bluuebunny/crossref_metadata_2025 huggingface dataset:
Responses of the hyper-diverse community of canopy-dwelling Hymenoptera to oak decline
Authors: Le Souchu E. , Cours J. , Cochenille T. , Bouget C. , Bankhead-Dronnet S. , Braet Y. , Burguet P. , Gabard C. , Galkowski C. , Gereys B. , Herbrecht F. , Joncour B. , Marhic E. , Michez D. , Buhl P. Neerup , Noblecourt T. , Notton D. G. , Penigot W. , Rasplus J.-Y. , Robert T. , Staverlokk A. , Vincent-Barbaroux C. , Sallé A.
Published: July 2023

Forest decline and dieback are growing phenomena worldwide, resulting in severe, large-scale degradation of the canopy. This can profoundly alter the provision of trophic resources and microhabitats for canopy-dwelling arthropods.

In 2019, we assessed the effect of oak decline on the community of canopy-dwelling Hymenoptera. We selected 21 oak stands, and 42 plots, located in three forests in France, presenting contrasting levels of decline. Insects were sampled at the canopy level with green multi-funnel and flight-interception traps.

We collected a particularly diverse community of 19,289 insect individuals belonging to 918 taxa, ten larval trophic guilds and five nesting guilds.

Oak decline had no effect on the abundance or richness of the overall community, but significantly reshaped the community assemblages. Decline had contrasting effects depending on the taxa and guilds considered. Specialist parasitoids were more abundant at intermediate levels of decline severity while generalists were negatively affected. Taxa depending on ground-related resources and microhabitats were promoted. Saproxylic taxa were more abundant while xylophagous insects were negatively impacted.

Reduced leaf area index promoted several guilds, and the diversity of the overall community. While an increasing tree mortality rate enhanced the abundance and diversity of deadwood resources, it had negative impacts on several Hymenoptera guilds. Our results suggest that micro-environmental changes at the ground-level due to canopy decline have major cascading effects on the communities of canopy-dwelling Hymenoptera.

Our study highlights the relevance of studying Hymenoptera communities to investigate the outcomes of disturbances on forest biodiversity.
Depletion of alloreactive B cells by chimeric alloantigen receptor T cells with drug resistance to prevent antibody-mediated rejection in solid organ transplantation
Authors: Dragon Anna C. , Bonifacius Agnes , Verboom Murielle , Hudecek Michael , Figueiredo Constanca , Blasczyk Rainer , Eiz-Vesper Britta
Published: July 2023

In the present study, we developed a novel cell therapy approach to selectively combat antibody-mediated rejection (AMR), a major and unresolved complication after solid organ transplantation (SOT) caused by donor-HLA-specific, alloreactive B cells. Current treatment options including B-cell depletion protocols are inefficient and result in complete loss of humoral immunity. To selectively eliminate alloreactive B cells characterized by corresponding anti-donor-HLA B-cell receptors (BCRs), we engineered T cells with a novel chimeric receptor comprising a truncated HLA molecule fused to intracellular 4-1BB/CD3ξ signaling domains to generate T cells overcoming rejection by antibodies (CORA-Ts). As proof-of-concept, CORA receptors based on HLA-A*02 were shown to bind anti-HLA-A*02 antibodies from the serum of kidney transplant recipients, indicating their suitability to also target the respective membrane-bound anti-HLA-A*02 BCRs on alloreactive B cells. In co-cultures with B-cell lines expressing and releasing anti-HLA-A*02 antibodies, CORA-Ts were specifically activated, released pro-inflammatory cytokines (e.g. IFN-γ, granzyme B), and exhibited strong cytotoxicity resulting in an effective reduction of anti-HLA-A*02 antibody release. A modification of the HLA-A*02 α3-domain within the CORA receptor effectively abrogated T-cell sensitization. Additionally, using CRISPR/Cas9-mediated knockout of a selected binding protein, CORA-Ts were able to resist immunosuppressive treatment to ensure high efficiency in transplant patients. Our results demonstrate that CORA-Ts are able to specifically recognize and eliminate alloreactive B cells, and thus selectively prevent formation of anti-HLA antibodies even under immunosuppressive conditions. This suggests CORA-Ts as potent novel approach to specifically combat AMR and improve long-term graft survival in SOT patients while preserving their overall B-cell immunity.
Opposing functions of glutamatergic inputs between the globus pallidus external segment and substantia nigra pars reticulata
Authors: Yoshida Atsushi , Hikosaka Okihide
Published: July 2023

The indirect pathway of the basal ganglia, including the subthalamic nucleus (STN) and globus pallidus external segment (GPe), is believed to play a crucial role in suppressing involuntary movements. However, recent evidence suggests the STN and GPe also facilitate voluntary movements. This study hypothesized that excitatory inputs from the STN to the GPe contribute to this facilitation, and that excitatory projections to the substantia nigra pars reticulata (SNr) are involved in the inhibition. To disrupt the STN-GPe or STN-SNr projections in monkeys during choice and fixation tasks, glutamate receptor inhibitors were injected into the GPe or SNr, which induced delayed saccade latencies toward good choices in the choice task (GPe) and caused frequent reflexive saccades to objects in the fixation task (SNr). Our findings suggest excitatory inputs to the GPe and SNr work in opposing manners, providing new insights that redefine our understanding of the functions of basal ganglia pathways.

Highlights

STN and GPe neuronal activity increased when good objects were chosen

SNr activity increased when rejecting bad objects and decreased when accepting good objects

Excitatory inputs inactivation in the GPe caused delayed saccade to good objects

Excitatory projection inhibition to the SNr suppressed involuntary saccade control
Learning attentional templates for value-based decision-making
Authors: Jahn Caroline I. , Markov Nikola T. , Morea Britney , Ebitz R. Becket , Buschman Timothy J.
Published: July 2023

Attention filters sensory inputs to enhance task-relevant information. It is guided by an ‘attentional template’ that represents the stimulus features that are relevant for the current task. To understand how the brain learns and uses new templates, we trained monkeys to perform a visual search task that required them to repeatedly learn new attentional templates. Neural recordings found templates were represented across prefrontal and parietal cortex in a structured manner, such that perceptually neighboring templates had similar neural representations. When the task changed, a new attentional template was learned by incrementally shifting the template towards rewarded features. Finally, we found attentional templates transformed stimulus features into a common value representation that allowed the same decision-making mechanisms to deploy attention, regardless of the identity of the template. Altogether, our results provide new insight into the neural mechanisms by which the brain learns to control attention and how attention can be flexibly deployed across tasks.
Evidence for ecological tuning of novel anuran biofluorescent signals
Authors: Whitcher Courtney , Ron Santiago R. , Ayala-Varela Fernando , Crawford Andrew , Herrera-Alva Valia , Castillo-Urbina Ernesto , Grazziotin Felipe , Bowman Randi M. , Lemmon Alan R. , Lemmon Emily Moriarty
Published: July 2023

Our study assesses the variability of amphibian biofluorescence and provides insight into its potential functions and role in anuran evolution. Via a field survey across South America, we discovered and documented patterns of biofluorescence in tropical amphibians. We more than tripled the number of species that have been tested for this trait and added representatives from previously untested anuran families. We found evidence for ecological tuning (i.e., the specific adaptation of a signal to the environment in which it is received) of the novel anuran biofluorescent signals. Across groups, the fluorescence excitation peak matches the wavelengths most available at twilight, the light environment in which most frog species are active. Additionally, biofluorescence emission spans both wavelengths of low availability in twilight and the peak sensitivity of green-sensitive rods in the anuran eye, likely increasing contrast of this signal for a conspecific receiver. With evidence of tuning to the ecology and sensory systems of frogs, our results suggest frog biofluorescence is likely functioning in anuran communication.
Population genetics ofGlossina palpalis gambiensisin the sleeping sickness focus of Boffa (Guinea) before and after eight years of vector control: no effect of control despite a significant decrease of human exposure to the disease
Authors: Kagbadouno Moise S. , Séré Modou , Ségard Adeline , Camara Abdoulaye Dansy , Camara Mamadou , Bucheton Bruno , Bart Jean-Mathieu , Courtin Fabrice , de Meeûs Thierry , Ravel Sophie
Published: July 2023

Human African trypanosomosis (HAT), also known as sleeping sickness, is still a major concern in endemic countries. Its cyclical vector are biting insects of the genusGlossinaor tsetse flies. In Guinea, the mangrove ecosystem contains the main HAT foci of Western Africa. There, the cyclical vector isGlossina palpalis gambiensis. A still ongoing vector control campaign (VCC) started in 2011 in the focus of Boffa, using tiny targets, with a 79% tsetse density reduction in 2016 and significant impact on the prevalence of the disease (from 0.3% in 2011 to 0.11% in 2013, 0.0352% in 2016 and 0.0097% in 2019). To assess the sustainability of these results, we have studied the impact of this VCC on the population biology ofG. p. gambiensisin Boffa. We used the genotyping at 11 microsatellite markers and population genetic tools of tsetse flies from different sites and at different dates before and after the beginning of the VCC. In variance with a significant impact of VCC on the apparent densities of flies captured in the traps deployed, the global population ofG. p. gambiensisdisplayed no variation of the sex-ratio, no genetic signature of control, and behaved as a very large population occupying the entire zone. This implies that targets deployment efficiently protected the human populations locally, but did not impact tsetse flies where targets cannot be deployed and where the main tsetse population exploits available resources. We thus recommend the pursuit of vector control measures with the same strategy, through the joint effect of VCC and medical surveys and treatments, in order to protect human populations from HAT infections until the disease can be considered as entirely eradicated from the focus.
Laser microdissection, proteomics and multiplex immunohistochemistry: a bumpy ride into the study of paraffin-embedded fetal and pediatric lung tissues
Authors: Cardoso dos Santos L.M. , Avila Y. , Schvartz D. , Rougemont A-L , Bochaton-Piallat M-L , Ruchonnet-Metrailler I.
Published: July 2023

Background

Knowledge about lung development or lung disease is mainly derived from data extrapolated from mouse models. This comes with obvious drawbacks in developmental diseases, particularly due to species differences. Our objective is to describe the development of complementary analysis methods that will allow a better understanding of the molecular mechanisms involved in the pathogenesis of rare congenital diseases.

Methods

Paraffin-embedded human pediatric and fetal lung samples were laser microdissected to enrich different lung regions, namely bronchioli or alveoli. These samples were analyzed by data independent acquisition-based quantitative proteomics and lung structures were subsequently compared. To confirm the proteomic data, we employed and optimizedSequentialIMmunoPeroxidaseLabeling andErasing (SIMPLE) staining for specific proteins of interest.

Results

By quantitative proteomics, we identified typical pulmonary proteins from being differentially expressed in the different regions. While the receptor for advanced glycation end products (RAGE), surfactant protein C (SFTPC) were downregulated, tubulin beta 4B (TUBB4B) was upregulated in bronchioli, compared to alveoli. In fetal tissue, CD31 was downregulated in fetal bronchioli, compared to canaliculi. Moreover, we confirmed their presence using SIMPLE staining. Some expected proteins did not show up in the proteomic data, like SOX-9 that was only detected by means of immunohistochemistry in the SIMPLE analysis.

Conclusion

Our data underlines the robustness and applicability of this type of experimental approach, especially for rare paraffin-embedded tissue samples. It also strengthens the importance of these methods for future studies, in particular, when considering developmental lung diseases, such as congenital lung anomalies.
Improved chromosome-level genome assembly for marigold (Tagetes erecta)
Authors: Jiang Fan , Yuan Lihua , Wang Sen , Wang Hengchao , Xu Dong , Wang Anqi , Fan Wei
Published: July 2023

Marigold (Tagetes erectaL.) is a popular ornamental plant of the Asteraceae family, and its petals are considered the most abundant source of lutein. A low-continuity chromosome-level genome sequence of marigold was published recently, with poor annotation of the protein-coding genes, which hinders the studies of lutein biosynthesis. Here, we generated a near telomere-to-telomere level genome assembly of marigold based on highly accurate high-fidelity (HiFi) long reads and Hi-C sequencing data. Compared to the previously reported marigold genome, the current assembly had obviously higher contiguity and higher completeness of gene set. The current genome assembly has a 27-fold increase in contig N50 size, a 12.1% increase in chromosome anchoring rate, and a 9.0% increase in BUSCO complete rate for the gene set. Besides, the current assembly has much fewer assembly errors. Based on this high-quality genome assembly, we found that the 170-bp repeats are the most abundant centromeric unit and all centromeric regions are distributed along the whole chromosomes for all 12 centromeres, indicating the existence of the holocentromeres in marigold. In addition, we analyzed the structure and phylogenetic relationship of the fourPSYgenes, and revealed that these genes have diversified and possibly executed different functions in various tissues. Our near telomere-to-telomere level genome assembly and comprehensive gene annotation will greatly facilitate the breeding of marigold and researches aimed at improving lutein production.
Burstprop for Learning in Spiking Neuromorphic Hardware
Authors: Stuck Mike , Naud Richard
Published: July 2023

The need for energy-efficient solutions in Deep Neural Network (DNN) applications has led to a growing interest in Spiking Neural Networks (SNNs) implemented in neuromorphic hardware. The Burstprop algorithm enables online and local learning in hier-archical networks, and therefore can potentially be implemented in neuromorphic hardware. This work presents an adaptation of the algorithm for training hierarchical SNNs on MNIST. Our implementation requires an order of magnitude fewer neurons than the previous ones. While Burstprop outper-forms Spike-timing dependent plasticity (STDP), it falls short compared to training with backpropagation through time (BPTT). This work establishes a foundation for further improvements in the Burst-prop algorithm, developing such algorithms is essential for achieving energy-efficient machine learning in neuromorphic hardware.
Inhibition of skeletal muscle Lands cycle ameliorates weakness induced by physical inactivity
Authors: Shahtout Justin L. , Eshima Hiroaki , Ferrara Patrick J. , Maschek J. Alan , Cox James E. , Drummond Micah J. , Funai Katsuhiko
Published: July 2023

Background

Lipid hydroperoxides (LOOH) have been implicated in skeletal muscle atrophy with age and disuse. Lysophosphatidylcholine acyltransferase 3 (LPCAT3), an enzyme of Lands cycle, conjugates a polyunsaturated fatty acyl chain to a lysophospholipid (PUFA-PL) molecule, providing substrates for LOOH propagation. Previous studies suggest that inhibition of Lands cycle is an effective strategy to suppress LOOH. Mice with skeletal muscle-specific tamoxifen-inducible knockout of LPCAT3 (LPCAT3-MKO) were utilized to determine if muscle-specific attenuation of LOOH may alleviate muscle atrophy and weakness with disuse.

Methods

LPCAT3-MKO and control mice underwent 7 days of sham or hindlimb unloading (HU model) to study muscle mass and force-generating capacity. LOOH was assessed by quantifying 4-hydroxynonenal (4-HNE)-conjugated peptides. Quantitative PCR and lipid mass spectrometry were used to validate LPCAT3 deletion.

Results

7 days of HU was sufficient to induce muscle atrophy and weakness concomitant to an increase in 4-HNE. Deletion of LPCAT3 reversed HU-induced increase in muscle 4HNE. No difference was found in body mass, body composition, or caloric intake between genotypes. The soleus (SOL) and plantaris (PLANT) muscles of the LPCAT3-MKO mice were partially protected from atrophy compared to controls, concomitant to attenuated decrease in cross-sectional areas in type I and IIa fibers. Strikingly, SOL and extensor digitorum longus (EDL) were robustly protected from HU-induced reduction in force-generating capacity in the LPCAT3-MKO mice compared to controls.

Conclusion

Our findings demonstrate that attenuation of muscle LOOH is sufficient to restore skeletal muscle function, in particular a protection from reduction in muscle specific force. Thus, muscle LOOH contributes to atrophy and weakness induced by HU in mice.
Quantifying Myelin Water Fraction in a Guinea Pig Model of Spontaneous Intrauterine Growth Restriction
Authors: Sethi Simran , Friesen-Waldner Lanette J. , Regnault Timothy R.H. , McKenzie Charles A.
Published: July 2023

Intrauterine growth restriction (IUGR) is an obstetrical outcome where a fetus has not achieved its genetic potential. A consequence of IUGR is a decrease in brain myelin content. Myelin water imaging (MWI) has previously assessed fetal myelin water fraction (MWF) and can potentially assess myelination changes associated with IUGR. Thus, this study aims to quantify and compare the MWF of non-IUGR and IUGR fetal guinea pigs (GPs) in late gestation. Our sample consisted of 22 pregnant Dunkin-Hartley GPs with 71 fetuses (34 male) [mean ± standard deviation: 60 ± 1.2 days gestation]. Eight SPGR volumes [flip angles (α): 2° – 16°], and two sets of 8 bSSFP volumes (α: 8° – 64°), at 0° and 180° phase increments were acquired at 3.0 T. MWF maps were generated for each fetal GP brain using multicomponent driven equilibrium single pulse observation of T1/T2(mcDESPOT). Regions of interest (ROIs) were placed in the fetal corpus callosum (CC), fornix (FOR), and parasagittal white matter (PSW). Linear regression was performed between five fetal IUGR markers [body volume (BV), body-to-pregnancy volume ratio (BPrVR), brain-to-liver VR (BLVR), brain-to-placenta VR (BPlVR), and brain-to-BVR (BBVR)] and MWF for all regions (coefficient of determination, R2). A t-test with a linear mixed model compared the MWF of non-IUGR and IUGR fetal GPs for all three regions (α = 0.05). The MWF values are as follows: (mean ± standard deviation): 0.23 ± 0.02 (fetal CC), 0.19 ± 0.02 (fetal CC – IUGR), 0.31 ± 0.02 (fetal FOR), 0.27 ± 0.01 (fetal FOR – IUGR), 0.28 ± 0.02 (fetal PSW), and 0.24 ± 0.03 (fetal PSW – IUGR). Significant differences in MWF were found between the non-IUGR and IUGR fetuses in every region. In conclusion, the mean MWF of IUGR fetal GPs is significantly lower than non-IUGR fetal GPs.
Architectural asymmetry enables DNA transport through theHelicobacter pylori cagtype IV secretion system
Authors: Ryan Mackenzie E. , Damke Prashant P. , Bryant Caitlynn , Sheedlo Michael J. , Shaffer Carrie L.
Published: July 2023

Structural asymmetry within secretion system architecture is fundamentally important for apparatus diversification and biological function. However, the mechanism by which symmetry mismatch contributes to nanomachine assembly and interkingdom effector translocation are undefined. Here, we show that architectural asymmetry orchestrates dynamic substrate selection and enables trans-kingdom DNA conjugation through theHelicobacter pylori cagtype IV secretion system (cagT4SS). Structural analyses of asymmetric units within thecagT4SS periplasmic ring complex (PRC) revealed intermolecular π-π stacking interactions that coordinate DNA binding and license trans-kingdom conjugation without disrupting the translocation of protein and peptidoglycan effector molecules. Additionally, we identified a novel proximal translocation channel gating mechanism that regulates cargo loading and governs substrate transport across the outer membrane. We thus propose a model whereby the organization and geometry of architectural symmetry mismatch exposes π−π interfaces within the PRC to facilitate DNA transit through thecagT4SS translocation channel.
The management of blunt pancreatic injury in children in New South Wales
Authors: Chung Sally T W , Holland Andrew J A , Brown Julie , Adams Susan E
Published: July 2023

Background

Blunt pancreatic injury is uncommon but associated with considerable morbidity. The optimal management strategy for children with this injury remains unclear, with laparotomy rates in North America of up to 55%. This has not been studied at a population level in Australia. This study aimed to examine the management of children with blunt pancreatic injury in New South Wales (NSW), Australia.

Methods

Using the NSW Admitted Patient Data Collection from 2001 to 2019, we identified patients <16 years old with blunt pancreatic injury. Cases were categorised as undergoing non-operative or operative management. Patient and injury characteristics and outcomes were compared between non-operative and operative groups. Independent predictors of operative management were identified using multivariable logistic regression.

Results

139 cases were identified: 37 (26.6%) underwent operative management, of whom 11 (29.7%) had a pancreas-specific operation. Two-thirds were managed at a paediatric trauma centre. Operation rates were highest in adult trauma centres, although treatment outside a paediatric trauma centre overall was not associated with operative management. Independent predictors of operative management were high-grade pancreatic injury, hollow viscus injury and transfusion. Morbidity and mortality were 30.2% and 1.4%, respectively.

Conclusion

Blunt pancreatic injury continues to carry substantial morbidity. Operation rates in NSW are lower than those reported in North America, with similar outcomes. Unlike other solid organ injuries, most children are managed at paediatric trauma centres. Future studies should investigate factors driving management decisions in the Australian context, with the aim of developing paediatric guidelines promoting non-operative management.

Highlights

Operation rates for children with BPI were much lower than reported in international studies, with comparable morbidity and lower mortality.

Operation rates were highest at ATCs, although, overall, children with BPI managed outside PTCs were not more likely to undergo an operation.

Penetrating pancreatic injury is rare compared to the US, likely reflecting that firearm-related injury in Australia remains uncommon.
Positive Airway Pressure Therapy Predicts Lower Mortality and Major Adverse Cardiovascular Events Incidence in Medicare Beneficiaries with Obstructive Sleep Apnea
Authors: Mazzotti Diego R , Waitman Lemuel R. , Miller Jennifer , Sundar Krishna M. , Stewart Nancy H. , Gozal David , Song Xing ,   Greater Plains Collaborative
Published: July 2023

Background

Obesity is associated with obstructive sleep apnea (OSA) and cardiovascular risk. Positive airway pressure (PAP) is the first line treatment for OSA, but evidence on its beneficial effect on major adverse cardiovascular events (MACE) prevention is limited. Using claims data, the effects of PAP on mortality and incidence of MACE among Medicare beneficiaries with OSA were examined.

Methods

A cohort of Medicare beneficiaries with ≥2 distinct OSA claims was defined from multi-state, state-wide, multi-year (2011-2020) Medicare fee-for-service claims data. Evidence of PAP initiation and utilization was based on PAP claims after OSA diagnosis. MACE was defined as a composite of myocardial infarction, heart failure, stroke, or coronary revascularization. Doubly robust Cox proportional hazards models with inverse probability of treatment weights estimated treatment effects controlling for sociodemographic and clinical factors.

Results

Among 888,835 beneficiaries with OSA (median age 73 years; 43.9% women; median follow-up 1,141 days), those with evidence of PAP initiation (32.6%) had significantly lower all-cause mortality (HR [95%CI]: 0.53 [0.52-0.54]) and MACE incidence risk (0.90 [0.89-0.91]). Higher quartiles of annual PAP claims were progressively associated with lower mortality (Q2: 0.84 [0.81-0.87], Q3: 0.76 [0.74-0.79], Q4: 0.74 [0.72-0.77]) and MACE incidence risk (Q2: 0.92 [0.89-0.95], Q3: 0.89 [0.86-0.91], Q4: 0.87 [0.85-0.90]).

Conclusion

PAP utilization was associated with lower all-cause mortality and MACE incidence among Medicare beneficiaries with OSA. Results might inform trials assessing the importance of OSA therapy towards minimizing cardiovascular risk and mortality in older adults.
Mid- and long-term risk of atrial fibrillation among breast cancer surgery survivors
Authors: Park Yong-Moon Mark , Jung Wonyoung , Yeo Yohwan , Park Sang Hyun , Fradley Michael G. , Malapati Sindhu J. , Tarun Tushar , Raj Vinay , Lee Hong Seok , Naqvi Tasneem Z. , Henry-Tillman Ronda S. , Mehta Jawahar L. , Schootman Mario , Amick Benjamin C. , Han Kyungdo , Shin Dong Wook
Published: July 2023

Background

The mid- and long-term risk of incident atrial fibrillation (AF) among breast cancer survivors, especially for younger women, and cancer treatment effects on the association remain unclear. We aimed to investigate the risk of AF among breast cancer survivors and evaluate the association by age group, length of follow-up, and cancer treatment.

Methods

Using data from the Korean Health Insurance Service database between January 2010 and December 2017, 113,232 women newly diagnosed with breast cancer (aged ≥18 years) without prior AF history who underwent breast cancer surgery were individually matched 1:5 by birth year to a sample female population without cancer (n=566,160). Sub-distribution hazard ratios (sHRs) and 95% confidence intervals (CIs) considering death as a competing risk were estimated, adjusting for sociodemographic factors and cardiovascular/non-cardiovascular comorbidities.

Results

During follow-up (mean [SD] follow-up, 5.1 [2.1] years), AF developed in 1,166 (1.0%) breast cancer surgery survivors at least 1 year after enrollment. Overall, breast cancer survivors had a slightly increased AF risk compared to their cancer-free counterparts (sHR 1.06; 95% CI 1.00-1.13), but the association disappeared over time. Younger breast cancer survivors (age<40 years) had more than a 2-fold increase in AF risk (sHR 2.79; 95% CI 1.98-3.94), with the association remaining similar over 5 years of follow-up. The increased risk was not observed among older breast cancer survivors, especially those aged>65 years. Breast cancer survivors who received anthracyclines had an increased risk of AF compared to those without the exposure (sHR 1.57; 95% CI 1.28-1.92) over the entire course of follow-up. The association between anthracyclines and AF incidence was also more robust in younger breast cancer survivors (sHR 1.94; 95% CI 1.40-2.69 in those aged ≤50 years). Sensitivity analyses, including further adjustments for obesity and lifestyle factors, supported the results.

Conclusions

Our findings suggest that younger breast cancer survivors had an elevated risk of incident AF, regardless of the length of follow-up. The use of anthracyclines may increase the mid-to-long-term AF risk among breast cancer surgery survivors.
Comparison of cardiovascular health profiles across population surveys from five high- to low-income countries
Authors: Ware Lisa , Vermeulen Bridget , Maposa Innocent , Flood David , Brant Luisa CC , Khandelwal Shweta , Singh Kavita , Soares Sara , Jessen Neusa , Perman Gastón , Riaz Baizid Khoorshid , Sachdev Harshpal Singh , Allen Norrina B , Labarthe Darwin R
Published: July 2023

Aims

With the greatest burden of cardiovascular disease morbidity and mortality increasingly observed in lower-income countries least prepared for this epidemic, focus is widening from risk factor management alone to primordial prevention to maintain high levels of cardiovascular health (CVH) across the life course. To facilitate this, the American Heart Association (AHA) developed CVH scoring guidelines to evaluate and track CVH. We aimed to compare the prevalence and trajectories of high CVH across the life course using nationally representative adult CVH data from five diverse high- to low-income countries.

Methods

Surveys with CVH variables (physical activity, cigarette smoking, body mass, blood pressure, blood glucose, and total cholesterol levels) were identified in Ethiopia, Bangladesh, Brazil, England, and the United States (US). Participants were included if they were 18-69y, not pregnant, and had data for these CVH metrics. Comparable data were harmonized and each of the CVH metrics was scored using AHA guidelines as high (2), moderate (1), or low (0) to create total CVH scores with higher scores representing better CVH. High CVH prevalence by age was compared creating country CVH trajectories.

Results

The analysis included 28,092 adults (Ethiopia n=7686, 55.2% male; Bangladesh n=6731, 48.4% male; Brazil n=7241, 47.9 % male; England n=2691, 49.5% male, and the US n=3743, 50.3% male). As country income level increased, prevalence of high CVH decreased (>90% in Ethiopia, >68% in Bangladesh and under 65% in the remaining countries). This pattern remained using either five or all six CVH metrics and following exclusion of underweight participants. While a decline in CVH with age was observed for all countries, higher income countries showed lower prevalence of high CVH already by age 18y. Excess body weight appeared the main driver of poor CVH in higher income countries, while current smoking was highest in Bangladesh.

Conclusion

Harmonization of nationally representative survey data on CVH trajectories with age in 5 highly diverse countries supports our hypothesis that CVH decline with age may be universal. Interventions to promote and preserve high CVH throughout the life course are needed in all populations, tailored to country-specific time courses of the decline. In countries where CVH remains relatively high, protection of whole societies from risk factor epidemics may still be feasible.
Century-old chromatin architecture preserved with formaldehyde
Authors: Hahn Erin E. , Stiller Jiri , Alexander Marina , Grealy Alicia , Taylor Jennifer M. , Jackson Nicola , Frere Celine H. , Holleley Clare E.
Published: July 2023

Co-ordinated regulation or dysregulation of chromatin architecture underpins fundamental biological processes, such as embryonic development, disease, cellular programming and response to environmental stress. The dynamic and plastic nature of chromatin accessibility is a major driver of phenotypic diversity, but we know shockingly little about the temporal dynamics of chromatin reorganisation and almost nothing prior to the existence of flash-frozen specimens. Linking two disparate fields by their common use and application of the preservative formaldehyde, we present an approach to characterise chromatin architecture in formaldehyde-preserved specimens up to 117 years old. We characterise how over-fixation modulates but does not eliminate genome-wide patterns of differential chromatin accessibility. Our novel analytical approach identifies promoter regions enriched for gene ontology terms matching the tissue of origin, resulting in sex-specific and environment-dependent genome-wide profiles. Contrary to prevailing dogma, we show that over-fixation is essential for the successful recovery of historical chromatin architecture. Our methodological and analytical advances open the door to the first detailed and comprehensive view of the epigenetic past and reveal a new role for museum collections in understanding chromatin architecture dynamics over the last century.
Sox3-null hypopituitarism depends on median eminence NG2-glia and is influenced by aspirin and gut microbiota
Authors: Galichet Christophe , Rizzoti Karine , Lovell-Badge Robin
Published: July 2023

The median eminence (ME), located at the base of the hypothalamus, is an essential centre of information exchange between the brain and the pituitary. We and others previously showed that mutations and duplications affecting the transcription factorSOX3/Sox3result in hypopituitarism, and this is likely of hypothalamic origin. We demonstrate here that the absence ofSox3predominantly affects the ME with phenotypes that first occur in juvenile animals, despite the embryonic onset of SOX3 expression. In the pituitary, reduction in hormone levels correlates with a lack of endocrine cell maturation. In parallel, ME NG2-glia renewal and oligodendrocytic differentiation potential are affected. We further show that low-dose aspirin treatment, which is known to affect NG2-glia, or changes in gut microbiota, rescue both proliferative defects and hypopituitarism inSox3mutants. Our study highlights a central role of NG2-glia for ME function during a transitional period of post-natal development, and indicates their sensitivity to environmental signals.
Single-cell gene expression prediction from DNA sequence at large contexts
Authors: Schwessinger Ron , Deasy Jacob , Woodruff Rob T. , Young Stephen , Branson Kim M.
Published: July 2023

Human genetic variants impacting traits such as disease susceptibility frequently act through modulation of gene expression in a highly cell-type-specific manner. Computational models capable of predicting gene expression directly from DNA sequence can assist in the interpretation of expression-modulating variants, and machine learning models now operate at the large sequence contexts required for capturing long-range human transcriptional regulation. However, existing predictors have focused on bulk transcriptional measurements where gene expression heterogeneity can be drowned out in broadly defined cell types. Here, we use a transfer learning framework, seq2cells, leveraging a pre-trained epigenome model for gene expression prediction from large sequence contexts at single-cell resolution. We show that seq2cells captures cell-specific gene expression beyond the resolution of pseudo-bulked data. Using seq2cells for variant effect prediction reveals heterogeneity within annotated cell types and enablesin silicotransfer of variant effects between cell populations. We demonstrate the challenges and value of gene expression and variant effect prediction at single-cell resolution, and offer a path to the interpretation of genomic variation at uncompromising resolution and scale.
The use of social information in vulture flight decisions
Authors: Yohan Sassi , Basile Nouzières , Martina Scacco , Yann Tremblay , Olivier Duriez , Benjamin Robira
Published: July 2023

Animals rely on a balance of personal and social information to decide when and where to move next in order to access a desired resource, such as food. The benefits from cueing on conspecifics to reduce uncertainty about resources availability can be rapidly overcome by the risks of within-group competition, often exacerbated toward low-ranked individuals. Being obligate soarers, relying on thermal updrafts to search for carcasses around which competition can be fierce, vultures represent ideal models to investigate the balance between personal and social information during foraging movements. Linking dominance hierarchy, social affinities and meteorological conditions to movement decisions of eight captive vultures,Gyps spp., released for free flights in natural-like soaring conditions, we found that they relied on social information (i.e. other vultures using/having used the thermals) to find the next thermal updraft, especially in unfavourable flight conditions. Low-ranked individuals were more likely to disregard social cues when deciding where to go next, possibly to minimise the competitive risk of social aggregation. These results exemplify the architecture of decision-making during flight in social birds. It suggests that the environmental context, the context of risk and the social system as a whole calibrate the balance between personal and social information use.
Noribogaine effects on wakefulness and sleep
Authors: Castro-Nin Juan Pedro , Serantes Diego , Rodriguez Paola , Gonzalez Bruno , Carrera Ignacio , Torterolo Pablo , González Joaquín
Published: July 2023

Ibogaine is a potent atypical psychedelic that has gained considerable attention due to its antiaddictive and antidepressant properties in preclinical and clinical studies. Previous research from our group showed that ibogaine suppresses sleep and produces an altered wakefulness state which resembles natural REM sleep. However, after systemic administration, ibogaine is rapidly metabolized to noribogaine, which also shows antiaddictive effects and a distinct pharmacological profile, making this drug a promising therapeutic candidate. Therefore, whether the sleep/wake alterations depend on ibogaine or its principal metabolite noribogaine remains unknown. To answer this question, we conducted polysomnographic recordings in rats following the administration of pure noribogaine. Our results show that noribogaine promotes wakefulness while reducing slow-wave sleep and blocking REM sleep. Thus, like ibogaine, noribogaine significantly alters the sleep-wake architecture, highlighting the possible role of serotonin reuptake inhibition as a likely candidate underlying the wake-promoting and REM sleep-suppressing effects.
Species -Shared and -Unique Gyral Peaks on Human and Macaque Brains
Authors: Zhang Songyao , Zhang Tuo , Cao Guannan , Zhou Jingchao , He Zhibin , Li Xiao , Ren Yudan , Liu Tao , Jiang Xi , Guo Lei , Han Junwei , Liu Tianming
Published: July 2023

Cortical folding is an important feature of primate brains that plays a crucial role in various cognitive and behavioral processes. Extensive research has revealed both similarities and differences in folding morphology and brain function among primates including macaque and human. The folding morphology is the basis of brain function, making cross-species studies on folding morphology important for understanding brain function and species evolution. However, prior studies on cross-species folding morphology mainly focused on partial regions of the cortex instead of the entire brain. Previously, we defined a whole-brain landmark based on folding morphology: the gyral peak. It was found to exist stably across individuals and ages in both human and macaque brains. In this study, we identified shared and unique gyral peaks in human and macaque, and investigated the similarities and differences in the spatial distribution, anatomical morphology, and functional connectivity of them.
Plasma Activated Water as a Pre-Treatment Strategy in the Context of Biofilm-Infected Chronic Wounds
Authors: Vyas Heema K. N. , Xia Binbin , Alam David , Gracie Nicholas P. , Rothwell Joanna G. , Rice Scott A. , Carter Dee , Cullen Patrick J. , Mai-Prochnow Anne
Published: July 2023

Healing and treatment of chronic wounds are often complicated due to biofilm formation by pathogens. Here, the efficacy of Plasma Activated Water (PAW) as a pre-treatment strategy has been investigated prior to the application of topical antiseptics polyhexamethylene biguanide, povidone iodine, and MediHoney, which are routinely used to treat chronic wounds. The efficacy of this treatment strategy was determined against biofilms ofEscherichia coliformed on a plastic substratum and on a human keratinocyte monolayer substratum used as anin vitrobiofilm-skin epithelial cell model. PAW pre-treatment greatly increased the killing efficacy of all the three antiseptics to eradicate theE. colibiofilms formed on the plastic and keratinocyte substrates. However, the efficacy of the combined PAW-antiseptic treatment and single treatments using PAW or antiseptic alone was lower for biofilms formed in thein vitrobiofilm-skin epithelial cell model compared to the plastic substratum. Scavenging assays demonstrated that reactive species present within the PAW were largely responsible for its anti-biofilm activity. PAW treatment resulted in significant intracellular RONS accumulation within theE. colibiofilms, while also rapidly acting on the microbial membrane leading to outer membrane permeabilisation and depolarisation. Together, these factors contribute to significant cell death, potentiating the antibacterial effect of the assessed antiseptics.
Impaired value-based decision-making in Parkinson’s Disease Apathy
Authors: Gilmour William , Mackenzie Graeme , Feile Mathias , Tayler-Grint Louise , Suveges Szabolcs , Macfarlane Jennifer A , Macleod Angus D , Marshall Vicky , Grunwald Iris Q , Steele J Douglas , Gilbertson Tom
Published: July 2023

Apathy is a common and disabling complication of Parkinson’s disease characterised by reduced goal-directed behaviour. Several studies have reported dysfunction within pre-frontal cortical regions and projections from brainstem nuclei whose neuromodulators include dopamine, serotonin and noradrenaline. Work in animal and human neuroscience have confirmed contributions of these neuromodulators on aspects of motivated decision making. Specifically, non-dopaminergic neuromodulators, influence decisions to explore alternative courses of action or persist in an existing strategy to achieve a rewarding goal.

Building upon this work, we hypothesised that Apathy in Parkinson’s disease should be associated with a failure to adequately monitor and make adaptive choices when the rewarding outcome of decisions are uncertain. Using a 4-armed restless bandit reinforcement learning task, we studied decision making in 75 volunteers; 53 patients with Parkinson’s disease, with and without clinical apathy, and 22 age matched healthy controls. Patients with Apathy exhibited impaired ability to choose the highest value bandit. Task performance predicted an individual patient’s apathy severity measured using the Lille Apathy Rating scale (R = -0.46, p<0.001). Computational modelling of the patient’s choices confirmed the apathy group made decisions that that were indifferent to the learnt value of the options, consistent with previous reports of reward insensitivity. Further analysis demonstrated a shift away from exploiting the highest value option and a reduction in perseveration which also correlated with apathy scores (R = -0.5, p<0.001).

We went on to acquire fMRI in 59 volunteers; a group of 19 patients with and 20 without apathy and 20 age matched controls performing the restless bandit task. Analysis of the fMRI signal at the point of reward feedback confirmed diminished signal within ventromedial prefrontal cortex in Parkinson’s disease, which was more marked in Apathy, but not predictive of their individual Apathy severity. Using a model-based categorisation of choice type, decisions to explore lower value bandits in the apathy group activated pre-frontal cortex to a similar degree to the age-matched controls. In contrast, Parkinson’s patientswithoutapathy demonstrated significantly increased activation across a distributed thalamo-cortical network. Enhanced activity in the thalamus predicted individual apathy severity across both patient groups and exhibited functional connectivity with dorsal anterior cingulate cortex and anterior insula.

Given that task performance in patients without apathy was no different to the age-matched controls, we interpret the recruitment of this network as a possible compensatory mechanism, which compensates against symptomatic manifestation of apathy in Parkinson’s disease.
Site-specific proximity labeling at single residue resolution for identification of protein partnersin vitroand on cells
Authors: Bartholow Thomas G. , Burroughs Paul , Elledge Susanna K. , Byrnes James R. , Kirkemo Lisa L. , Garda Virginia , Leung Kevin K. , Wells James A.
Published: July 2023

The cell surface proteome, or surfaceome, is encoded by more than 4000 genes, but we are only beginning to understand the complexes they form. Rapid proximity labeling around specific membrane targets allows for capturing weak and transient interactions expected in the crowded and dynamic environment of the surfaceome. Recently, a high-resolution approach called μMap has been described (Geri, J. B., Oakley, J. V., Reyes-Robles, T., Wang, T., McCarver, S. J., White, C. H., Rodriguez-Rivera, F. P., Parker, D. L., Hett, E. C., Fadeyi, O. O., Oslund, R. C., and MacMillan, D. W. C. (2020)Science 367, 1091–1097) in which an iridium (Ir)-based photocatalyst is attached to a specific antibody to target labeling of neighbors utilizing light-activated generation of carbenes from diazirine compounds via Dexter Energy Transfer (DET). Here we studied and optimized the spatial resolution for the method using an oncoprotein complex between the antibody drug, trastuzumab (Traz), and its target HER2. A set of eight single site-specific Ir-catalytic centers were engineered into Traz to study intra- and inter-molecular labelingin vitroand on cells by mass spectrometry. From this structurally well-characterized complex we observed a maximum distance of ∼110 Å for labeling. Labeling occurred almost uniformly over the full range of amino acids, unlike the residue specific labeling of other techniques. To examine on cell labeling that is specific to HER2 as opposed to simply being on the membrane, we compared the labeling patterns for the eight Traz-catalyst species to random labeling of membrane proteins using a metabolically integrated fatty acid catalyst. Our results identified 20 high confidence HER2 neighbors, many novel, that were more than 6-fold enriched compared to the non-specific membrane tethered catalyst. These studies define distance labeling parameters from single-site catalysts placed directly on the membrane target of interest, and more accurately compare to non-specific labeling to identify membrane complexes with higher confidence.
A REM-active basal ganglia circuit that regulates anxiety
Authors: Ba Wei , Nollet Mathieu , Yu Xiao , Wong Sara , Miao Andawei , Beckwith Esteban , Harding Edward C. , Ma Ying , Yustos Raquel , Vyssotski Alexei L. , Wisden William , Franks Nicholas P.
Published: July 2023

REM sleep has been hypothesized to promote emotional resilience, but any neuronal circuits mediating this have not been identified. We find that in mice, somatostatin (Som) neurons in the entopeduncular nucleus (EPSom)/internal globus pallidus are predominantly active selectively during REM sleep. This unique REM activity is necessary and sufficient for maintaining normal REM sleep. Inhibiting or exciting EPSomneurons reduced or increased REM sleep duration, respectively. Activation of the sole downstream target of EPSomneurons, Vglut2 cells in the lateral habenula (LHb), increased sleep via the ventral tegmental area (VTA). A simple chemogenetic scheme to periodically inhibit the LHb over 4 days selectively removed a significant amount of cumulative REM sleep. Chronic REM reduction correlated with mice becoming anxious and more sensitive to aversive stimuli. Therefore, we suggest that REM sleep, in part generated by the EP→LHb→VTA circuit identified here, could contribute to stabilizing reactions to habitual aversive stimuli.