bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic architecture underlying response to the fungal pathogenDothistroma septosporumin lodgepole pine, jack pine, and their hybrids
Authors: Lu Mengmeng , Feau Nicolas , Lind Brandon , Vidakovic Dragana Obreht , Singh Pooja , Aitken Sally N. , Hamelin Richard C. , Yeaman Sam
Published: April 2024

In recent decades,Dothistromaneedle blight (DNB), a pine tree disease caused by the fungal pathogenDothistroma septosporum, has severely damaged lodgepole pine (Pinus contortaDougl. ex. Loud.) in British Columbia, Canada, and raised health concerns for jack pine (Pinus banksianaLamb.). The pathogen has already shown signs of host shift eastward to the hybrid populations between lodgepole pine and jack pine (Pinus contorta×P. banksiana), and possibly into pure jack pine. However, we have little knowledge about mechanisms of resistance toD. septosporum, especially the underlying genetic basis of variation in pines. In this study, we conducted controlled inoculations to induce infection byD. septosporumand performed a genome-wide case-control association study with pooled sequencing (pool-seq) data to dissect the genetic architecture underlying response in lodgepole pine, jack pine, and their hybrids. We identified candidate genes associated withD. septosporumresponse in lodgepole pine and in hybrid samples. We also assessed genetic structure in hybrid populations and inferred how introgression may affect the distribution of genetic variation involved inD. septosporumresponse in the studied samples. These results can be used to develop genomic tools to evaluate DNB risk, guide forest management strategies, and potentially select for resistant genotypes.
Bee pasture as a buffer against flower-mediated disease transmission
Authors: Rabajante Jomar Fajardo
Published: April 2024

Bees play a crucial role as pollinators in ecosystems, yet they face the risk of flower-mediated diseases that can spread among their communities. Infected bees can inadvertently transmit infective agents, such as microbial spores, to other bee colonies through shared floral resources during foraging. To address this challenge, we propose a solution involving the strategic planting of bee pasture as buffer zones around foraging areas, coupled with the careful placement of beehives to segregate bee colonies. However, this strategy presents dual potential outcomes: the buffer zone could act as a protective barrier, reducing disease transmission; or attract more bees from other colonies, thereby increasing infection risk. Employing mathematical modeling, we explore the intricate dynamics of this strategy to minimize negative outcomes, considering factors such as colony strength, optimal foraging behavior, and foraging area locations. Our results recommend implementing the following measures to safeguard the target bee colony against disease: (i) ensuring ample food sources are available in the vicinity of the target bee colony, and (ii) establishing bee pasture in a distinct, outlying area to serve as a buffer zone. While the bee pasture buffer zone cannot guarantee complete immunity from infection, it can effectively delay the spread of inter-colony diseases. This proposed strategy should be combined with other sound beekeeping practices for comprehensive disease management. Our analysis aims to provide insights into optimizing practices to protect the health of both managed and wild bee populations, and bolster ecological resilience.

Significance Statement

Bees, vital pollinators in ecosystems, face the risk of flower-mediated diseases transmitted between colonies. Flower-mediated disease transmission occurs when bees spread pathogens to each other through sharing of flowers during foraging. To mitigate this, we propose planting bee pasture buffer zones around foraging areas. Using mathematical modeling, we recommend ensuring nearby food sources for the target bee colony and establishing bee pasture buffers. While not guaranteeing immunity, this strategy can delay disease spread. Combining this with other beekeeping practices can comprehensively manage diseases. This research underscores the importance of bee pasture areas for protecting both managed and wild bee populations and strengthening ecosystem resilience.

MSC Classification

92-10, 92D40, 92D30
Maternal obesity may disrupt offspring metabolism by inducing oocyte genome hyper-methylation via increased DNMTs
Authors: Chao Shuo , Lu Jun , Li Li-Jun , Guo Hong-Yan , Xu Kui-Peng , Wang Ning , Zhao Shu-Xian , Jin Xiao-Wen , Wang Shao-Ge , Yin Shen , Shen Wei , Zhao Ming-Hui , Huang Gui-An , Sun Qing-Yuan , Ge Zhao-Jia
Published: April 2024

Maternal obesity has deleterious effects on the process of establishing oocyte DNA methylation; yet the underlying mechanisms remain unclear. In the present study, we found that maternal obesity induced by high-fat diet (HFD) disrupted the genomic methylation of oocytes, and that at least a part of the altered DNA methylation was transmitted to the F2 oocytes and the livers via females. We further examined the metabolome of serum and found that the altered metabolites such as melatonin may play a key role in the disrupted genomic methylation in the oocytes of obese mice. We further found that exogenous melatonin treatment significantly reduced the hyper-methylation of HFD oocytes, and the increased expression of DNMT3a and DNMT1 in HFD oocytes was also decreased. To address how melatonin regulates the expression of DNMTs, the function of melatonin was inhibited or activated upon oocytes. Results revealed that melatonin may regulate the expression of DNMTs via the cAMP/PKA/CREB pathway. These results suggest that maternal obesity induces genomic methylation alterations in oocytes, which can be partly transmitted to F2 in females, and that melatonin is involved in regulating the hyper-methylation of HFD oocytes by increasing the expression of DNMTs via the cAMP/PKA/CREB pathway.
Navigating the Night: Effects of Artificial Light on the Behaviour of Atlantic Puffin Fledglings
Authors: Brown T.M. , Wilhelm S.I. , Slepkov A.D. , Baker K. , Mastromonaco G.F. , Burness G.
Published: April 2024

Every year in Newfoundland, young Atlantic Puffins (Fratercula arctica) departing their nests at night for the first time become stranded in towns near their breeding colonies, a phenomenon thought to be caused by attraction toward artificial light. To test this hypothesis, we conducted three behavioural experiments. First, we illuminated beaches near a breeding colony to determine whether more fledglings would become stranded in illuminated versus dark conditions. Next, we conducted a Y-maze experiment to test stranded fledglings for phototactic behaviour in general and for preferences among High Pressure Sodium (HPS), Warm White Light-Emitting Diode (LED), Cool White LED, Blue LED, and Orange LED light. Lastly, we quantified activity levels of stranded fledglings in an open field test during exposure to several different light types. We found significantly more fledglings stranded when beaches were illuminated, and fledglings significantly preferred light over darkness in the Y-maze, supporting our hypothesis that Atlantic Puffin fledglings become stranded due to light attraction. Fledglings displayed no preferences for certain light types over others in the Y-maze, potentially suggesting that strandings in this species may not be mitigable by changing the streetlight type in stranding-prone towns. Interestingly, fledglings exhibited higher activity levels in darkness and HPS light than in LED light, potentially holding implications for rescue, rehabilitation, and husbandry programs. Overall, our findings demonstrate that the only evidence-based strategy for the reduction of Atlantic Puffin strandings remains to be the reduction of coastal artificial lighting; however, further research is needed to determine if aspects of artificial light besides bulb type may be altered to effectively reduce light attraction in this species.
A Multiresolution Approach with Method-Informed Statistical Analysis for Quantifying Lymphatic Pumping Dynamics
Authors: Razavi Mohammad S. , Ruscic Katarina J. , Korn Elizabeth G. , Marquez Marla , Houle Timothy T. , Singhal Dhruv , Munn Lance L. , Padera Timothy P.
Published: April 2024

Despite significant strides in lymphatic system imaging, the timely diagnosis of lymphatic disorders remains elusive. One main cause for this is the absence of standardized, quantitative methods for real-time analysis of lymphatic contractility. Here, we address this unmet need by combining near-infrared lymphangiography imaging with an innovative analytical workflow. We combined data acquisition, signal processing, and statistical analysis to integrate traditional peak and-valley with advanced wavelet time-frequency analyses. Decision theory was used to evaluate the primary drivers of attributable variance in lymphangiography measurements to generate a strategy for optimizing the number of repeat measurements needed per subject to increase measurement reliability. This approach not only offers detailed insights into lymphatic pumping behaviors across species, sex and age, but also significantly boosts the reliability of these measurements by incorporating multiple regions of interest and evaluating the lymphatic system under various gravitational loads. By addressing the critical need for improved imaging and quantification methods, our study offers a new standard approach for the imaging and analysis of lymphatic function that can improve our understanding, diagnosis, and treatment of lymphatic diseases. The results highlight the importance of comprehensive data acquisition strategies to fully capture the dynamic behavior of the lymphatic system.
Adaptation to soil type contributes little to local adaptation in an Italian and a Swedish population ofArabidopsis thalianagrowing on contrasting soils
Authors: Ellis Thomas James , Ågren Jon
Published: April 2024

Natural populations are subject to selection caused by a range of biotic and abiotic factors in their native habitats. Identifying these agents of selection and quantifying their effects is key to understanding how populations adapt to local conditions. We performed a fully factorial reciprocal transplant experiment using locally adapted accessions ofArabidopsis thalianaat their native sites to distinguish the contributions of adaptation to soil type and climate. Overall adaptive differentiation was strong at both sites. However, we found only very small differences in the strength of selection on local and non-local soil, and adaptation to soil type at most constituted only a few percent of overall adaptive differentiation. These results indicate that adaptation to local climatic conditions rather than soil type is the primary driver of adaptive differentiation between these ecotypes.
Worldwide study of the taste of bitter medicines and their modifiers
Authors: Nguyen Ha , Lin Cailu , Bell Katherine , Huang Amy , Hannum Mackenzie , Ramirez Vicente , Christensen Carol , Rawson Nancy E. , Colquitt Lauren , Domanico Paul , Sasimovich Ivona , Herriman Riley , Joseph Paule , Braimah Oghogho , Reed Danielle R.
Published: April 2024

The bitter taste of medicines hinders patient compliance, but not everyone experiences these difficulties because people worldwide differ in their bitterness perception. To better understand how people from diverse ancestries perceive medicines and taste modifiers, 338 adults, European and recent US and Canada immigrants from Asia, South Asia, and Africa, rated the bitterness intensity of taste solutions on a 100-point generalized visual analog scale and provided a saliva sample for genotyping. The taste solutions were five medicines, tenofovir alafenamide (TAF), moxifloxacin, praziquantel, amodiaquine, and propylthiouracil (PROP), and four other solutions, TAF mixed with sucralose (sweet, reduces bitterness) or 6-methylflavone (tasteless, reduces bitterness), sucralose alone, and sodium chloride alone. Bitterness ratings differed by ancestry for two of the five drugs (amodiaquine and PROP) and for TAF mixed with sucralose. Genetic analysis showed that people with variants in one bitter receptor variant gene (TAS2R38) reported PROP was more bitter than did those with a different variant (p= 7.6e-19) and that people with either anRIMS2or aTHSD4genotype found sucralose more bitter than did others (p=2.6e-8, p=7.9e-11, resp.). Our findings may help guide the formulation of bad- tasting medicines to meet the needs of those most sensitive to them.
Assessing the application of landmark-free morphometrics to macroevolutionary analyses
Authors: Mulqueeney James M. , Ezard Thomas H. G. , Goswami Anjali
Published: April 2024

The study of phenotypic evolution has been transformed by methods allowing three-dimensional quantification of anatomical form. The present state-of-the-art 3D geometric morphometrics, which relies heavily on manual landmarking, is time-consuming, prone to operator bias, and cannot effectively compare disparate shapes. Emerging automated approaches, notably landmark-free techniques, offer promise but have only been applied to closely related species. Here, we compare landmark-free approaches with high-density geometric morphometric methods on 322 mammals across 180 families. Leveraging the benefits of Poisson meshes, which combine open and closed projections, we show how landmark-free methods have greater power to differentiate major taxonomic groups. Although there is coarse correspondence in shape variation between the two methods, the finer features of the landmark-free approach likely reflect its broader sampling of the surface structure. Our study underscores the robustness of landmark-free methods for large-scale comparative analysis and helps propel morphometrics into a new era of bigger data.
Projection-TAGs enable multiplex projection tracing and multi-modal profiling of projection neurons
Authors: Yang Lite , Liu Fang , Hahm Hannah , Okuda Takao , Li Xiaoyue , Zhang Yufen , Kalyanaraman Vani , Heitmeier Monique R. , Samineni Vijay K.
Published: April 2024

Single-cell multiomic techniques have sparked immense interest in developing a comprehensive multi-modal map of diverse neuronal cell types and their brain wide projections. However, investigating the spatial organization, transcriptional and epigenetic landscapes of brain wide projection neurons is hampered by the lack of efficient and easily adoptable tools. Here we introduce Projection-TAGs, a retrograde AAV platform that allows multiplex tagging of projection neurons using RNA barcodes. By using Projection-TAGs, we performed multiplex projection tracing of the mouse cortex and high-throughput single-cell profiling of the transcriptional and epigenetic landscapes of the cortical projection neurons. Projection-TAGs can be leveraged to obtain a snapshot of activity-dependent recruitment of distinct projection neurons and their molecular features in the context of a specific stimulus. Given its flexibility, usability, and compatibility, we envision that Projection-TAGs can be readily applied to build a comprehensive multi-modal map of brain neuronal cell types and their projections.
PROSTATE CELL HETEROGENEITY AND CXCL17 UPREGULATION IN MOUSE STEROID HORMONE IMBALANCE
Authors: Silver Samara V. , Tucker Kayah J. , Vickman Renee E , Lanman Nadia A. , Semmes O John , Alvarez Nehemiah S. , Popovics Petra
Published: April 2024

Benign prostatic hyperplasia (BPH) is a prevalent age-related condition often characterized by debilitating urinary symptoms. Its etiology is believed to stem from hormonal imbalance, particularly an elevated estradiol-to-testosterone ratio and chronic inflammation. Our previous studies using a mouse steroid hormone imbalance model identified a specific increase in macrophages that migrate and accumulate in the prostate lumen where they differentiate into lipid-laden foam cells in mice implanted with testosterone and estradiol pellets, but not in sham animals. The current study focused on further characterizing the cellular heterogeneity of the prostate in this model as well as identifying the specific transcriptomic signature of the recruited foam cells. Moreover, we aimed to identify the epithelia-derived signals that drive macrophage infiltration and luminal translocation.

Male C57BL/6J mice were implanted with slow-release testosterone and estradiol pellets (T+E2) and harvested the ventral prostates two weeks later for scRNA-seq analysis, or performed sham surgery. We identifiedEar2+ andCd72+ macrophages that were elevated in response to steroid hormone imbalance, whereas aMrc1+ resident macrophage population did not change. In addition, an Spp1+ foam cell cluster was almost exclusively found in T+E2 mice. Further markers of foam cells were also identified, includingGpnmbandTrem2, and GPNMB was confirmed as a novel histological marker with immunohistochemistry. Foam cells were also shown to express known pathological factorsVegf, Tgfb1, Ccl6, Cxcl16andMmp12. Intriguingly, a screen for chemokines identified the upregulation of epithelial-derivedCxcl17, a known monocyte attractant, in T+E2 prostates suggesting that it might be responsible for the elevated macrophage number as well as their translocation to the lumen.

Our study identified macrophage subsets that respond to steroid hormone imbalance as well as further confirmed a potential pathological role of luminal foam cells in the prostate. These results underscore a pathological role of the identified prostate foam cells and suggests CXCL17-mediated macrophage migration as a critical initiating event.
SECRET-GWAS: Confidential Computing for Population-Scale GWAS
Authors: Rosenblum Jonah , Dong Juechu , Narayanasamy Satish
Published: April 2024

Genomic data from a single institution lacks global diversity representation, especially for rare variants and diseases. Confidential computing can enable collaborative GWAS without compromising privacy or accuracy, however, due to limited secure memory space and performance overheads previous solutions fail to support widely used regression methods. We present SECRET-GWAS: a rapid, privacy-preserving, population-scale, collaborative GWAS tool. We discuss several system optimizations, including streaming, batching, data parallelization, and reducing trusted hardware overheads to efficiently scale linear and logistic regression to over a thousand processor cores on an Intel SGX-based cloud platform. In addition, we protect SECRET-GWAS against several hardware side-channel attacks, including Spectre, using data-oblivious code transformations and optimized speculative load hardening. SECRET-GWAS is an open-source tool and works with the widely used Hail genomic analysis framework. Our experiments on Azure’s Confidential Computing platform demonstrate that SECRET-GWAS enables multivariate linear and logistic regression GWAS queries on population-scale datasets (one million patients, four million SNPs, 12 covariates) from ten independent sources in just 4.5 and 29 minutes, respectively.
HSD2 neurons are evolutionarily conserved and required for aldosterone-induced salt appetite
Authors: Gasparini Silvia , Peltekian Lila , McDonough Miriam C. , Mitchell Chidera J.A. , Hefti Marco , Resch Jon M. , Geerling Joel C.
Published: April 2024

Excessive aldosterone production increases the risk of heart disease, stroke, dementia, and death. Aldosterone increases both sodium retention and sodium consumption, and increased sodium consumption predicts end-organ damage in patients with aldosteronism. Preventing this increase may improve outcomes, but the behavioral mechanisms of aldosterone-induced sodium appetite remain unclear. In rodents, we identified aldosterone-sensitive neurons, which express the mineralocorticoid receptor and its pre-receptor regulator, 11-beta-hydroxysteroid dehydrogenase 2 (HSD2). Here, we identify HSD2 neurons in the human brain and use a mouse model to evaluate their role in aldosterone-induced salt intake. First, we confirm that dietary sodium deprivation increases aldosterone production, HSD2 neuron activity, and salt intake. Next, we show that activating HSD2 neurons causes a large and specific increase in salt intake. Finally, we use dose-response studies and genetically targeted ablation of HSD2 neurons to show that aldosterone-induced salt intake requires these neurons. Identifying HSD2 neurons in the human brain and their necessity for aldosterone-induced salt intake in mice improves our understanding of appetitive circuits and highlights this small cell population as a therapeutic target for moderating dietary sodium.
Integrative Data Analysis to Uncover Transcription Factors Involved in Gene Dysregulation of Nine Autoimmune and Inflammatory Diseases
Authors: Naghavi Nader Hosseini , Kerfoot Steven M. , Shooshtari Parisa
Published: April 2024

Autoimmune and inflammatory diseases are a group of > 80 complex diseases caused by loss of immune tolerance for self-antigens. The biological mechanisms of autoimmune diseases are largely unknown, preventing the development of effective treatment options. Integrative analysis of genome-wide association studies and chromatin accessibility data has shown that the risk variants of autoimmune diseases are enriched in open chromatin regions of immune cells, supporting their role in gene regulation. However, we still lack a systematic and unbiased identification of transcription factors involved in disease gene regulation. We hypothesized that for some of the disease-relevant transcription factors, their binding to DNA is affected at multiple genomic sites rather than a single site, and these effects are cell-type specific. We developed a statistical approach to assess enrichment of transcription factors in being affected by disease risk variants at multiple genomic sites. We used genetic association data of nine autoimmune diseases and identified 99% credible set SNPs for each trait. We then integrated the credible SNPs and chromatin accessibility data of 376 samples comprising 35 unique cell types, and employed a probabilistic model to identify the SNPs that are likely to change binding probability of certain transcription factors at specific cell types. Finally, for each transcription factor, we used a statistical test to assess whether the credible SNPs show enrichments in terms of changing the binding probability of that transcription factor at multiple sites. Our analysis resulted in identification of significantly enriched transcription factors and their relevant cell types for each trait. The prioritized immune cell types varied across the diseases. Our analysis proved that our predicted regulatory sites are active enhancers or promoters in the relevant cell types. Additionally, our pathway analysis showed that the majority of the significant biological pathways are immune-related. In summary, our study has identified disease-relevant transcription factors and their relevant cell types, and will facilitate discovering specific gene regulatory mechanisms of autoimmune diseases.
Iris Morphological and Biomechanical Factors Influencing Angle Closure During Pupil Dilation
Authors: Tan Royston K.Y. , Ng Gim Yew , Tun Tin A. , Braeu Fabian A. , Nongpiur Monisha E. , Aung Tin , Girard Michael J.A.
Published: April 2024

Purpose

To use finite element (FE) analysis to assess what morphological and biomechanical factors of the iris and of the anterior chamber are more likely to influence angle narrowing during pupil dilation.

Methods

The study consisted of 1,344 FE models comprising of the cornea, sclera, lens and iris (stroma, sphincter and dilator tissues) to simulate pupil dilation and to assess changes in angle. For each model, we varied the following parameters: anterior chamber depth (ACD = 2 –4 mm) and width (ACW = 10–12 mm), iris convexity (IC = 0–0.3 mm), thickness (IT = 0.3–0.5 mm), stiffness (E= 4–24 kPa) and Poisson’s ratio (v= 0–0.3), and simulated pupil dilation. We evaluated for the change in anterior chamber angle (△∠) and the final dilated anterior chamber angles (∠f) from baseline to dilation for each parameter.

Results

The final dilated AC angles decreased with a smaller ACD (∠f= 53.4°±12.3° to 21.3°±14.9°), smaller ACW (∠f= 48.2°±13.5° to 26.2°±18.2°), larger IT (∠f= 52.6°±12.3° to 24.4°±15.1°), larger IC (∠f= 45.0°±19.2° to 33.9°±16.5°), largerE(∠f= 40.3°±17.3° to 37.4°±19.2°) and largerv(∠f= 42.7°±17.7° to 34.2°±18.1°).

The change in AC angle increased with larger ACD (△∠ = 9.37°±11.1° to 15.4°±9.3°), smaller ACW (△∠ = 7.4°±6.8° to 16.4°±11.5°), larger IT (△∠ = 5.3°±7.1° to 19.3°±10.2°), smaller IC (△∠ = 5.4°±8.2° to 19.5°±10.2°), largerE(△∠ = 10.9°±12.2° to 13.1°±8.8°) and largerv(△∠ = 8.1°±9.4° to 16.6°±10.4°).

Conclusions

This parametric study offered valuable insights into the factors that could influence angle closure. The morphology of the iris (IT and IC) and its innate biomechanical behavior (Eandv) were crucial in influencing the way the iris deformed during dilation, and angle closure was further exacerbated by decreased AC biometry (ACD and ACW).
Ecosystem engineers cause biodiversity spill-over: beavers affect breeding bird assemblages on both wetlands and adjacent terrestrial habitats
Authors: Fedyń Izabela , Sobociński Wojciech , Czyżowicz Sławomir , Wyka Jakub , Ciach Michał
Published: April 2024

The influence of ecosystem engineers on habitats and communities is commonly acknowledged in a site-bounded context, i.e. in places directly affected by the presence of the focal species. However, the spatial extent of the effects of such engineering is poorly understood, raising the question as to what impact they have on ecosystems situated beyond the species’ direct influence. BeaversCastorspp., iconic ecosystem engineers, are capable of significantly transforming aquatic ecosystems. Their presence boosts biodiversity in near-water habitats, but as a result of cascading processes, beavers may affect terrestrial habitats situated beyond the range of their immediate activity. Our study investigates the breeding bird assemblage along a spatial gradient from the water to the forest interior on central European watercourses modified and unmodified by beavers. The results show that beaver sites are characterized by a higher species richness and abundance of breeding birds than unmodified watercourses. Such sites also host a different species pool, as 27% of the recorded bird species occurred exclusively on the beaver sites. The effect of the beaver’s presence on the bird assemblage caused this to spill over from the wetlands to adjacent terrestrial habitats located up to 100 m from the water’s edge, where the species richness and abundance was higher and the species composition was substantially modified. We also found a positive correlation between the total area of beaver wetland and the numbers of bird species and individuals recorded. Our study indicates that beaver activity has major consequences for ecosystem functioning that extend beyond the wetland, spilling over on to adjacent terrestrial ecosystems. These findings add to the general understanding of the spatial context of the ecosystem engineering concept, as the changes brought about by engineers have an influence beyond the area of their immediate occurrence. Our work also has implications for landscape planning and management, where existing beaver sites with terrestrial buffer zones may constitute a network of biodiversity hot-spots.

Highlights:

• Beavers create hot-spots of bird richness and abundance in temperate forests

• The beaver’s impact spills over beyond wetlands on to terrestrial ecosystems

• Bird richness, number and composition is changed up to 100 m from beaver sites

• The area of a beaver wetland positively correlates with bird richness and numbers

• The beaver is an umbrella species for the riparian forest bird community
Protection against experimental cryptococcosis elicited by Cationic Adjuvant Formulation 01-adjuvanted subunit vaccines
Authors: Wang Ruiying , Oliveira Lorena V. N. , Hester Maureen M. , Carlson Diana , Christensen Dennis , Specht Charles A. , Levitz Stuart M.
Published: April 2024

The fungal infection, cryptococcosis, is responsible for >100,000 deaths annually. No licensed vaccines are available. We explored the efficacy and immune responses of subunit cryptococcal vaccines adjuvanted with Cationic Adjuvant Formulation 01 (CAF01). CAF01 promotes humoral and T helper (Th) 1 and Th17 immune responses and has been safely used in human vaccine trials. Four subcutaneous vaccines, each containing single recombinantCryptococcus neoformansprotein antigens, partially protected mice from experimental cryptococcosis. Protection increased, up to 100%, in mice that received bivalent and quadrivalent vaccine formulations. Vaccinated mice that received a pulmonary challenge withC. neoformanshad an influx of leukocytes into the lung including robust numbers of polyfunctional CD4+T cells which produced Interferon gamma (IFNγ), tumor necrosis factor alpha (TNFα), and interleukin (IL)-17 upon ex vivo antigenic stimulation. Cytokine-producing lung CD8+T cells were also found, albeit in lesser numbers. A significant, durable IFNγ response was observed in the lungs, spleen, and blood. Moreover, IFNγ secretion following ex vivo stimulation directly correlated with fungal clearance in the lungs. Thus, we have developed multivalent cryptococcal vaccines which protect mice from experimental cryptococcosis using an adjuvant which has been safely tested in humans. These preclinical studies suggest a path towards human cryptococcal vaccine trials.

Author summary

Cryptococcosis is a fungal infection that poses great challenges to public health, especially in resource-limited regions with high HIV prevalence. Despite the urgent need, no licensed vaccines are currently available. In this study, we used a lethal mouse model of cryptococcosis to explore protection and immune responses elicited by vaccines consisting of recombinant cryptococcal proteins formulated with CAF01, an adjuvant that has an established safety and immunogenicity profile in human clinical vaccine trials. We discovered that while vaccines containing a single protein partially protected mouse strains, the protection was greatly augmented when the mice received vaccines formulated with multiple antigens. The lungs of vaccinated and infected mice had a robust influx of CD4+T cells, many of which made the cytokines IFNγ and IL-17 when stimulated ex vivo. Moreover, we found the production of IFNγ directly correlated with clearance of fungi from the lungs. Cytotoxic CD8+T cell responses were also observed, albeit in lesser numbers. Our promising findings from this preclinical research paves the way for future human cryptococcal vaccine trials.
The role of mitochondrial DNA copy number in neuropsychiatric disorders: A bidirectional two-sample Mendelian randomization study
Authors: Niu Mengqi , Chen Chen , Maes Michael
Published: April 2024

Background

Inconsistent findings characterize studies on mitochondrial DNA copy number (mtDNA-CN) and its relation to neuropsychiatric disorders. This bidirectional two-sample Mendelian Randomization (MR) study explores potential causal links between mtDNA-CN and neuropsychiatric disorders, including Alzheimer’s disease, Attention-deficit/hyperactivity disorder, Anorexia nervosa, Autism spectrum disorder (ASD), Bipolar disorder, Major depressive disorder, Obsessive-compulsive disorder, Schizophrenia, Anxiety disorders, and Post-traumatic stress disorder.

Methods

Genetic associations with mtDNA-CN were drawn from the UK Biobank’s GWAS data (n = 395,718), while neuropsychiatric disorder data came from the Psychiatric Genomics Consortium and FinnGen Consortium. Three MR methods—Inverse Variance Weighting (IVW), MR-Egger, and Weighted Median—were used to establish relationships. Cochran’s Q test, MR-PRESSO, and MR-Egger’s intercept test assessed heterogeneity and pleiotropy. A leave-one-out analysis evaluated the impact of individual SNPs on MR results, and a bidirectional analysis examined the relationship between mtDNA-CN and neuropsychiatric disorders.

Results

The MR analysis indicated a causal relationship between mtDNA-CN and ASD using the IVW method (OR = 0.735, 95%CI: 0.597 to 0.905; P = 0.004). Conversely, a causal relationship was identified between Anxiety disorders and mtDNA-CN (β= 0.029, 95%CI: 0.010 to 0.048; P = 0.003). No causal associations were found for other disorders. Sensitivity tests corroborated the robustness of these findings.

Conclusion

In this study, potential causal relationships between mtDNA-CN and both ASD and Anxiety disorders were established. These findings provide insights into the biological mechanisms of mtDNA-CN on ASD and underscore the significance of mtDNA copy number as a potential biomarker for Anxiety disorders.
Maternity care professionals’ preparedness for and experiences of screening and responding to disclosures of domestic violence in the peripartum period: a protocol for a qualitative evidence synthesis
Authors: O’Shea Laura , Corbally Melissa , Daly Déirdre
Published: April 2024

Background

Maternity care professionals, such as midwives, public health nurses, doctors, and social workers, are in the unique position of having regular contact with women in the peripartum period. They are well-placed to recognise and respond to disclosures of domestic violence, however many lack confidence and feel unprepared for this in practice. While there are screening tools used for enquiry about domestic violence in pregnancy, there are variations in the tools used, the frequency and timing of enquiry, and the response/referral pathways across professions. Research exists on the role of health care professionals such as midwives, doctors, and nurses with regards to domestic violence, however little is understood about the collective and shared experience of maternity care professionals who screen for and respond to domestic violence in the peripartum period.

Methods

A qualitative evidence synthesis of maternity care professionals’ preparedness for and experiences of screening and responding to disclosures of domestic violence in the peripartum period will be conducted. Qualitative studies of any design, and mixed method and other design studies where qualitative data can be extracted will be considered for inclusion. A systematic search of the following electronic bibliographic databases will be conducted: ASSIA, CINAHL, EMBASE, Maternity and Infant Care, MEDLINE, PsycINFO and SocINDEX. The Critical Skills Appraisal Programme (CASP) qualitative studies tool will be used to assess methodological quality of included studies. Data synthesis will involve three sequential stages, coding, development of descriptive themes and generation of analytical themes. Confidence in findings will be assessed using the Grading of Recommendations Assessment, Development and Evaluation-Confidence in the Evidence from Reviews of Qualitative research (GRADE-CERQual) tool.

Discussion

This QES will provide a deeper understanding of maternity care professionals’ preparedness for and experiences of screening and responding to domestic violence disclosures in the peripartum period. The findings will, potentially, identify what aspects of education and preparedness work well and what might be improved.
Prevalence of Dural Puncture headache after caesarean section at a Tertiary Hospital in the Gambia
Authors: Anyanwu Matthew , Coker Admire , Simon Donkor
Published: April 2024

Background

Following a caesarean section performed under spinal anaesthesia, a common complication is post-dural puncture headache (PDPH). Spinal anaesthesia has become the most common anaesthetic procedure during caesarean section in our practice. Therefore, knowing the prevalence and risk factors of PDPH will inform practice and add value in our obstetrics practice.

Methodology

A cross-sectional study was conducted at Edward Francis Small Teaching Hospital from July to. September 2023. A structured data collection tool was used to collect data. The data was entered into a computer database and analyzed using the SPSS version 26. Pain was graded using a 10-cm visual analogue scale. Results were expressed in simple descriptive statistics and test of significance was set at p-value 0.05.

Results

A total of 89 participants with mean age of 28 years (SD±6.1) and majority 45(50.6%), between 21 to 30 years. Majority had low parity (0 to 3), 64(71.9%), emergency CS of 71(79.8%), while only 20.2% (n=18) were elective CS. Overall prevalence of Post Dural Puncture Headache (PDPH) was 42.7% with majority of cases presenting with Occipital headache (29.2%), lasting for 3hrs (18%). A statistically significant association between PDPH and Gestational age withp-value (p=0.02); number of attempts withp-value (p=0.01);larger needle gauge and number of CSF drops (p=0.01), respectively were observed.

Conclusion

Prevalence of PDPH was high and associated with the use of large needle gauges, multiple attempts and increased CSF drops. Patients that underwent emergency CS, have a higher risk of developing Post-Dural Puncture Headache.
Infant spatial relationships with adult males in a wild primate: males as mitigators or magnifiers of intergenerational effects of early adversity?
Authors: Zipple Matthew N , Southworth Chelsea A , Zipple Stefanie P , Archie Elizabeth A , Tung Jenny , Alberts Susan C
Published: April 2024

Adult male mammals can provide infants with protection and enhance their access to resources. They can also pose a risk to infants, either directly through infanticide or other aggression, or indirectly by placing infants at increased risk of conspecific or heterospecific conflict. Both benefits and costs may be especially important for offspring born to mothers in poor condition. Here we present the most detailed analysis to date of the influence of adult non-human primate males on a wide range of infant behaviors, and a description of the predictors of individual infants’ proximity to adult males. We show that the number of adult males near an infant predicts many infant behavioral traits, including aspects of the mother-infant relationship, infant activity budgets, and the frequency of social interactions with non-mothers. Infant exposure to adult males is statistically significantly repeatable over time (R = 0.16). This repeatability is partially explained by whether the infant’s mother experienced early life adversity: offspring of high-adversity mothers spent time in close proximity to more males during the first months of life. Our results are consistent with the possibility that the effects of maternal early life adversity can be mitigated or magnified by relationships with adult males.
Quantitative chromatin protein dynamics during replication origin firing in human cells
Authors: Gadi Sampath Amitash , Hendriks Ivo Alexander , Nielsen Christian Friberg , Popova Petya , Hickson Ian D. , Nielsen Michael Lund , Toledo Luis
Published: April 2024

Accurate genome duplication requires a tightly regulated DNA replication program, which relies on the fine regulation of origin firing. While the molecular steps involved in origin firing have been determined predominantly in budding yeast, the complexity of this process in human cells has yet to be fully elucidated. Here, we describe a straightforward proteomics approach to systematically analyse protein recruitment to the chromatin during induced origin firing in human cells. Using a specific inhibitor against CHK1 kinase, we induced a synchronised wave of dormant origin firing (DOF) and assessed the S phase chromatin proteome at different time points. We provide time-resolved loading dynamics of 3,269 proteins, including the core replication machinery and origin firing factors. This dataset accurately represents known temporal dynamics of proteins on the chromatin during the activation of replication forks and the subsequent DNA damage due to the hyperactivation of excessive replication forks. Finally, we used our dataset to identify the condensin II subunit NCAPH2 as a novel factor required for efficient origin firing and replication. Overall, we provide a comprehensive resource to interrogate the protein recruitment dynamics of replication origin firing events in human cells.
Yap is a Nutrient Sensor Sensitive to the Amino Acid L-Isoleucine and Regulates Expression of Ctgf in Cardiomyocytes
Authors: Nelson Victoria L. , Eadie Ashley L. , Madhu Malav , Platt Mathew , Mercer Angella , Pulinilkunnil Thomas , Kienesberger Petra , Simpson Jeremy A. , Brunt Keith R.
Published: April 2024

Myocardial infarction and reperfusion is a complex injury consisting of many distinct molecular stress patterns that influence cardiomyocyte survival and adaptation. Cell signalling that is essential to cardiac development also presents potential disease-modifying opportunities to recover and limit myocardial injury or maladaptive remodelling. Here we hypothesized that Yap signalling could be sensitive to one or more molecular stress patterns associated with early acute ischemia. Yap, not Taz, patterns of expression differ in post-myocardial infarct compared to peri-infarct tissue suggesting cell-specificity that would be challenging to resolve for causation in vivo. Using H9c2 ventricular myotubes in vitro as a model, Yap levels were most sensitive to nutrient deprivation compared to other stress patterns typified by ischemia within the first hour of stress. Moreover, this is mediated by amino acid availability, dominantly L-isoleucine, and influences the expression of Ctgf—a major determinant of myocardial adaptation after injury. These findings present novel opportunities for future therapeutic development and risk assessment for myocardial injury and adaptation.
Bayesian estimation of trunk-leg coordination during walking using phase oscillator models
Authors: Furukawa Haruma , Arai Takahiro , Funato Tetsuro , Aoi Shinya , Aoyagi Toshio
Published: April 2024

In human walking, the legs and other body parts coordinate to produce a rhythm with appropriate phase relationships. From the point of view for rehabilitating gait disorders, such as Parkinson Disorders, it is important to understand the control mechanism of the gait rhythm. A previous study showed that the antiphase relationship of the two legs during walking is not strictly controlled using the reduction of the motion of the legs during walking to coupled phase oscillators. However, the control mechanisms other than those of the legs remains unknown. In particular, the trunk moves in tandem with the legs and must play an important role in stabilizing walking because it is above the legs and accounts for more than half of the mass of the human body. This study aims to uncover the control mechanism of the leg-trunk coordination in the sagittal plane using the coupled phase oscillators model and Bayesian estimation. We demonstrate that the leg-trunk coordination is not strictly controlled, as well as the interleg coordination.
Systematic identification of exercise-induced anti-aging processes involving intron retention
Authors: Kodama Hayata , Ijima Hirotaka , Matsui Yusuke
Published: April 2024

Exercise is one of the most promising anti-aging interventions for maintaining skeletal muscle health in older adults. Nine “Aging Hallmarks”, proposed by López-Otín, offer insights into the aging process; however, the link between these hallmarks and exercise is not fully elucidated. In this study, we conducted a systematic multi-omics analysis of skeletal muscles, focusing on aging and exercise, based on gene signatures for aging hallmarks. It is posited that mRNA splicing activity, linked to genomic instability, constitutes a fundamental hallmark of aging, and it exhibits divergent expression patterns in response to aging and exercise. Additionally, we analysed splicing events and discovered that intron retention (IR) is significantly impacted by aging, exhibiting contrasting changes to those induced by resistance training in the older cohort. The isoforms characterised by IR are notably enriched in mitochondrial functions. Conclusively, our results underscore the significance of splicing mechanisms as a novel aspect of aging hallmarks in skeletal muscles and propose a new mechanism by which exercise exerts its anti-aging effects on skeletal muscles through intron retention.

Key points summary

Skeletal muscle aging involves significant structural and functional changes, including loss of muscle mass, decline in strength, and mitochondrial dysfunction, all influenced by genomic instability.

Exercise has been identified as a key intervention that counters genomic instability and modulates mRNA splicing patterns, particularly through the regulation of Intron Retention, to mitigate aging effects in skeletal muscle.

We reveal the novel role of IR, especially in principal isoforms, where it is linked to critical cellular processes like mitochondrial function, suggesting a targeted pathway through which exercise exerts its anti-aging effects.

The findings provide new insights into the molecular mechanisms underlying the beneficial effects of exercise on aging skeletal muscle.

This study lays the groundwork for future research on exercise-induced modulation of mRNA splicing as a therapeutic strategy for aging and potentially age-related diseases, pointing towards a significant shift in how we approach aging intervention strategies.
SCREP: Towards Single-Cell Drug Response Prediction by Pharmacogenomic Embedding Enhanced Meta-Pretraining and Few-Shot Transfer Learning
Authors: Ge Shuang , Sun Shuqing , Ren Yiming , Xu Huan , Cheng Qiang , Ren Zhixiang
Published: April 2024

Objective

Single-cell pharmacogenomic data is crucial for identifying biomarkers and understanding resistance mechanisms. However, the limited availability of those data poses significant challenges for efficient pre-training and thus hinders the generalization capability of the model. This paper aims to develop an efficient predictive model for single-cell drug response inference by leveraging knowledge from a bulk dataset.

Methods

To translate knowledge from bulk cell lines to single-cell analysis, this paper proposes a meta-pretraining and few-shot transfer learning frame-work based on pharmacogenomic embeddings. To enhance feature representation and alignment, genomic information is processed by a position-based feature extraction network to extract contextual features. Simultaneously, a graph-aware Transformer is developed to capture interatomic relations for drug information representation. Underlying this framework, key drug action pathways can be identified at the cellular level through the proposed gene gradient attribution algorithm.

Results

This model integrates drug response data from 223 drugs across 14 tissues for meta pre-training, followed by transfer and testing on seven single-cell datasets. In comparison to other models, the proposed framework achieves an average accuracy increase of 4.58% for pre-trained drugs and demonstrates a 20% improvement in generalization performance for previously unseen drugs. Case studies further illustrate its capability to differentiate between resistance genes.

Conclusion

The proposed framework exhibits enhanced generalization capabilities in predicting cellular responses across multiple drugs, including unseen drugs. This model serves as an effective tool for investigating drug action pathways and elucidating resistance mechanisms from single-cell insights, with significant implications for guiding clinical medication practices.