repair also depends on STK19, a factor previously implicated in transcription recovery after UV exposure. A 1.9 Å cryo-electron microscopy structure shows that STK19 joins the TC-NER complex by binding CSA and the RPB1 subunit of Pol II. Furthermore, AlphaFold predicts that STK19 interacts with the XPD subunit of TFIIH, and disrupting this interface impairs cell-free repair. Molecular modeling suggests that STK19 positions TFIIH ahead of Pol II for lesion verification. In summary, our analysis of cell-free TC-NER suggests that STK19 couples RNA polymerase II stalling to downstream repair events.
Functional optimization in distinct tissues and conditions constrains the rate of protein evolution
Authors: Usmanova Dinara R. , Plata Germán , Vitkup Dennis
Published: July 2024

Understanding the main determinants of protein evolution is a fundamental challenge in biology. Despite many decades of active research, the molecular and cellular mechanisms underlying the substantial variability of evolutionary rates across cellular proteins are not currently well understood. It also remains unclear how protein molecular function is optimized in the context of multicellular species and why many proteins, such as enzymes, are only moderately efficient on average. Our analysis of genomics and functional datasets reveals in multiple organisms a strong inverse relationship between the optimality of protein molecular function and the rate of protein evolution. Furthermore, we find that highly expressed proteins tend to be substantially more functionally optimized. These results suggest that cellular expression costs lead to more pronounced functional optimization of abundant proteins, and that the purifying selection to maintain high levels of functional optimality significantly slows protein evolution. We observe that in multicellular species both the rate of protein evolution and the degree of protein functional efficiency are primarily affected by expression in several distinct cell types and tissues. Specifically, in developed neurons with upregulated synaptic processes in animals and in young and fast-growing tissues in plants. Overall, our analysis reveals how various constraints from the molecular, cellular, and species’ levels of biological organization jointly affect the rate of protein evolution and the level of protein functional adaptation.
Localization ofDrosophilaformin, Cappuccino, influences posterior oocyte organization
Authors: Bailey Hannah M. , Cullimore Peter B. M. , Bailey Liam A. , Quinlan Margot E.
Published: July 2024

Abstract

Cappuccino (Capu) and Spire build actin networks in numerous systems, including the mouse oocyte, melanocytes, and the Drosophila oocyte. As observed in mammalian systems, the localization of the Capu homologues (FMN1/2), influences the function of the actin network. Therefore, we established and interrogated the impact of altering Capu’s localization in the Drosophila oocyte to better understand its role and that of the actin mesh it builds. This mesh restricts bulk cytoplasmic flows, streaming, but otherwise remains undescribed functionally. Using a gene specific driver, capu-Gal4, to better study Capu transgenes, we found that fertility was markedly decreased when restricting Capu to membranes in the oocyte, although its canonical role in actin mesh assembly was apparently unaltered. Instead, we observed a defect in posterior anchoring of the mRNA oskar during mid-oogenesis. However, the defect did not fall into the traditional posterior group phenotype. The data suggest that Capu, independently of Spire, tethers the posterior determinants to the cortex but does not anchor them to each other, supporting that Capu localization influences the posterior oocyte organization.
Engineered microvasculature using maskless photolithography and on-chip hydrogel patterning: a facile approach
Authors: Kasi Dhanesh G. , de Graaf Mees N. S. , Nahon Dennis M. , van den Hil Francijna E. , van den Maagdenberg Arn M. J. M. , Mummery Christine L. , Orlova Valeria V.
Published: July 2024

In vitromodels of human microvasculature are increasingly used to understand blood vessel diseases and to support drug development. Most engineered models, however, are slow and labor-intensive to produce. Here, we used a single commercial digital micromirror device (DMD)-based setup for maskless photolithography to both fabricate microfluidic chips and pattern the inside of these chips with gelatin methacrylate (GelMA) hydrogels. These hydrogel scaffolds had tunable stiffness, could be generated rapidly and were suitable for forming perfusable microvasculature from human induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs). When cultured in narrow channels, the hiPSC-ECs adopted a tubular morphology that was similar to capillariesin vivo, but they followed the square channel geometry in wider channels. Compartmentalization of the chips allowed co-culture of hiPSC-ECs with hiPSC-derived astrocytes, thereby increasing model complexity. Furthermore, valve-like structures could be patterned inside the channels, mimicking functional vascular valves, holding promise for thrombosis and lymphatic vasculature research.
Identification of novel loci regulating dormancy in barley and association with hypoxia sensitivity
Authors: Farquharson Lochlen , Samanfar Bahram , Khanal Raja , Bekele Wubishet , Brauer Elizabeth K.
Published: July 2024

Low seed dormancy is an essential trait in malting barley since malting involves rapid and uniform induction of germination. At least two major QTLs on chromosome 5H, SD1 and SD2, regulate dormancy in multiple barley populations, and additional genetic regions are thought to be involved. To identify novel genetic loci that might be associated with dormancy, a panel of genotypes from diverse agro-ecosystems were evaluated alongside two Canadian biparental populations for germination rate. Association mapping revealed QTLs within the SD1 and SD2 loci in the Canadian populations, while neither of these loci were linked to dormancy in the diversity panel. The diversity panel identified 14 additional marker-trait associations, including novel genetic loci. An alanine aminotransferase (AlaAT1) underlies dormancy regulation at the SD1 allele and is thought to help mitigate the suppressive effects of hypoxia on respiration during grain fill. Additional testing with four genotypes carrying either dormant or non-dormantAlaAT1alleles revealed that dormant alleles had increased hypoxia sensitivity and hypoxia-responsive gene expression during grain fill. Together, this work indicates that multiple genetic regions influence dormancy and suggests that hypoxia influences dormancy establishment in barley.

Highlight

Dormancy is regulated by distinct genetic regions in North American barley compared to African barley. The SD1 locus influences dormancy in North American lines and genotypes with the dormant SD1 allele are more sensitive to hypoxia.
Stimulation of locus coeruleus inputs to the frontal cortex in mice induces cell type-specific expression of theApoegene
Authors: Craig Genevieve E. , Ramos Lizbeth , Essig Samuel R. , Eagles Nicholas J. , Jaffe Andrew E. , Martinowich Keri , Hallock Henry L.
Published: July 2024

Deficits in attention are common across a range of neuropsychiatric disorders. A multitude of brain regions, including the frontal cortex (FC) and locus coeruleus (LC), have been implicated in attention. Regulators of these brain regions at the molecular level are not well understood, but might elucidate underlying mechanisms of disorders with attentional deficits. To probe this, we used chemogenetic stimulation of neurons in the LC with axonal projections to the FC, and subsequent bulk RNA-sequencing from the mouse FC. We found that stimulation of this circuit caused an increase in transcription of theApoegene. To investigate cell type-specific expression ofApoein the FC, we used a dual-virus approach to express either the excitatory DREADD receptor hM3Dq in LC neurons with projections to the FC, or a control virus, and found that increases inApoeexpression in the FC following depolarization of LC inputs is enriched in GABAergic neurons in a sex-dependent manner. The results of these experiments yield insights into howApoeexpression affects function in cortical microcircuits that are important for attention-guided behavior, and point to interneuron-specific expression ofApoeas a potential target for the amelioration of attention symptoms in disorders such as attention-deficit hyperactivity disorder (ADHD), schizophrenia, and Alzheimer’s disease (AD).

Significance Statement

Identifying patterns of gene expression in specific brain circuits is an important first step toward developing treatments for cognitive and behavioral symptoms that rely on those circuits. In this paper, we describe a transcriptome-scale motif in one such circuit - neurons in the LC that project to the FC. This circuit has been implicated in attention, and attentional deficits are common across many neuropsychiatric disorders, suggesting that targeting this circuit could have therapeutic potential for ameliorating attentional symptoms in these disorders. We further explored one of the top differentially expressed genes,Apoe,to identify how it is expressed in distinct cell types following stimulation of this circuit, paving the way for spatially- and genetically-specific targeting of this gene in attention.
A disinhibitory basal forebrain to cortex projection supports sustained attention
Authors: Li Shu-Jing , Hangya Balazs , Gupta Unmukt , Fischer Kyle B. , Sturgill James Fitzhugh , Callaway Edward M. , Kepecs Adam
Published: July 2024

Sustained attention, as an essential cognitive faculty governing selective sensory processing, exhibits remarkable temporal fluctuations. However, the underlying neural circuits and computational mechanisms driving moment-to-moment attention fluctuations remain elusive. Here we demonstrate that cortex-projecting basal forebrain parvalbumin-expressing inhibitory neurons (BF-PV) mediate sustained attention in mice performing an attention task. BF-PV activity predicts the fluctuations of attentional performance metrics ― reaction time and accuracy ― trial-by-trial, and optogenetic activation of these neurons enhances performance. BF-PV neurons also respond to motivationally salient events, such as predictive cues, rewards, punishments, and surprises, which a computational model explains as representing motivational salience for allocating attention over time. Furthermore, we found that BF-PV neurons produce cortical disinhibition by inhibiting cortical PV+ inhibitory neurons, potentially underpinning the observed attentional gain modulation in the cortex. These findings reveal a disinhibitory BF-to-cortex projection that regulates cortical gain based on motivational salience, thereby promoting sustained attention.

HIGHLIGHTS

BF-PV activity predicts attentional performance metrics: reaction time and accuracy

BF-PV responses reflect the computation of motivational salience-guided attention allocation

Optogenetic activation of BF-PV neurons improves attentional performance

BF-PV neurons produce cortical disinhibition through topographic projections and mediate gain modulation
Efficacy and Safety of Middle Meningeal Artery Embolization for Patients with Chronic Subdural Hematoma: A Systematic Review and Meta-Analysis
Authors: Kabir N , Owais B , Trifan G , Testai FD
Published: July 2024

Background

Chronic subdural hematoma (CSDH) is characterized by the collection of blood beneath the dura mater. Traditional treatments involve surgical drainage of the hematoma, but recurrence rates can be high. A highly vascularized neo-membrane irrigated by the middle meningeal artery (MMA) may be involved in CSDH re-accumulation.

Objective

We conducted a systematic review and meta-analysis of studies that compared the efficacy and safety of MMA embolization to conventional treatment alone for CSDH.

Material and Methods

A systematic search of PubMed, Embase Ovid, andClinicalTrials.govidentified observational and randomized clinical studies comparing MMA embolization to conventional treatment for chronic subdural hematoma. The efficacy outcomes were hematoma recurrence and good functional outcome (as defined by a modified Rankin Scale score (mRS) of 0-2). Safety outcomes were the rate of major complication and mortality. Heterogeneity among studies were evaluated using the I2statistic. Analyses were conducted using Cochrane Review Manager software, with risk ratios (RR) and 95% confidence intervals (95% CI) presented for key outcomes. Absolute risk reduction (ARR, 95% CI) 1000 patients were also calculated using GRADEpro software.

Results

The analysis included data from 13 studies (4 RCTs and 9 observational studies) with a total number of 2960 patients (35.3% in the MMA group and 64.7% in the conventional treatment group). Compared to conventional treatment, MMA embolization decreased risk of hematoma recurrence by 60% (13 studies, RR=0.40, 95% CI 0.25-0.63; I2=50%), for an absolute effect of 119 fewer events/1000 patients (95% CI 70-149), with similar risk of major complications (9 studies, RR=0.82, 95% CI=0.54-1.25) and mortality risk (13 studies, RR=0.90, 95% CI=0.54-1.51). In subgroup analyses by study type, pooled results from RCTs showed similar direction effects as those from observational studies for both efficacy and safety outcomes.

Conclusion

MMA embolization in CSDH management is a safe and effective approach for CSDH.
A Data-Driven Sliding-window Pairwise Comparative Approach for the Estimation of Transmission Fitness of SARS-CoV-2 Variants and Construction of the Evolution Fitness Landscape
Authors: Pantho Md Jubair , Bauder Landen Alexander , Huang Sophia , Qin Hong
Published: July 2024

Estimating the transmission fitness of SARS-CoV-2 variants and understanding their evolutionary landscape is important for epidemiological forecasting. Existing methods are often constrained by their parametric natures and do not satisfactorily align with the observations during COVID-19. Here, we introduce a sliding-window data-driven pairwise comparison method, Differential Population Growth Rate (DPGR), that uses viral strains as internal controls to mitigate sampling biases. DPGR is applicable in time windows in which the logarithmic ratio of two variant subpopulations is approximately linear. We apply DPGR to genomic surveillance data and focus on Variants of Concern (VOCs) in multiple countries and regions. We found the log-linear assumption of DPGR can be found in appropriate time windows in many regions. We show that DPGR can provide estimates of transmission fitness and quantify the transmission advantage of key variants such as Omicron by location. We show that DPGR estimates agree with other methods for estimating pathogenic transmission. Furthermore, DPGR allowed us to construct viral fitness landscapes that capture the evolutionary trends of SARS-CoV-2, reflecting the relative changes of transmission traits for key genotypic changes represented by major variants. The straightforward log-linear regression approach of DPGR may also facilitate its easy adoption. This study shows that DPGR is a promising new tool in our repertoire for addressing future pandemics.
Precision Education Tools for Pediatrics Trainees: A Mixed-Methods Multi-Site Usability Assessment
Authors: Fidel Alexander , Mai Mark V. , Muthu Naveen , Dziorny Adam C.
Published: July 2024

Background

Exposure to patients and clinical diagnoses drives learning in graduate medical education (GME). Measuring practice data, how trainees each experience that exposure, is critical to planned learning processes including assessment of trainee needs. We previously developed and validated an automated system to accurately identify resident provider-patient interactions (rPPIs). In this follow-up study, we employ user-centered design methods to meet two objectives: 1) understand trainees’ planned learning needs; 2) design, build, and assess a usable, useful, and effective tool based on our automated rPPI system to meet these needs.

Methods

We collected data at two institutions new to the American Medical Association’s “Advancing Change” initiative, using a mixed-methods approach with purposive sampling. First, interviews and formative prototype testing yielded qualitative data which we analyzed with several coding cycles. These qualitative methods illuminated the work domain, broke it into learning use cases, and identified design requirements. Two theoretical models—the Systems Engineering Initiative for Patient Safety (SEIPS) and Master-Adaptive Learner (MAL)—structured coding efforts. Feature-prioritization matrix analysis then transformed qualitative analysis outputs into actionable prototype elements that were refined through formative usability methods. Lastly, qualitative data from a summative usability test validated the final prototype with measures of usefulness, usability, and intent to use. Quantitative methods measured time on task and task completion rate.

Results

We represent GME work domain learnings through process-map-design artifacts which provide target opportunities for intervention. Of the identified decision-making opportunities, trainee-mentor meetings stood out as optimal for delivering reliable practice-area information. We designed a “mid-point” report for the use case of such meetings, integrating features from qualitative analysis and formative prototype testing into iterations of the prototype. A final version showed five essential visualizations. Usability testing resulted in high performance in subjective and objective metrics. Compared to currently available resources, our tool scored 50% higher in terms of Perceived Usability and 60% higher on Perceived Ease of Use.

Conclusions

We describe the multi-site development of a tool providing visualizations of log level electronic health record data, using human-centered design methods. Delivered at an identified point in graduate medical education, the tool is ideal for fostering the development of master adaptive learners. The resulting prototype is validated with high performance on a summative usability test. Additionally, the design, development, and assessment process may be applied to other tools and topics within medical education informatics.
Genetic ancestral patterns inCYP2D6alleles: structural variants, rare variants, and clinical associations in 479,144 UK Biobank genomes
Authors: Jiang Xiao , Hu Fengyuan , Zou Xueqing Zoe , Abbasi Ali , Deevi Sri V. V. , Atanur Santosh S. , O’Neill Amanda , Harrow Jen , Fabre Margarete , Wang Quanli , Petrovski Slavé , Rae William , Burren Oliver , Smith Katherine R.
Published: July 2024

Cytochrome P450 2D6 (CYP2D6) is involved in metabolising over 20% of clinical drugs, yet its genetic variation across ancestries is underexplored in large-scale whole-genome sequencing (WGS) datasets. We analysed WGS data from 479,144 UK Biobank participants, identifying 95 distinctCYP2D6star alleles across five biogeographic groups. Of these, 48 alleles had currently unknown effects. These alleles were more prevalent in African, admixed American, and South Asian groups (∼5%) compared to European and East Asian groups (∼2%), affecting the ability to provide pharmacogenomics recommendations across ancestries. We identified 99,656 (20.8%) individuals carryingCYP2D6structural variations and predicted theCYP2D6ultra-rapid metaboliser phenotype to be most common in Africans (4.5%) and rarest in East Asians (0.32%). Less than half (45.7%) of rare protein-truncating variant carriers were categorised as poor or intermediate metabolisers, indicating an underrepresentation of rare functional variants in the currentCYP2D6star allele evaluation. Phenome-wide association studies confirmed links with narcotic allergies and found new associations with plasma BAFFR and BAFF proteins, offering insights for the BAFF-targeted clinical therapy. Collectively, this largest WGS study ofCYP2D6to date highlights the importance of leveraging all genetic variations for pharmacogenomic insights affecting therapeutic safety and development.
Reevaluating the Role of ACE Inhibitors in Skin Fibrosis Risk: Evidence from Mendelian Randomization
Authors: Wei Yangyang , Wan Ziqi , Jiang Yiwen , Liu Zhengye , Yang Ming , Tang Jieying
Published: July 2024

Background

Skin fibrosis, characterized by excessive extracellular matrix deposition, leads to hypertrophic scars and keloids, which are both common and often detrimental conditions. Angiotensin-converting enzyme (ACE) inhibitors have shown promise in animal studies and limited clinical trials for reducing scar formation. However, the causal relationship between ACE inhibition and skin fibrosis remains unclear.

Methods

This study employed two-sample Mendelian randomization (MR) analysis to investigate the causal effect of ACE inhibition on skin fibrotic diseases. We utilized genetic variants associated with serum ACE levels, ACE inhibition, and effect of decreasing blood pressure by ACE inhibition as instrumental variables. We analyzed the association between these exposures and the incidence of skin fibrosis, hypertrophic scars, and keloids using various MR methods.

Results

We found no significant causal relationship between genetically proxied serum ACE levels, or local skin tissue ACE expression and the risk of skin fibrosis, hypertrophic scars, or keloids. Additionally, there was no direct causal relationship between the effect of ACE inhibitors on blood pressure reduction and the risk of skin fibrotic diseases. However, we observed a significant negative association between systolic blood pressure (SBP) and the risk of hypertrophic scars. Conversely, we found a positive association between β-blockers and the risk of skin fibrosis.

Conclusion

Our findings suggest that ACE inhibitors do not have a direct causal effect on the risk of skin fibrotic diseases, including hypertrophic scars and keloids. This challenges the potential of ACE inhibitors as a therapeutic option for preventing or treating these conditions.
Th2 cell extracellular vesicles promote eosinophil survival through the cytokine cargo IL-3 and prolong airway eosinophilia
Authors: Bunn Kaitlyn E. , Giese-Byrne Brenna G. , Pua Heather H.
Published: July 2024

Background

Extracellular vesicles (EVs) mediate intercellular communication during immune responses. EVs are abundant in respiratory biofluids, and the composition of EVs in the lung changes during inflammation.

Objective

We aimed to quantify the contribution of T cells to airway EVs in allergic lung inflammation and ascertain their function during a type 2 inflammatory response.

Methods

Genetic membrane tagging was combined with single vesicle flow cytometry to quantify T cell EVs in the airways of mice challenged with ovalbumin or house dust mite. EVs were purified from T helper type 2 (Th2) cell cultures and their functions on eosinophils assessed by flow cytometry and RNA sequencing. Th2 cell EVs were instilled into the lungs of mice to determine effects on lung eosinophilia. Finally, the function of an EV protein cargo was tested using inhibitors and blocking antibodies.

Results

T cell EVs are increased in the airways of mice with induced allergic inflammation. EVs secreted by Th2 cells inhibit apoptosis and induce activating pathways in eosinophilsin vitro.This effect depends on re-stimulation through the T cell receptor. Th2 cell EVs prolong eosinophiliain vivoduring allergic airway inflammation. Th2 cell EVs carry a potent form of the cytokine IL-3 on their surfaces, which inhibits apoptosis by activating Jak1/2-dependent pro-survival programs in eosinophils.

Conclusion

Th2 cell EVs promote eosinophil survival and prolong eosinophilia during allergic airway inflammation. This function depends on the EV cargo IL-3, supporting a role for EVs as vehicles of cytokine-based communication in lung inflammation.

Key Messages

T cells secrete extracellular vesicles in the airway during allergic lung inflammation.

Th2 cell extracellular vesicles inhibit eosinophil apoptosis and prolong airway eosinophilia during allergic lung inflammation.

IL-3 carried on Th2 cell EVs is a functional cargo, supporting a role for cytokine-carrying EVs as drivers of type 2 inflammation.

Capsule summary

This study supports that T cell extracellular vesicles may be important drivers of eosinophilic inflammation through the cytokine cargo IL-3, offering new insights into pro-inflammatory signaling in the allergic lung of patients with asthma.