bluuebunny/crossref_metadata_2025 huggingface dataset:
Morphological ant mimics: constrained to imperfection?
Authors: McLean Donald James , Cassis Gerasimos , Herberstein Marie E.
Published: February 2024

Adaptive evolution relies on both heritable variation and selection. Variation is the raw material upon which selection acts, so any mechanism that limits or prevents the generation of heritable variation reduces the power of selection to lead to adaptation. Such limitations are termed evolutionary constraints. While it is widely accepted that constraints play an important role in shaping evolutionary outcomes, their relative importance, as opposed to adaptation, in determining evolutionary outcomes remains a subject of debate. Evolutionary constraints are often evoked as the reason behind the persistence of inaccurate mimicry. Here, we compared the variation and accuracy of body-shape mimicry in ant-mimicking spiders with that of ant-mimicking insects, predicting greater constraints, and hence inaccuracy, in spiders mimicking ants, due to their evolutionary distance from the ant model. We found high inter-species variation in mimetic accuracy, but dorsally, no overall difference in mimetic accuracy between spider and insect mimics, which is inconsistent with a constraint causing inaccurate mimicry. Our study provides empirical evidence suggesting that imperfect mimicry in spiders and insects is predominantly shaped by adaptive processes rather than constraints or chance. Our findings contribute to our understanding of the mechanisms underlying evolutionary diversity and the processes that shape phenotypic outcomes.
Per Andersen. 12 January 1930—17 February 2020
Authors: Bliss FRS Tim , Lømo Terje
Published: February 2024

Per Andersen was one of the leading neuroscientists of the second half of the twentieth century. He spent his entire career at the University of Oslo, apart from an exceptionally productive postdoctoral period with Sir John Eccles FRS at the Australian National University in Canberra between 1961 and 1963. As a PhD student he laid the foundation of field potential analysis, which allowed synaptic function in laminated cortical structures such as the hippocampus to be followed for long periods in intact animals, an essential technical prerequisite for the study of the synaptic basis of memory. In Canberra he identified the neurons responsible for feed-back inhibition in the hippocampus and feed-forward inhibition in the cerebellum, the first inhibitory neurons to be functionally identified in the mammalian brain. Per's Canberra achievements catapulted him to superstar status, and enabled him on his return to Oslo in 1963 to establish a laboratory that played a major role over the following decades in characterizing the functional properties of hippocampal synapses. From his laboratory emerged a string of significant advances, including the discovery of long-term potentiation, a form of synaptic plasticity widely believed to support learning and memory, and the introduction of the transverse hippocampal slice, which rapidly became the dominant preparation for investigating the properties of hippocampal neurons. Young researchers, many from the USA and Canada, flocked to his laboratory for postdoctoral training, adding to the steady stream of Norwegian doctoral students, two of whom went on to win the Nobel Prize. Per was also committed to the importance of communicating scientific advances to the general public, and contributed prolifically over the years to the Norwegian media, commentating on advances in neuroscience and their relevance to neurological disorders.
Sir Michael George Parke Stoker. 4 July 1918—13 August 2013
Authors: Weiss FRS Robin A.
Published: February 2024

Michael Stoker was a renowned virologist and cell biologist. He gained his interest in research while serving as a medical officer during the Second World War in India, studying infectious diseases such as typhus. He began to study viruses in the Department of Pathology in Cambridge and in 1958 was appointed to the first established UK chair of virology and as head of the Medical Research Council Virus Unit at the University of Glasgow. He pioneered studies of cancer-causing viruses using polyomavirus of mice, and developed the baby hamster kidney cell lines still used today for vaccine production. In 1968 he moved to London as director of research at the Imperial Cancer Research Fund (ICRF) Laboratories, now part of the Cancer Research UK funded laboratories at the Francis Crick Institute. He brought many virologists to ICRF, while he himself turned to cell biology, first of mesenchymal cells and then of normal and malignant epithelial cells, particularly breast epithelium. Returning to Cambridge in 1978, he discovered scatter factor (also known as hepatocyte growth factor), a paracrine cytokine that stimulates motility and proliferation of epithelial cells. Michael had broad-ranging interests and there are few virologists in the UK who have not been influenced either by him directly or by his protégés. Among the many activities beyond the institutions where he worked, he served from 1976 to 1981 as Foreign Secretary and Vice-President of the Royal Society.
miR-1202 acts as anti-oncomiR in myeloid leukaemia by down-modulating GATA-1
S
expression
Authors: Sessa Raffaele , Trombetti Silvia , Bianco Alessandra Lo , Amendola Giovanni , Catapano Rosa , Cesaro Elena , Petruzziello Fara , D'Armiento Maria , Maruotti Giuseppe Maria , Menna Giuseppe , Izzo Paola , Grosso Michela
Published: February 2024

Transient abnormal myelopoiesis (TAM) is a Down syndrome-related pre-leukaemic condition characterized by somatic mutations in the haematopoietic transcription factor GATA-1 that result in exclusive production of its shorter isoform (GATA-1
S
). Given the common hallmark of altered miRNA expression profiles in haematological malignancies and the pro-leukaemic role of GATA-1
S
, we aimed to search for miRNAs potentially able to modulate the expression of GATA-1 isoforms. Starting from an
in silico
prediction of miRNA binding sites in the GATA-1 transcript, miR-1202 came into our sight as potential regulator of GATA-1 expression. Expression studies in K562 cells revealed that miR-1202 directly targets GATA-1, negatively regulates its expression, impairs GATA-1
S
production, reduces cell proliferation, and increases apoptosis sensitivity. Furthermore, data from TAM and myeloid leukaemia patients provided substantial support to our study by showing that miR-1202 down-modulation is accompanied by increased GATA-1 levels, with more marked effects on GATA-1
S
. These findings indicate that miR-1202 acts as an anti-oncomiR in myeloid cells and may impact leukaemogenesis at least in part by down-modulating GATA-1
S
levels.
Possible monitoring of mesophotic scleractinian corals using an underwater mini-ROV to sample coral eDNA
Authors: Nishitsuji Koki , Nagahama Shinichiro , Narisoko Haruhi , Shimada Kazuo , Okada Nobuhiro , Shimizu Yuki , Satoh Noriyuki
Published: February 2024

Mesophotic coral ecosystems (MCEs) are light-dependent tropical or subtropical communities occurring at depths of 30–150 m. Broader surveys of MCEs are needed to better understand stony corals, the keystone species of coral-reef ecosystems. While MCEs have been studied by professional SCUBA divers and with deep-sea robots, comprehensive surveys of MCEs are required. An eDNA metabarcoding method has recently been used to survey scleractinian corals in shallow reefs. We tested whether MCEs might be more comprehensively surveyed by collecting seawater samples using an underwater mini-remote operated vehicle (mini-ROV). Seawater was collected 1–2 m above reef tops at depths of 20–80 m at 24 sites in six locations around the Zamami Islands (Okinawa, Japan). Water samples were then subjected to coral-specific eDNA amplification. Metabarcoding analyses of amplicons showed that except for one site, coral-specific eDNA from approximately 0.5 l seawater samples was sufficient to identify genera. The proportion of
Acropora
eDNA was higher at shallow reefs and upper ridges of slopes, while the proportion of
Porites
increased at mesophotic sites
.
Although further technical improvements are required, this study suggests that it may be possible to monitor mesophotic corals to the generic level using eDNA collected using mini-ROVs.
Lessons to be popular: the chemical basis of aggregation inTrypanosoma cruzi-infected and non-infected Chagasic bugs
Authors: Alavez-Rosas David , Gutiérrez-Cabrera Ana E. , Cruz-López Leopoldo , Córdoba-Aguilar Alex
Published: February 2024

Aggregation is one of the most remarkable behaviours in the animal kingdom—a process that is usually governed by pheromones. Triatomines are blood-sucking bugs that act as vectors ofTrypanosoma cruzi, the etiological agent of Chagas disease in mammals, including humans. Triatomines usually gather in roosting refuges by using aggregation pheromones of unknown chemical structure. In terms of vector control, one option to reduce triatomine–human contact is via capturing the insects into traps baited with lures based on such aggregation pheromones. As a first step towards this aim, we elucidated the aggregation pheromone in the triatomineTriatoma pallidipennis, usingT. cruzi-infected and non-infected bugs. We used different extraction techniques and gas chromatography coupled to mass spectrometry for the identification. Also, two different bioassays were implemented for evaluating the attractant and arrestant activity of the pheromone. We found thatT. pallidipennisproduced short-chain aldehydes as attractants, and nitrogen-derived compounds as arrestants. We detected differences in the production and perception of these compounds according to whether animals were infected or not. These findings show thatT. cruzimay influence triatomine chemical ecology and are promising tools for triatomine control.
Pneumatic elastostatics of multi-functional inflatable lattices: realization of extreme specific stiffness with active modulation and deployability
Authors: Sinha P. , Mukhopadhyay T.
Published: February 2024

As a consequence of intense investigation on possible topologies of periodic lattices, the limit of specific elastic moduli that can be achieved solely through unit cell-level geometries in artificially engineered lattice-based materials has reached a point of saturation. There exists a robust rationale to involve more elementary-level mechanics for pushing such boundaries further to develop extreme lightweight multi-functional materials with adequate stiffness. We propose a novel class of inflatable lattice materials where the global-level stiffness can be derived based on a fundamentally different mechanics compared with conventional lattices having beam-like solid members, leading to extreme specific stiffness due to the presence of air in most of the lattice volume. Furthermore, such inflatable lattices would add multi-functionality in terms of on-demand performances such as compact storing, portability and deployment along with active stiffness modulation as a function of air pressure. We have developed an efficient unit cell-based analytical approach therein to characterize the effective elastic properties including the effect of non-rigid joints. The proposed inflatable lattices would open new frontiers in engineered materials and structures that will find critical applications in a range of technologically demanding industries such as aircraft structures, defence, soft robotics, space technologies, biomedical and various other mechanical systems.
Pressure induced transformation of biomass to a highly durable, low friction film on steel
Authors: Lanigan Joseph L. , Faas Laura , Butcher Thomas , Skipper William A. , Silva Mariana P. , Lewis Roger , Gomez Leonardo D.
Published: February 2024

Herein the authors report a detailed insight into the tribological and chemical mechanisms that take place when leaf matter is present at the wheel/rail interface. The approach used enables further insight into the formation and subsequent effects on friction from leaf derived layers. Results shed insight on the process that facilitates the formation of leaf derived layers, their structure and chemical make-up. Our analysis indicates that polyphenols, a chemical family that include tannins, have an important role in layer formation and hypothesis on the layer's stability, when formed under high pressures. The data indicate that the high pressure found at the wheel/rail interface facilitates conversion of biomass into a tenacious, thin film. This is shown by the increase in the amount of phenolic compounds present. Phenolic compounds are typically rich in oxygen functional groups that have the ability to bind to metal ions. This insight into the composition of the film is expected to enable the development of novel remediation strategies. It highlights the potential for cleaning agents to be used as tools for restoring friction to safe values. This should lead to improvements in the operational performance and safety of rail transport for passengers and train operators.
Spontaneous de-bonding, buckling and delamination of an elastic plate adhering to a rigid base: theoretical limits
Authors: Adams George G.
Published: February 2024

An infinitely long elastic plate is under compression and adhering to a flat rigid base. Many studies have investigated such a layer with a pre-existing flaw in the bond (i.e. an initially de-bonded region) which may then lead to buckling and possibly to delamination. The present investigation considers the possibility of spontaneous de-bonding and simultaneous buckling, followed by delamination, in an initially homogeneous stress field without a pre-existing flaw. It is shown that a sufficiently large pre-stress can lead to this sequence of events. This limiting pre-stress depends on the plane strain elastic modulus, the layer thickness and the stiffness characteristic of the adhesion law. These results lead to theoretical limits on the pre-stress for the prevention of de-bonding, buckling and subsequent delamination under ideal bond conditions.
Evolution of parental care in haploid–diploid plants
Authors: Bessho Kazuhiro , Sasaki Akira
Published: February 2024

In bryophytes that alternate between haploid gametophytes and diploid sporophytes through sexual reproduction, sporophytes are often attached to and nurtured on the female gametophyte. A similar phenomenon is seen in Florideophyceae (a group of red algae). These systems in which a gametophyte (mother) invests nutrients in sporophytes (offspring) are ideal for studying the evolution of ‘parental care’ in non-animal organisms. Here, we propose a model of a haploid–diploid life cycle and examine the evolution of maternal investment in sporophytes focusing on two effects: the degree of paternal or maternal control of investment and the number of sporophytes. We find that when the female dominantly controls the investment, the evolutionarily stable level of investment is that which maximizes the expected reproductive success of the female gametophyte. The genomic conflict between maternal and paternal alleles complicates the evolutionary outcome; however, a greater male allelic effect and a higher number of sporophytes favour a higher energy investment, which may lead to evolutionary branching or run-away escalation of the investment level. This suggests that the selfishness of the paternal gene is the evolutionary driver of parental care and that complex structures such as fusion cells in red algae may have evolved to suppress it.
Differentiating spillover: an examination of cross-habitat movement in ecology
Authors: Harman Rachel R. , Kim Tania N.
Published: February 2024

Organisms that immigrate into a recipient habitat generate a movement pattern that affects local population dynamics and the environment. Spillover is the pattern of unidirectional movement from a donor habitat to a different, adjacent recipient habitat. However, ecological definitions are often generalized to include any cross-habitat movement, which limits within- and cross-discipline collaboration. To assess spillover nomenclature, we reviewed 337 studies within the agriculture, disease, fisheries and habitat fragmentation disciplines. Each study's definition of spillover and the methods used were analysed. We identified four descriptors (movement, habitat type and arrangement, and effect) used that differentiate spillover from other cross-habitat movement patterns (dispersal, foray loops and edge movement). Studies often define spillover as movement (45%) but rarely measure it as such (4%), particularly in disease and habitat fragmentation disciplines. Consequently, 98% of studies could not distinguish linear from returning movement out of a donor habitat, which can overestimate movement distance. Overall, few studies (12%) included methods that matched their own definition, revealing a distinct mismatch. Because theory shows that long-term impacts of the different movement patterns can vary, differentiating spillover from other movement patterns is necessary for effective long-term and inter-disciplinary management of organisms that use heterogeneous landscapes.
Progression of Frailty and Cardiovascular Outcomes Among Medicare Beneficiaries
Authors: Gong Yusi , Song Yang , Xu Jiaman , Dong Huaying , Orkaby Ariela R. , Kramer Daniel B. , Dodson John A. , Strom Jordan B.
Published: February 2024

Background

Frailty is associated with adverse cardiovascular outcomes independent of age and comorbidities, yet the independent influence of frailty progression remains uncertain.

Methods

Medicare Fee-for-service beneficiaries ≥ 65 years at cohort inception with continuous enrollment from 2003-2015 were included. Frailty trajectory was measured by annualized change in a validated claims-based frailty index (CFI) over a 5-year period. Linear mixed effects models, adjusting for baseline frailty, were used to estimate CFI change over a 5-year period. Survival analysis was used to evaluate associations of frailty progression and future health outcomes (major adverse cardiovascular and cerebrovascular events [MACCE], all-cause death, heart failure, myocardial infarction, ischemic stroke, and days alive at home [DAH] within the following calendar year).

Results

26.4 million unique beneficiaries were included (mean age 75.4 ± 7.0 years, 57% female, 13% non-White). In total, 20% had frailty progression, 66% had no change in frailty, and 14% frailty regression over median follow-up of 2.4 years. Compared to those without a change in CFI, when adjusting for baseline frailty, those with frailty progression had significantly greater risk of incident MACCE (hazard ratio [HR] 2.30, 95% confidence interval [CI] 2.30-2.31), all-cause mortality (HR 1.59, 95% CI 1.58-1.59), acute myocardial infarction (HR 1.78, 95% CI 1.77-1.79), heart failure (HR 2.78, 95% CI 2.77-2.79), and stroke (HR 1.78, 95% CI 1.77-1.79). There was also a graded increase in risk of each outcome with more rapid progression and significantly fewer DAH with the most rapid vs. the slowest progression group (270.4 ± 112.3 vs. 308.6 ± 93.0 days, rate ratio 0.88, 95% CI 0.87-0.88, p < 0.001).

Conclusions

In this large, nationwide sample of Medicare beneficiaries, frailty progression, independent of baseline frailty, was associated with fewer DAH and a graded risk of MACCE, all-cause mortality, myocardial infarction, heart failure, and stroke compared to those without progression.

NON-STANDARD ABBREVIATIONS AND ACRONYMS

Claims-based frailty index (CFI)

Major adverse cardiovascular and cerebrovascular events (MACCE)

Number of days alive at home within the following calendar year (DAH)

Medicare Fee-for-Service (FFS)
Human cytomegalovirus glycoprotein variants governing viral tropism and syncytium formation in epithelial cells and macrophages
Authors: Cimato Giorgia , Zhou Xuan , Brune Wolfram , Frascaroli Giada
Published: February 2024

Human cytomegalovirus (HCMV) displays a broad cell tropism, and the infection of biologically relevant cells such as epithelial, endothelial, and hematopoietic cells supports viral transmission, systemic spread, and pathogenesis in the human host. HCMV strains differ in their ability to infect and replicate in these cell types, but the genetic basis of these differences has remained incompletely understood. In this study, we investigated HCMV strain VR1814, which is highly infectious for epithelial cells and macrophages and induces cell-cell fusion in both cell types. A VR1814-derived bacterial artificial chromosome (BAC) clone, FIX-BAC, was generated many years ago but has fallen out of favor because of its modest infectivity. By sequence comparison and genetic engineering of FIX, we demonstrate that the high infectivity of VR1814 and its ability to induce syncytium formation in epithelial cells and macrophages depends on VR1814-specific variants of the envelope glycoproteins gB, UL128, and UL130. We also show that UL130-neutralizing antibodies inhibit syncytium formation, and a FIX-specific mutation in UL130 is responsible for its low infectivity by reducing the amount of the pentameric glycoprotein complex in viral particles. Moreover, we found that a VR1814-specific mutation in US28 further increases viral infectivity in macrophages, possibly by promoting lytic rather than latent infection of these cells. Our findings show that variants of gB and the pentameric complex are major determinants of infectivity and syncytium formation in epithelial cells and macrophages. Furthermore, the VR1814-adjusted FIX strains can serve as valuable tools to study HCMV infection of myeloid cells.

Importance

HCMV is a major cause of morbidity and mortality in transplant patients and the leading cause of congenital infections. HCMV infects various cell types, including epithelial cells and macrophages, and some strains induce the fusion of neighboring cells, leading to the formation of large multinucleated cells called syncytia. This process may limit the exposure of the virus to host immune factors and facilitate its spread. However, the reason why some HCMV strains exhibit a broader cell tropism and why some induce cell fusion more than others is not well understood. We compared two closely related HCMV strains and provided evidence that small differences in viral envelope glycoproteins can massively increase or decrease the virus infectivity and its ability to induce syncytium formation. The results of the study suggest that natural strain variations may influence HCMV infection and pathogenesis in humans.
Tackling inequalities in preconception health and care: barriers, facilitators and recommendations for action from the 2023 UK Preconception EMCR Network conference
Authors: Schoenaker Danielle , Hall Jennifer , Stewart Catherine , Hanley Stephanie J. , Cassinelli Emma H. , Benton Madeleine , Wynn-Jones Alexandra Azzari , Chawla Mehar , Currie Sinéad ,   2023 UK Preconception EMCR Network conference workshop participants
Published: February 2024

Reducing inequalities in preconception health and care is critical to improving the health and life chances of current and future generations. A hybrid workshop was held at the 2023 UK Preconception Early and Mid-Career Researchers (EMCR) Network conference to co-develop recommendations on ways to address inequalities in preconception health and care. The workshop engaged multi-disciplinary professionals across diverse career stages and people with lived experience (total n=69). Interactive discussions explored barriers to achieving optimal preconception health, driving influences of inequalities, and recommendations. The Socio-Ecological Model framed the identified themes, with recommendations structured at interpersonal (e.g. community engagement), institutional (e.g. integration of preconception care within existing services) and environmental/societal levels (e.g. education in schools). The co-developed recommendations provide a framework for addressing inequalities in preconception health, emphasising the importance of a whole-systems approach. Further research and evidence-based interventions are now needed to advance the advocacy and implementation of our recommendations.
COVID-19 vaccination was a rare potential etiology for cause of death after medicolegal autopsy. A Finnish nationwide study
Authors: Pakanen Lasse , Nieminen Tuomo , Kuvaja Paula , Nohynek Hanna , Goebeler Sirkka , Artama Miia , Hovi Petteri
Published: February 2024

COVID-19 vaccinations began globally at the end of 2020. By the end of 2021, 9.8 million doses were given in Finland. Regarding safety, most vaccine-related adverse reactions have been mild, but serious and lethal ones have also occurred. Autopsies in post vaccination deaths may give insight to the extent of fatal health conditions with potential COVID-19 vaccine etiology and provide new hypotheses of possible causalities between vaccination and severe health conditions. We searched the complete documentation on all medicolegal autopsies in Finland between December 2020 and December 2021 to assess how often the basis for autopsy was a suspected fatal adverse reaction to COVID-19 vaccination, and whether vaccination remained a potential etiology for any health condition determined as a cause of death after the autopsy. We linked register-based data on individual COVID-19 vaccination course and pre-existing health conditions.

We found 428 autopsy cases with a mention of COVID-19 vaccination, and prior to autopsy, vaccination was suspected to play a part in 76 deaths. Post autopsy, a forensic pathologist considered vaccination as a potential etiology in five underlying and seven contributory causes of death. These included seven thromboembolisms, two diabetic ketoacidoses, one myocarditis, one acute pancreatitis, and one eosinophilic granulomatosis with polyangiitis. In relation to the number of vaccinations within Finland, a suspicion of vaccine-related serious adverse reaction was rarely an indication for medicolegal autopsy. Even less frequently was vaccination considered to play a part in the process leading to death, although considerable doubt remains in the accuracy of individual considerations, and autopsy cannot definitively confirm causality between vaccination and death. Regarding vaccination safety, continuing evaluation of suspected vaccine-related deaths is essential, and an autopsy should be part of the investigation when such a suspicion arises.
Was CED the Right Choice? A Decision-Theoretic Evaluation of CMS’s ‘Cover with Evidence Development’ Policy for Aducanumab
Authors: Popp Jonah , Jutkowitz Eric , Trikalinos Thomas
Published: February 2024

Background

In 2022, the Centers for Medicare & Medicaid Services (CMS) issued its final national coverage policy for aducanumab, a novel FDA-approved treatment for Alzheimer’s disease, deciding to ‘Cover with Evidence Development’ (CED). CMS will thus only pay for the treatment of AD patients enrolled in an approved randomized controlled trial (RCT). We sought to understand whether, given current evidence, CED was best from a societal perspective.

Methods

We conducted a modeling-based expected value of sample information analysis to estimate the expected net decision-theoretic value of a further RCT to evaluate the clinical efficacy of high-dose (10 mg/kg) aducanumab and to determine what sized trial, if any, is optimal conditional on an initial decision to cover or not. We also evaluated the expected net benefit of the manufacturer’s proposed RCT (‘ENVISION’). We considered two post-trial decision criteria: cost-effectiveness given updated evidence (‘efficiency’) and does the new trial demonstrate a statistical significant (p<0.05) clinical benefit. Results were used to calculate the expected population net monetary benefit (NMB) of four decision alternatives (including CED) depending on an initial coverage and trial decision. We ranked alternatives and calculated the expected opportunity loss of a suboptimal decision. We used a societal perspective and focused on willingness-to-pay (WTP) values for a quality-adjusted life year (QALY) between $50K-$200K. We conducted scenario analyses using different assumptions about population size, efficacy, and drug cost.

Findings

CMS’s decision to not cover aducanumab avoids an expected societal loss (NMB) of $15B-$110B. Even an optimally designed RCT would confer no or negative decision-theoretic value for WTP≤$100K or with statistical significance as a post-trial decision criterion, respectively, and thus denying coverage without a trial (rather than CED) is clearly preferable. For WTP=$150K (WTP=$200K) and assuming an efficiency criterion, CED with ENVISION or a similar trial is reasonable (decidedly optimal). The case for future research would become less ambiguous if the manufacturer again voluntarily dropped the price ≥50%.

Interpretation

The societal net value of a future trial (and thus CED) depends on how CMS would use the trial results to update its coverage decision and the WTP per QALY. Assuming CMS policymakers can avoid the pitfalls of a legal framework that limits their ability to consider costs in coverage decisions, the CED decision is at least reasonable, if not optimal, if a QALY is valued ≥$150K.
Unbiased characterization of atrial fibrillation phenotypic architecture provides insight to genetic liability and clinically relevant outcomes
Authors: Davogustto Giovanni , Zhao Shilin , Li Yajing , Farber-Eger Eric , Lowery Brandon D. , Shaffer Lauren Lee , Mosley Jonathan D. , Shoemaker M. Benjamin , Xu Yaomin , Roden Dan M. , Wells Quinn S.
Published: February 2024

Background

Atrial Fibrillation (AF) is a common and clinically heterogeneous arrythmia. Machine learning (ML) algorithms can define data-driven disease subtypes in an unbiased fashion, but whether the AF subgroups defined in this way align with underlying mechanisms, such as high polygenic liability to AF or inflammation, and associate with clinical outcomes is unclear.

Methods

We identified individuals with AF in a large biobank linked to electronic health records (EHR) and genome-wide genotyping. The phenotypic architecture in the AF cohort was defined using principal component analysis of 35 expertly curated and uncorrelated clinical features. We applied an unsupervised co-clustering machine learning algorithm to the 35 features to identify distinct phenotypic AF clusters. The clinical inflammatory status of the clusters was defined using measured biomarkers (CRP, ESR, WBC, Neutrophil %, Platelet count, RDW) within 6 months of first AF mention in the EHR. Polygenic risk scores (PRS) for AF and cytokine levels were used to assess genetic liability of clusters to AF and inflammation, respectively. Clinical outcomes were collected from EHR up to the last medical contact.

Results

The analysis included 23,271 subjects with AF, of which 6,023 had available genome-wide genotyping. The machine learning algorithm identified 3 phenotypic clusters that were distinguished by increasing prevalence of comorbidities, particularly renal dysfunction, and coronary artery disease. Polygenic liability to AF across clusters was highest in the low comorbidity cluster. Clinically measured inflammatory biomarkers were highest in the high comorbid cluster, while there was no difference between groups in genetically predicted levels of inflammatory biomarkers. Subgroup assignment was associated with multiple clinical outcomes including mortality, stroke, bleeding, and use of cardiac implantable electronic devices after AF diagnosis.

Conclusion

Patient subgroups identified by unsupervised clustering were distinguished by comorbidity burden and associated with risk of clinically important outcomes. Polygenic liability to AF across clusters was greatest in the low comorbidity subgroup. Clinical inflammation, as reflected by measured biomarkers, was lowest in the subgroup with lowest comorbidities. However, there were no differences in genetically predicted levels of inflammatory biomarkers, suggesting associations between AF and inflammation is driven by acquired comorbidities rather than genetic predisposition.
Interference of mid-level sound statistics underlie human speech recognition sensitivity in natural noise
Authors: Clonan Alex C. , Zhai Xiu , Stevenson Ian H. , Escabí Monty A.
Published: February 2024

Recognizing speech in noise, such as in a busy restaurant, is an essential cognitive skill where the task difficulty varies across environments and noise levels. Although there is growing evidence that the auditory system relies on statistical representations for perceiving1-5and coding4,6-9natural sounds, it’s less clear how statistical cues and neural representations contribute to segregating speech in natural auditory scenes. We demonstrate that human listeners rely on mid-level statistics to segregate and recognize speech in environmental noise. Using natural backgrounds and variants with perturbed spectro-temporal statistics, we show that speech recognition accuracy at a fixed noise level varies extensively across natural backgrounds (0% to 100%). Furthermore, for each background the unique interference created by summary statistics can mask or unmask speech, thus hindering or improving speech recognition. To identify the neural coding strategy and statistical cues that influence accuracy, we developedgeneralized perceptual regression, a framework that links summary statistics from a neural model to word recognition accuracy. Whereas a peripheral cochlear model accounts for only 60% of perceptual variance, summary statistics from a mid-level auditory midbrain model accurately predicts single trial sensory judgments, accounting for more than 90% of the perceptual variance. Furthermore, perceptual weights from the regression framework identify which statistics and tuned neural filters are influential and how they impact recognition. Thus, perception of speech in natural backgrounds relies on a mid-level auditory representation involving interference of multiple summary statistics that impact recognition beneficially or detrimentally across natural background sounds.

Significance Statement

Recognizing speech in natural auditory scenes with competing talkers and environmental noise is a critical cognitive skill. Although normal listeners effortlessly perform this task, for instance in a crowded restaurant, it challenges individuals with hearing loss and our most sophisticated machine systems. We tested human participants listening to speech in natural noises with varied statistical characteristics and demonstrate that they rely on a statistical representation of sounds to segregate speech from environmental noise. Using a model of the auditory system, we then demonstrate that a brain inspired statistical representation of natural sounds accurately predicts human perceptual trends across wide range of natural backgrounds and noise levels and reveals key statistical features and neural computations underlying human abilities for this task.
A haplotype-resolved reference genome ofQuercus albasheds light on the evolutionary history of oaks
Authors: Larson Drew A. , Staton Margaret E. , Kapoor Beant , Islam-Faridi Nurul , Zhebentyayeva Tetyana , Fan Shenghua , Stork Jozsef , Thomas Austin , Ahmed Alaa S. , Stanton Elizabeth C. , Houston Allan , Schlarbaum Scott E. , Hahn Matthew W. , Carlson John E. , Abbott Albert G. , DeBolt Seth , Dana Nelson C.
Published: February 2024

White oak (Quercus alba) is an abundant forest tree species across eastern North America that is ecologically, culturally, and economically important.

We report the first haplotype-resolved chromosome-scale genome assembly ofQ. albaand conduct comparative analyses of genome structure and gene content against other published Fagaceae genomes. In addition, we probe the genetic diversity of this widespread species and investigate its phylogenetic relationships with other oaks using whole-genome data.

Our genome assembly comprises two haplotypes each consisting of 12 chromosomes. We found that the species has high genetic diversity, much of which predates the divergence ofQ. albafrom other oak species and likely impacts divergence time estimation inQuercus. Our phylogenetic results highlight phylogenetic discordance across the genus and suggest different relationships among North American oaks than have been reported previously. Despite a high preservation of chromosome synteny and genome size across theQuercusphylogeny, certain gene families have undergone rapid changes in size including resistance genes (R genes).

The white oak genome represents a major new resource for studying genome diversity and evolution inQuercusand forest trees more generally. Future research will continue to reveal the full scope of genomic diversity across the white oak clade.
A selection of Golden Gate vectors to simplify recombinant protein production inEscherichia coli
Authors: Fairhead Michael , Koekemoer Lizbe , Williams Eleanor , von Delft Frank
Published: February 2024

In this work multiple plasmids have been created to allow the simple Golden Gate cloning of a target gene for recombinant protein production inEscherichia coli. To simplify as much as possible the generation of different target gene vector combinations, the 22 plasmids contain the same Golden Gate cloning sites (BsaI), antibiotic resistance (kanamycin) and promoter (T7) for expression in the standard protein production strain ofE. coliBL21[DE3]. The plasmid set includes commonly used tags for purification and assays (his, twin-strep and avi tag) as well as fusion protein partners that may aid target protein solubility and yield, SUMO, MBP, GST and sfGFP. Also included are plasmids with secretion peptide signals for transport of the target protein to theE. coliperiplasmviavarious pathways (SEC, SRP, TatA).

We have evaluated the 4 of the vectors using a test super folder GFP insert and found that using the Golden Gate process allows cloning efficiencies of greater than 90% to be routinely obtained. Vectors were further evaluated by expressing and purifying the target insert. The plasmid vector set described herein should prove useful to any investigator who has to routinely evaluate numerous protein expression constructs and are freely available through Addgene.
Pseudotyped virus infection of multiplexed ACE2 libraries reveals SARS-CoV-2 variant shifts in receptor usage
Authors: Shukla Nidhi , Roelle Sarah M. , Snell John C. , DelSignore Olivia , Bruchez Anna M. , Matreyek Kenneth A.
Published: February 2024

Pairwise compatibility between virus and host proteins can dictate the outcome of infection. During transmission, both inter- and intraspecies variabilities in receptor protein sequences can impact cell susceptibility. Many viruses possess mutable viral entry proteins and the patterns of host compatibility can shift as the viral protein sequence changes. This combinatorial sequence space between virus and host is poorly understood, as traditional experimental approaches lack the throughput to simultaneously test all possible combinations of protein sequences. Here, we created a pseudotyped virus infection assay where a multiplexed target-cell library of host receptor variants can be assayed simultaneously using a DNA barcode sequencing readout. We applied this assay to test a panel of 30 ACE2 orthologs or human sequence mutants for infectability by the original SARS-CoV-2 spike protein or the Alpha, Beta, Gamma, Delta, and Omicron BA1 variant spikes. We compared these results to an analysis of the structural shifts that occurred for each variant spike’s interface with human ACE2. Mutated residues were directly involved in the largest shifts, although there were also widespread indirect effects altering interface structure. The N501Y substitution in spike conferred a large structural shift for interaction with ACE2, which was partially recreated by indirect distal substitutions in Delta, which does not harbor N501Y. The structural shifts from N501Y greatly influenced the set of animal orthologs the variant spike was capable of interacting with. Out of the thirteen non-human orthologs, ten exhibited unique patterns of variant-specific compatibility, demonstrating that spike sequence changes during human transmission can toggle ACE2 compatibility and potential susceptibility of other animal species, and cumulatively increase overall compatibilities as new variants emerge. These experiments provide a blueprint for similar large-scale assessments of protein compatibility during entry by diverse viruses. This dataset demonstrates the complex compatibility relationships that occur between variable interacting host and virus proteins.
LbCas12-mediated multiplex gene editing and 2-fluoroadenine counter-selection inPhytophthora palmivora
Authors: Verhoeven Tim , Pluis Max HJ , Peippo Maaria , Couillaud Gabriel , van den Berg Grardy CM , Evangelisti Edouard
Published: February 2024

CRISPR-Cas systems have moved forward genetic engineering in virtually any organism amenable to genetic modification. In particular, these systems have unlocked unprecedented possibilities to generate mutants in oomycetes, a group of filamentous microbes comprising over two hundredPhytophthoraspecies, including the cacao killerPhytophthora palmivora. Here, we showcase multiplex gene editing inP. palmivorausing LbCas12. We have developed a straightforward protocol to simultaneously knock out two genes encoding adenine phosphoribosyltransferase (APT), an essential enzyme of the purine salvage pathway. We show thatAPTknockouts (ΔPpATP1/2) are insensitive to 2-fluoroadenine (2-FA) and retain full virulence onNicotiana benthamiana. We rely on zoospore electroporation using an all-in-one construct to facilitate the rapid editing of multiple genes. This work enhances the genetic toolbox forPhytophthoraspecies and simplifies the exploration of gene function, laying the groundwork for future innovations aiming to tackle oomycete plant diseases.
MicroRNA-29a-5p Attenuates Oxygen-glucose Deprivation and Reoxygenation Injury in Astrocytes by Targeting Glycogen Synthase Kinase 3β
Authors: Li Chang-Luo , Zhuang Jin-Kun , Liu Zhong , Huang Zhong-Run , Xiang Chun , Shi Zhong-Song
Published: February 2024

Background

Cerebral ischemia-reperfusion injury (CIRI) after endovascular reperfusion treatment is associated with adverse prognosis in acute ischemic stroke patients. MicroRNAs contribute to CIRI and become the diagnostic and prognosis biomarkers for acute ischemic stroke. In this study, we investigate the role of microRNA-29a-5p in CIRI in the oxygen-glucose deprivation and reoxygenation (OGD/R) model of neurovascular cells.

Methods

The expression of microRNA-29a-5p in rat neurons, astrocytes, brain microvascular endothelial cells, microglia, and pericytes model of OGD/R were assessed. The astrocyte injury, phenotype shifting of reactive astrocytes, and regulation of microRNA-29a-5p target genes were evaluated after microRNA-29a-5p mimics and inhibitors treatment in the OGD/R model.

Results

MicroRNA-29a-5p decreased in the astrocyte model 24 hours after OGD/R but did not significantly change in the other neurovascular cells after OGD/R. Twelve predicted target genes for microRNA-29a-5p were significantly differentially expressed in the astrocyte OGD/R model; eleven participated in the Wnt signaling pathway. Increased microRNA-29a-5p alleviated astrocyte injury and cell apoptosis. Overexpression of microRNA-29a-5p suppressed neurotoxic A1 astrocyte markers of complement 3, FK506 binding protein 51, and Serping1 and increased neuroprotective A2 astrocyte markers of S100a10, Pentraxin 3, and Emp1. MicroRNA-29a-5p effectively regulated the direct target gene of Glycogen synthase kinase (GSK)-3β expression and its downstream β-catenin in astrocytes after OGD/R.

Conclusions

MicroRNA-29a-5p alleviated astrocyte injury, transformed the A1/A2 phenotype of reactive astrocyte, and regulated its direct target gene of GSK-3β and its downstream mediator of β-catenin in astrocytes after OGD/R. Astrocytic microRNA-29a-5p may be a protective target for reducing CIRI.
Mitigation of Fetal Irradiation Injury from Mid-Gestation Total Body Radiation with Mitochondrial-Targeted GS-Nitroxide JP4-039
Authors: Wu Yijen L. , Christodoulou Anthony G. , Beumer Jan H. , Rigatti Lora H. , Fisher Renee , Ross Mark , Watkins Simon , Cortes Devin R. E. , Ruck Cody , Manzoor Shanim , Wyman Samuel K. , Stapleton Margaret C. , Goetzman Eric , Bharathi Sivakama , Wipf Peter , Tan Tuantuan , Eiseman Julie L. , Christner Susan M. , Guo Jianxia , Lo Cecilia W. Y. , Epperly Michael W. , Greenberger Joel S.
Published: February 2024

Victims of a radiation terrorist event will include pregnant women and unborn fetuses. Mitochondrial dysfunction and oxidative stress are key pathogenic factors of fetal irradiation injury. The goal of this preclinical study is to investigate the efficacy of mitigating fetal irradiation injury by maternal administration of the mitochondrial-targeted gramicidin S (GS)- nitroxide radiation mitigator, JP4-039. Pregnant female C57BL/6NTac mice received 3 Gy total body ionizing irradiation (TBI) at mid-gestation embryonic day 13.5 (E13.5). Using novel time- and-motion-resolved 4Din uteromagnetic resonance imaging (4D-uMRI), we found TBI caused extensive injury to the fetal brain that included cerebral hemorrhage, loss of cerebral tissue, and hydrocephalus with excessive accumulation of cerebrospinal fluid (CSF). Histopathology of the fetal mouse brain showed broken cerebral vessels and elevated apoptosis. Further use of novel 4D Oxy-wavelet MRI capable of probingin vivomitochondrial function in intact brain revealed significant reduction of mitochondrial function in the fetal brain after 3Gy TBI. This was validated byex vivoOroboros mitochondrial respirometry. Maternal administration JP4-039 one day after TBI (E14.5), which can pass through the placental barrier, significantly reduced fetal brain radiation injury and improved fetal brain mitochondrial respiration. This also preserved cerebral brain tissue integrity and reduced cerebral hemorrhage and cell death. As JP4-039 administration did not change litter sizes or fetus viability, together these findings indicate JP4-039 can be deployed as a safe and effective mitigator of fetal radiation injury from mid-gestational in utero ionizing radiation exposure.

One Sentence Summary

Mitochondrial-targeted gramicidin S (GS)-nitroxide JP4-039 is safe and effective radiation mitigator for mid-gestational fetal irradiation injury.
Molecular signatures of cortical expansion in the human fetal brain
Authors: Ball G. , Oldham S. , Kyriakopoulou V. , Williams L. Z. J. , Karolis V. , Price A. , Hutter J. , Seal M.L. , Alexander-Bloch A. , Hajnal J.V. , Edwards A.D. , Robinson E.C. , Seidlitz J.
Published: February 2024

The third trimester of human gestation is characterised by rapid increases in brain volume and cortical surface area. A growing catalogue of cells in the prenatal brain has revealed remarkable molecular diversity across cortical areas.1,2Despite this, little is known about how this translates into the patterns of differential cortical expansion observed in humans during the latter stages of gestation. Here we present a new resource, μBrain, to facilitate knowledge translation between molecular and anatomical descriptions of the prenatal developing brain. Built using generative artificial intelligence, μBrain is a three-dimensional cellular-resolution digital atlas combining publicly-available serial sections of the postmortem human brain at 21 weeks gestation3with bulk tissue microarray data, sampled across 29 cortical regions and 5 transient tissue zones.4Using μBrain, we evaluate the molecular signatures of preferentially-expanded cortical regions during human gestation, quantifiedin uterousing magnetic resonance imaging (MRI). We find that differences in the rates of expansion across cortical areas during gestation respect anatomical and evolutionary boundaries between cortical types5and are founded upon extended periods of upper-layer cortical neuron migration that continue beyond mid-gestation. We identify a set of genes that are upregulated from mid-gestation and highly expressed in rapidly expanding neocortex, which are implicated in genetic disorders with cognitive sequelae. Our findings demonstrate a spatial coupling between areal differences in the timing of neurogenesis and rates of expansion across the neocortical sheet during the prenatal epoch. The μBrain atlas is available from:https://garedaba.github.io/micro-brain/and provides a new tool to comprehensively map early brain development across domains, model systems and resolution scales.