bluuebunny/crossref_metadata_2025 huggingface dataset:
SMoRe GloS: An efficient and flexible framework for inferring global sensitivity of agent-based model parameters
Authors: Bergman Daniel R. , Jackson Trachette , Jain Harsh Vardhan , Norton Kerri-Ann
Published: September 2024

Agent-based models (ABMs) have become essential tools for simulating complex biological, ecological, and social systems where emergent behaviors arise from the interactions among individual agents. Quantifying uncertainty through global sensitivity analysis is crucial for assessing the robustness and reliability of ABM predictions. However, most global sensitivity methods demand substantial computational resources, making them impractical for highly complex models. Here, we introduce SMoRe GloS (SurrogateModeling forRecapitulatingGlobalSensitivity), a novel, computationally efficient method for performing global sensitivity analysis of ABMs. By leveraging explicitly formulated surrogate models, SMoRe GloS allows for comprehensive parameter space exploration and uncertainty quantification without sacrificing accuracy. We demonstrate our method’s flexibility by applying it to two biological ABMs: a simple 2D cell proliferation assay and a complex 3D vascular tumor growth model. Our results show that SMoRe GloS is compatible with simpler methods like the Morris one-at-a-time method, and more computationally intensive variance-based methods like eFAST. SMoRe GloS accurately recovered global sensitivity indices in each case while achieving substantial speedups, completing analyses in minutes. In contrast, direct implementation of eFAST amounted to several days of CPU time for the complex ABM. Remarkably, our method also estimates sensitivities for ABM parameters representing processes not explicitly included in the surrogate model, further enhancing its utility. By making global sensitivity analysis feasible for computationally expensive models, SMoRe GloS opens up new opportunities for uncertainty quantification in complex systems, allowing for more in depth exploration of model behavior, thereby increasing confidence in model predictions.
Machine Learning-based Predictions of Spatial Metabolic Profiles Demonstrate the Impact of Morphology on Astrocytic Energy Metabolism
Authors: Papavasileiou Paris , Farina Sofia , Koronaki Eleni D. , Boudouvis Andreas G. , Bordas Stéphane P.A. , Skupin Alexander
Published: September 2024

This work introduces a machine learning framework that allows the investigation of the influence of reaction centers on the metabolic state of astrocyte cells. The proposed ML framework takes advantage of spatial astrocyte metabolic data stemming from numerical simulations for different reaction center configurations and allows for the following: (i) Discovery of cell groups of similar metabolic states and investigation of the reaction center configuration within each group. This approach allows for an analysis of the importance of the specific location of the reaction centers for a potentially critical metabolic state of the cell. (ii) Qualitative prediction of the energetic state of the cell (based on [ATP]: [ADP]) and quantitative prediction of the metabolic state of the cell by predicting the spatial average concentration of the metabolites or the complete spatial metabolic profile within the cell. (iii) Finally, the framework allows for the post hoc analysis of the developed quantitative predictive models using a SHAP approach to investigate the influence of the reaction center positions for further support of the insights drawn in steps (i)-(iii). Following the implementation of the framework, we observe that a uniform mitochondrial distribution within the cell results in the most robust energetic cell state. On the contrary, realizations of polarized mitochondrial distributions exhibit the worst overall cell health. Furthermore, we can make accurate qualitative predictions regarding cell health (accuracy= 0.9515,recall= 0.9753) and satisfactory predictions for the spatial average concentration and spatial concentration profiles of most of the metabolites involved. The techniques proposed in this study are not restricted to the dataset used. They can be easily used in other datasets that include findings from various metabolic computational models.
Recent origin of modern clades of iron oxidizers and low clade fidelity of iron metabolisms
Authors: Tamre Erik , Fournier Gregory
Published: September 2024

Reduced iron was abundant in Earth's surface environments before their oxygenation, so iron oxidation could have been a common metabolism on the early Earth. Consequently, modern microbial iron oxidation is sometimes seen as a holdover from an earlier biosphere, but the continuity of involved lineages or the metabolic process itself has not been verified. Modern neutrophilic iron oxidizers use cytochrome-porin Cyc2 as the initial electron acceptor in iron oxidation. With the protein as a proxy for the metabolism, we performed a phylogenetic analysis of Cyc2 to understand the evolutionary history of this microbial iron oxidation pathway. In addition to known iron oxidizers, we identified Cyc2 orthologs in gammaproteobacterial endosymbionts of lucinid bivalves. These bivalves have a robust fossil record and rely on sea-grass meadows that only appear in the Cretaceous, providing a valuable time calibration in the evolutionary history of Cyc2. Our molecular clock analysis shows that extant sampled Cyc2 diversity has surprisingly recent common ancestry, and iron oxidation metabolisms in Gallionellaceae, Zetaproteobacteria, and photoferrotrophic Chlorobi likely originated in the Neoproterozoic or the Phanerozoic via multiple transfer events. The groups responsible for microbial iron oxidation have thus changed over Earth history, possibly reflecting the instability of niches with sufficient reduced iron. We note that frequent transfer and changing taxonomic distribution may be a general pattern for traits which are selected for sporadically across space and time. Based on iron metabolism and other processes, we explore this concept of a trait's "clade fidelity" (or lack thereof) and establish its evolutionary importance.
Robust RNA Secondary Structure Prediction with a Mixture of Deep Learning and Physics-based Experts
Authors: Qiu Xiangyun
Published: September 2024

A mixture of experts (MoE) approach is developed to mitigate poor out-of-distribution (OOD) generalization of deep learning (DL) models for single-sequence-based prediction of RNA secondary structure. The main idea is to use DL models for in-distribution (ID) test sequences to take advantage of their superior ID performances, while relying on physics-based models for OOD sequences to ensure robust predictions. One key ingredient of the pipeline, named MoEFold2D, is automated ID/OOD detection via consensus analysis of an ensemble of DL model predictions without accessing training data during inference. Specifically, motivated by the clustered distribution of known RNA structures, a collection of distinct DL models is trained by iteratively leaving one cluster out. Each DL model hence serves as an expert on all but one cluster in the training data. Consequently, for an ID sequence, all but one DL model makes accurate predictions consistent with one another, while an OOD sequence yields highly inconsistent predictions among all DL models. Consensus analysis of DL predictions categorizes test sequences as ID or OOD. ID sequences are then predicted by averaging the DL models in consensus, and OOD sequences are predicted using physics-based models. Instead of remediating generalization gaps with alternative approaches such as transfer learning and sequence alignment, MoEFold2D circumvents unpredictable ID-OOD gaps and combines the strengths of DL and physics-based models to achieve accurate ID and robust OOD predictions.
Acute tuft cell ablation induces malabsorption and alterations in secretory and immune cell lineages in small intestine
Authors: Momoh Michael , Adeniran Francisca , Ramos Cynthia , DelGiorno Kathleen E. , Seno Hiroshi , Roland Joseph T. , Kaji Izumi
Published: September 2024

Background & Aims

Intestinal tuft cells have recently been the interest of studies in several human gastrointestinal diseases. However, the impact of tuft cell deletion on intestinal physiological functions are not fully understood. This study investigated the effects of acute tuft cell loss on nutrient absorption and cell lineage differentiation.

Methods

Tuft cell deletion was induced inDCLK1-IRES-GFP-CreERT2/+;Rosa-DTA(DCLK1-DTA) mice by a single tamoxifen injection concomitant with littermate controls. Intestinal tissues were analyzed two-, four-, or seven-days post tamoxifen injection.

Results

DCLK1-DTA mice showed significantly shortened small intestinal length and body weight loss on day 4. Impaired activities of Na+-dependent glucose transporter 1 (SGLT1) and cystic fibrosis transmembrane regulator (CFTR) were observed in Ussing chamber experiments. Tissue immunostaining revealed a transient deletion of intestinal and biliary tuft cells, which was maximal on day 4 and recovered by day 7. On day 4 post tamoxifen, cholecystokinin (CCK)+ enteroendocrine cell numbers were increased particularly in the ileum. Correlated with the tuft cell reduction, the frequency of mislocalized Paneth cells, which were co-labeled by Paneth and goblet cell markers, was increased in the villus regions. In the lamina propria, fewer mast cells and leukocytes were found in the day 4 DCLK1-DTA mice than in controls.

Conclusion

Ablation of intestinal tuft cells may induce nutrient malabsorption through alterations in epithelial cell proliferation and differentiation along with changes in mucosal defense response. These observations elucidate a new role for tuft cells in regulating intestinal absorption and mucosal regeneration.
BCR ligation selectively inhibits IgE class switch recombination
Authors: Wade-Vallance Adam K. , Yang Zhiyong , Libang Jeremy B. , Krishnapura Ananya R. , Jung James B. , Matcham Emily W. , Robinson Marcus J. , Allen Christopher D. C.
Published: September 2024

Mechanisms that restrict class switch recombination (CSR) to IgE limit the subsequent production of IgE antibodies and therefore the development of allergic disease. Mice with impaired B cell receptor (BCR) signaling have significantly increased IgE responses, consistent with a role for BCR signaling in IgE regulation. While prior work focused on BCR signaling in IgE-expressing cells to explain these findings, it has been reported that BCR signaling can reduce CSR. Therefore, we investigated the possibility that IgE CSR might be particularly sensitive to inhibition by BCR signaling in unswitched B cells. We found that immunization of mice with high-affinity antigen resulted in reduced representation of IgE-expressing cells among germinal center B cells and plasma cells relative to a low-affinity antigen. Mechanistic experiments with cultured mouse B cells demonstrated that BCR ligands selectively inhibited IgE CSR in a dose-, affinity-, and avidity-dependent manner. Signaling via Syk was required for the inhibition of IgE CSR following BCR stimulation, whereas inhibition of the PI3K subunit p110δ increased IgE CSR independently of BCR ligation. The inhibition of IgE CSR by BCR ligands synergized with IL-21 or TGFβ1. BCR ligation also inhibited CSR to IgE in human tonsillar B cells, and this inhibition was also synergistic with IL-21. These findings establish that IgE CSR is uniquely susceptible to inhibition by BCR signaling in mouse and human B cells, with important implications for the regulation and pathogenesis of allergic disease.
Examination of INPP5A in uveal melanoma uncovers novel calcium transients
Authors: Onken Michael D. , Kaltenbronn Kevin M. , Makepeace Carol M. , Piggott Kisha D. , Blumer Kendall J.
Published: September 2024

Uveal melanoma is a highly aggressive intraocular cancer that metastasizes in about half of patients whereupon it is inexorably fatal. Uveal melanomas (UM) are distinct from other melanomas because they are driven by constitutively activating mutation in the heterotrimeric G protein alpha subunits Gq (GNAQ) and G11 (GNA11). This results in constitutive production of inositol trisphosphate (IP3) by phospholipase C-beta downstream of Gq/11. In normal cells, increased IP3 causes calcium release from the endoplasmic reticulum, which would be cytotoxic if maintained chronically, but UM cells are able to survive constitutive IP3 production. INPP5A, which dephosphorylates and thus inactivates IP3, is highly upregulated in UM cells compared to other melanomas and another study has shown that INPP5A is necessary for UM cell survival. To understand the mechanism of calcium regulation in response to IP3, we collected single-cell calcium measurements and found that UM cells driven by constitutively active Gq/11 produce spontaneous calcium transients. These calcium oscillations are not seen in any other melanoma cell lines unless induced by an agonist, but they are present in patient UM tumor samples. Moreover, these calcium oscillations are lost in UM cells treated with the Gq/11 inhibitor FR900359, demonstrating their dependence on constitutive Gq/11 activity. We found that the INPP5A inhibitor YU144369 causes significant changes in calcium oscillations in UM cells, demonstrating a role for INPP5A in this system. INPP5A is tethered to membranes by C-terminal prenylation and palmitoylation, suggesting that localization may play a role in INPP5A regulation of IP3 levels. GFP-tagged INPP5A was localized to plasma membrane, nuclear envelop, endoplasmic reticulum, and lysosomes. Mutation of the palmitoylation site significantly reduced localization to the plasma membrane, while mutation of the prenylation site resulted in purely nucleoplasmic localization of INPP5A. These results demonstrate a role of palmitoylation in the regulation of INPP5A localization and mobilization in UM cells.
Placozoan secretory cell types implicated in feeding, innate immunity and regulation of behavior
Authors: Mayorova Tatiana D. , Koch Thomas Lund , Kachar Bechara , Jung Jae Hoon , Reese Thomas S. , Smith Carolyn L.
Published: September 2024

Placozoa are millimeter-sized, flat, irregularly shaped ciliated animals that crawl on surfaces in warm oceans feeding on biofilms, which they digest externally. They stand out from other animals due to their simple body plans. They lack organs, body cavities, muscles and a nervous system and have only seven broadly defined morphological cell types, each with a unique distribution. Analyses of single cell transcriptomes of four species of placozoans revealed greater diversity of secretory cell types than evident from morphological studies, but the locations of many of these new cell types were unknown and it was unclear which morphological cell types they represent. Furthermore, there were contradictions between the conclusions of previous studies and the single cell RNAseq studies. To address these issues, we used mRNA probes for genes encoding secretory products expressed in different metacells inTrichoplax adhaerensto localize cells in whole mounts and in dissociated cell cultures, where their morphological features could be visualized and identified. The nature and functions of their secretory granules were further investigated with electron microscopic techniques and by imaging secretion in live animals during feeding episodes. We found that two cell types participate in disintegrating prey, one resembling a lytic cell type in mammals and another combining features of zymogen gland cells and enterocytes. We identified secretory epithelial cells expressing glycoproteins or short peptides implicated in defense. We located seven peptidergic cell types and two types of mucocytes. Our findings reveal mechanisms that placozoans use to feed and protect themselves from pathogens and clues about neuropeptidergic signaling. We compare placozoan secretory cell types with cell types in other animal phyla to gain insight about general evolutionary trends in cell type diversification, as well as pathways leading to the emergence of synapomorphies.
Halogenated cholesterol alters the phase behavior of ternary lipid membranes
Authors: Mehta Deeksha , Crumley Elizabeth K. , Lou Jinchao , Best Michael D. , Waxham M. Neal , Heberle Frederick A.
Published: September 2024

Eukaryotic plasma membranes exhibit nanoscale lateral lipid heterogeneity, a feature that is thought to be central to their function. Studying these heterogeneities is challenging since few biophysical methods are capable of detecting domains at sub-micron length scales. We recently showed that cryogenic electron microscopy (cryo-EM) can directly image nanoscale liquid-liquid phase separation in extruded liposomes due to its ability to resolve the intrinsic thickness and electron density differences of ordered and disordered phases. However, the intensity contrast between these phases is poor compared to conventional fluorescence microscopy and is thus both a limiting factor and a focal point for optimization. Because the fundamental source of intensity contrast is the spatial variation in electron density within the bilayer, lipid modifications aimed at selectively increasing the electron density of one phase might enhance the ability to resolve coexisting phases. To this end, we investigated model membrane mixtures of DPPC/DOPC/cholesterol in which one hydrogen of cholesterol’s C19 methyl group was replaced by an electron-rich halogen atom (either bromine or iodine). We characterized the phase behavior as a function of composition and temperature using fluorescence microscopy, FRET, and cryo-EM. Our data suggest that halogenated cholesterol variants distribute approximately evenly between liquid-ordered and liquid-disordered phases and are thus ineffective at enhancing the intensity difference between them. Furthermore, replacing more than half of the native cholesterol with halogenated cholesterol variants dramatically reduces the size of membrane domains. Our results reinforce how small changes in sterol structure can have a large impact on the lateral organization of membrane lipids.
gReLU: A comprehensive framework for DNA sequence modeling and design
Authors: Lal Avantika , Gunsalus Laura , Nair Surag , Biancalani Tommaso , Eraslan Gokcen
Published: September 2024

Deep learning models are increasingly being used to perform a variety of tasks on DNA sequences, such as predicting tissue- and cell type- specific sequence activity, deriving cis-regulatory rules, predicting non-coding variant effects, and designing synthetic regulatory sequences. However, these models require specialized knowledge to build, train and interpret correctly. In addition, the field is hampered by the lack of interoperability between models and software built by different groups. Here we present gReLU, a comprehensive software framework that enables users to easily execute advanced sequence modeling pipelines, including data preprocessing, model training, hyperparameter tuning, evaluation, interpretation, variant effect prediction, and design of novel regulatory elements. The software is accompanied by a model zoo containing state-of-the-art pre-trained models that can easily be downloaded, applied, and fine-tuned. This framework and resources will accelerate research across the field of DNA sequence modeling and enable the effective design of synthetic regulatory elements.
Loss ofTbx4Affects Postnatal Lung Development and Predisposes to Pulmonary Hypertension
Authors: Maldonado-Velez Gabriel , Mickler Elizabeth A. , Cook Todd G. , Aldred Micheala A.
Published: September 2024

Pulmonary arterial hypertension (PAH) is a progressive vascular disease characterized by remodeling of the precapillary pulmonary arteries. Genomic variation within the T-box 4 (TBX4) transcription factor is the second most common genetic cause of PAH, and can also cause severe lung developmental disorders with neonatal PH. Currently, the effect of TBX4 loss-of-function on later stages of lung development and predisposition to lung disease, including PH, is not well understood. Therefore, we have generatedTbx4conditional knockout (Tbx4-CKO) mice in whichCre recombinasedeletes exon 5 ofTbx4within the embryonic lung mesenchyme to create a null allele. We harvested lungs from these mice at various timepoints to examine alveologenesis, vascularization, vascular remodeling, lung cellular composition, and disruption of transcriptional activity compared with control lungs. Right ventricular systolic pressure (RVSP) was measured in six-month-old mice to evaluate for PH.Tbx4-CKOlungs show enlargement of airspaces, as confirmed by an increase in mean linear intercept at P14 (24.9%), P36 (31.5%), and P180 (49.6%). These lungs also show a 39.3% decrease in von Willebrand Factor-positive vessels and a 14.2% increase in vessel wall thickness. Consistent with these results,Tbx4-CKOmice show a statistically significant increase of 15.7% in RVSP and 16.3% in the Fulton index. Bulk-RNA sequencing analysis revealed enrichment of pathways and genes relevant to lung alveologenesis, angiogenesis, and PH. Our results show that disruption ofTbx4expression during early lung development is sufficient to disrupt postnatal lung development and circulation.
Gli2 Overexpression Alters the Differentiation Status of Dedifferentiated Liposarcoma Cells and Results in an Immunosuppressive Myeloid Phenotype in Orthotopic Tumors
Authors: Bennett Natalie E. , Beadle Erik P. , Parker Dominique V. , Coe Erykah J. , Cottam Matthew A. , Baum Jennifer E. , Miller Jade S. , Serrenho Joseph A. , Rhoades Julie A.
Published: September 2024

Sarcomas are a rare classification of tumor derived from tissues of mesenchymal origin including bone, fat, muscle, cartilage, and blood vessels. These tumors often grow rapidly and have limited treatment options with few significant therapeutic advances in recent years. Liposarcomas (LPSs), the most common type of malignant soft tissue sarcoma, are derived from mesenchymal progenitors that have undergone an adipogenic lineage commitment compared to their multipotent counterparts. Interestingly, the grade of differentiation within LPS can vary highly, and the differentiation status of these tumors can drastically affect prognosis and likelihood of metastasis, making tumor differentiation a potential mechanism to target in liposarcoma development. Here, we show that overexpression of the Hedgehog transcription factor Gli2 in dedifferentiated liposarcoma (DDLPS) cells represses adipogenic differentiation while simultaneously activating markers of osteoblast differentiationin vitro. In addition, we observed marked differences in cytokine expression and secretion, prompting us to perform orthotopic fat pad injections of control and Gli2 overexpressing DDLPS cells. Using flow cytometry, we observed distinct changes in fat pad macrophage populations, with a particular increase in M2-like macrophages. Taken together, we find that overexpression of Gli2 in DDLPS cells alters their differentiation capacity and interactions between tumor cells and macrophages, highlighting a novel role for this developmental transcription factor in liposarcoma pathogenesis.
Complex genomic ancestry in southern regions and drivers of continental-level genetic diversity in the wolves of Asia
Authors: Hennelly Lauren M. , Parreira Barbara R , Noble Ash , Scharff-Olsen Camilla , Kemahlı Aytekin M. Çisel , Şekercioğlu Çağan H. , Kosintsev Pavel , Paule Ladislav , Hulva Pavel , Stenøien Hans K. , Habib Bilal , Fatima Hira , Sarwar Ghulam , El-Haddad Samara P. , Hailer Frank , Sun Xin , Gomes Martins Nuno Filipes , Gilbert M Thomas P , Sinding Mikkel-Holger S. , Sacks Benjamin N , Gopalakrishnan Shyam
Published: September 2024

Gray wolves (Canis lupus) in Asia encompass most of the species’ global genetic diversity and many endangered populations. However, a clear understanding of the evolutionary history of wolves from many parts of Asia, especially southern regions, is lacking. We used 98 whole genomes of wolves sampled across Eurasia to better resolve their evolutionary history by investigating phylogenetic and gene flow histories across the genome, and to characterize their demographic history and genetic diversity. The strongest barriers to gene flow coincided with boundaries separating the three major extant wolf lineages - Indian, Tibetan, and Holarctic. Wolves in the central Asian mountain ranges belonged to the Holarctic lineage, and despite their geographic adjacency only share minimal ancestry with the Tibetan lineage. In contrast, wolves from eastern Asia share population-wide ancestry with the Tibetan lineage, which may reflect an unsampled lineage similar, but not exactly to, the modern-day Tibetan lineage. Wolves from southwestern Asia also share population-wide ancestry with the Indian lineage, likely due to old (>6kya) admixture events. Long-term historical declines over the last 100,000 years, geographic isolation, and recent inbreeding have resulted in the Indian and Tibetan wolves having some of the lowest levels of genetic diversity and highest realized genetic loads. In contrast, adjacent populations exhibit some of the highest genetic diversity, due in part to admixture along contact zones. Our study illustrates how using multiple approaches that consider heterogenous signals across the genome can more fully resolve the historical and contemporary processes that have led to present-day species’ diversity.
Rapid parallel adaptation in distinct invasions of Ambrosia artemisiifolia is driven by large-effect structural variants
Authors: Battlay Paul , Craig Samuel , Putra Andhika R , Monro Keyne , De Silva Nissanka P , Wilson Jonathan , Bieker Vanessa C , Kabir Saila , Shamaya Nawar , van Boheemen Lotte , Rieseberg Loren H , Stinchcombe John R , Fournier-Level Alexandre , Martin Michael D , Hodgins Kathryn R
Published: September 2024

When introduced to multiple distinct ranges, invasive species provide a compelling natural experiment for understanding the repeatability of adaptation. Ambrosia artemisiifolia is an invasive, noxious weed and chief cause of hay fever. Leveraging over 400 whole-genome sequences spanning the native range in North America and two invasions in Europe and Australia, we inferred demographically distinct invasion histories on each continent. Despite substantial differences in genetic source and effective population size changes during introduction, scans of both local climate adaptation and divergence from the native range revealed genomic signatures of parallel adaptation between invasions. Disproportionately represented among these parallel signatures are 37 large haploblocks - indicators of structural variation - that cover almost 20% of the genome and exist as standing genetic variation in the native range. Many of these haploblocks are associated with traits important for adaptation to local climate, like size and the timing of flowering, and have rapidly reformed native range clines in invasive ranges. Others show extreme frequency divergence between ranges, consistent with a response to divergent selection on different continents. Our results demonstrate the key role of large-effect standing variants in rapid adaptation during range expansion, a pattern that is robust to diverse invasion histories.
Assessing Aquatic Avian Biodiversity along Hydropower Dam Gradient: Understanding Impacts of Kurichhu Dam-Induced River Fragmentation in Kurrichu River Basin
Authors: Nidup Tshering , Dorji Yonten
Published: September 2024

Humans are the dominant ecological and evolutionary force on the planet today, transforming habitats, polluting environments, and changing climates. Obstruction to the passage of flowing rivers has a significant environmental impact on fish. It causes rippling effects on wildlife, food web, and habitat throughout the river ecosystem. However, little is known about how these fragmented habitats impact aquatic avifaunal diversity and composition along the stretch of the river. The Kurichhu hydropower dam has disconnected the continuity of upper and lower portions of the Kurichhu River for over 14 years. To investigate this, avian community data were collected at 51 point-count stations, with 17 plots each: in R (Reservoir), AR (Above Reservoir), and BD (Below Dam) along the Kurichhu hydropower dam gradient. In total, 587 individual birds of 33 species distributed under 14 families were encountered. Shannon-wiener diversity among these three sites was higher for the R pool (H′= 3.04) than AR (H′= 2.74), and the lowest was in BD (H′= 2.44). Menhinicks richness index was higher for AR (D= 2.40) than the R pool (D =1.95) and lowest found in BD (D =1.73). This study recorded two species of birds in vulnerable and another two species of the ordercharadriformesin the near-threatened category. Our findings found that habitats along Kurichhu, around Gyelposhing area, are an important stopover and staging area for migratory waterbird species. In light of these findings, addressing the ecological ramifications of river fragmentation on avian diversity is crucial. The marked variation in species richness and diversity across the river segments highlights the pressing need for targeted conservation strategies. To mitigate adverse impacts, we recommend implementing ecological flow regimes and creating wildlife corridors to reconnect fragmented habitats, enhancing habitat quality and supporting avian biodiversity.
First report ofHexamita nelsoniin blue mussel (Mytilus edulis): morphology, phylogeny, and host-parasite interaction
Authors: Alfjorden Anders , Jerlström Hultqvist Jon , Svärd Staffan , Burki Fabien
Published: September 2024

Bivalve diseases caused by protozoan parasitic infection are monitored by coordinated surveillance programs across European member countries. These routine monitorings of bivalve health, however, only survey a few relatively well known parasites, which may leave undetected a range of lesser known opportunistic protozoan agents. Under increased stress, for example due to shifting environmental conditions affecting water quality and nutrient access, these opportunistic parasites may develop pathogenicity impacting reproduction or growth and therefore decreasing the success and future development of aquaculture or wild population sustainability. During routine histopathological surveillance of blue mussels in Sweden, we noticed cryptic lesions in the adductor muscle in high prevalence over a period ranging from 2017 to 2022. These lesions suggested cell infiltration and degenerative changes in the muscle tissues. In this study, we report on the isolation, identification, and culture of the protistan cells likely responsible for at least some of these lesions. Using histology and cytology, molecular phylogeny, and catalyzed reporter deposition fluorescence in situ hybridization (CARD-FISH), we show that the cells correspond to theH. nelsonisequence initially isolated from oysters. We also reveal the presence ofH. nelsoniin the digestive glands and mantel, and that this parasite might be horizontally transmitted from adult to larvae via infections within gonads, ovaries. This study represents the first report ofH. nelsoniin blue mussel.
Adaptive Nesting Strategies of Dusky Crag Martins in desert ecoregions: Implications for Conservation and Bioinspired Innovations
Authors: Mukherjee Manasi , Pant Aali , Sankhala Kirti , Sandeep Devavrath , Mukerji Mitali
Published: September 2024

Understanding the adaptive strategies of species in extreme environments is crucial for biodiversity conservation. This study is the first to explore the nesting behavior of the Dusky Crag MartinPtyonoprogne concolorin the Thar Desert, Rajasthan. It examined the bird’s site selection, nesting frequency, and construction methods. Soil samples from nest sites and source locations were analyzed to identify structural and elemental properties.

The bird adopts several strategies, such as aligning its nesting period with the monsoon, reusing nests, and utilizing both macro and micro-level additive construction techniques. Detailed analysis revealed a preference for cohesionless sand with low moisture and higher Soil Organic Carbon (SOC) content. The bird strategically alternates light and dark soil layers in its nest. Structural and elemental analyses using optical microscopy and Scanning Electron Microscopy (SEM), and X-ray Fluorescence (XRF), shows the light layers is rich in calcium oxide and fibrous material, and dark layers containing higher iron oxide and partially decomposed litter fromProsopis cineraria.

The study concludes that alternating calcium-rich and iron-rich layers enhances energy efficiency, structural integrity, and pathogen resistance in nest construction. his behavior underscores the evolutionary adaptations ofP. concolorto the extreme desert environment. These findings highlight the importance of conserving desert habitats and provide bio-inspired insights for sustainable building and agricultural practices in arid regions.
Investigating the use of novel blood processing methods to boost the identification of biomarkers of non-small cell lung cancer
Authors: McMahon Rosalee , Lucas Natasha , Hill Cameron , Pascovici Dana , Herbert Ben , Karsten Elisabeth
Published: September 2024

1.

Background and objectives

Diagnosis of non-small cell lung cancer (NSCLC) currently relies on imaging and in-clinic visits, however these methods are not effective at detecting early-stage disease. The investigation into blood-based biomarkers aims to simplify the diagnostic process and has the potential for identifying disease-associated changes before they can be seen using imaging techniques.

Methods and design

In this study, plasma and frozen whole blood cell pellets from patients with NSCLC and healthy controls were processed using both classical as well as novel techniques to produce a unique set of 4 sample types from a single blood draw. Samples were analysed using 12 commercially available immunoassay kits in addition to liquid chromatography mass spectrometry using a Q Exactive HF-X Orbitrap to collectively screen 3974 proteins as potential biomarkers.

Results and conclusions

Analysis of all sample types produced a set of 522 differentially expressed proteins, with conventional blood analysis (proteomic analysis of plasma) accounting for only 7 of that total. Boosted regression tree analysis of the differentially expressed proteins produced a panel of 13 proteins that were able to discriminate between controls and NSCLC patients with an area under the ROC curve (AUC) of 0.864 for the set. Our rapid and reproducible blood preparation and analysis methods enable the production of high-quality data from small aliquots of complex samples that are typically seen as requiring significant fractionation prior to proteomic analysis.
Navigating a fine balance: point-mutant cheater viruses disrupt the viral replication cycle
Authors: Meir Moran , Kahn Arielle , Farage Carmel , Maoz Yael , Harel Noam , Zvi Adi Ben , Segev Shir , Volkov Maria , Yahud Ravit , Gophna Uri , Stern Adi
Published: September 2024

Cheater viruses, alternatively denoted as defective interfering viruses, cannot replicate on their own yet replicate faster than the wild type (WT) when the two viruses coinfect the same cell. Cheaters must possess dual genetic features: a defect, which leads to their inability to infect cells on their own, and a selective advantage over WT during co-infection. Previously, we have discovered two point-mutant cheaters of the MS2 bacteriophage. Here, we set out to discover the possible repertoire of cheater MS2 viruses by performing experimental evolution at a very high multiplicity of infection (MOI). Our results revealed a third point-mutant cheater that arose in eight biological replicas. Each of the three cheaters disrupts the fine balance necessary for phage replication, in different ways that create a defect + advantage. We found that over time, the point mutant cheaters accumulate additional “helper” mutations, which alter other stages of the viral replication cycle, complementing the disruptions created by the original cheater. Intriguingly, cheater and helper mutations almost always reside in very close proximity on the genome. This region encodes for multiple functions: overlapping reading frames as well as overlapping RNA structures critical for transitioning from one stage to another in the viral replication cycle. This region of overlap explains the dual functions of cheaters, as one mutation can have pleiotropic effects. Overall, these findings underscore how viruses, whose dense genomes often have overlapping functions, can easily evolve point-mutant cheaters, and how cheaters can evolve to alter the intricate balance of the viral replication cycle.
Secondary brain injury after parenchymal cerebral hemorrhage in humans: the role of oxidative stress and Endothelin-1
Authors: De Michele M. , Amisano P. , Schiavo O.G. , Carnevale R. , Cammisotto V. , Ciacciarelli A. , Berto I. , Angeloni U. , Pugliese S. , Toni D. , Lorenzano S.
Published: September 2024

Background and aims

Perihematomal hypoperfusion may lead to ischemic damage during intraparenchymal cerebral hemorrhage (ICH), resulting in worse prognosis. We aimed to (1) investigate the relationship between serum biomarkers related to oxidative stress and vasoactive substances and the occurrence of hypoperfusion and ischemic perihematomal lesions in ICH, (2) to evaluate their correlation with the volumetric evolution of the hematoma and perihematomal edema.

Methods

We enrolled 28 patients affected by ICH. Blood samples were collected at timepoint T0 (admission to Emergency-Room), T1 (12-24hs from symptoms onset), T2 (48- 72hs from onset), to measure Endothelin-1 (ET-1), nitrites/nitrates (NO), NADPH oxidase-2 (NOX-2), metalloproteinase-12 (MMP12) and asymmetric dimethylarginine (ADMA). Patients underwent brain MRI with perfusion study at T1 and MRI without perfusion at T2.

Results

12 patients had ischemic perihematomal lesions at T1. A higher NOX-2 concentration at T0 was observed in patients with ischemic perihematomal lesions compared to those without, (34.9 pg/ml vs 22.4 pg/ml, p=0.051) and with a more severe perihematomal edema at T2 (37.99 pg/ml vs. 19.17 pg/ml, p=0.011). The ischemic perihematomal lesions development was also associated with an increased hematoma volume (p<0.005), perilesional edema (p=0.046), greater midline shift (p=0.036). ET-1 values at T1 inversely correlated with hemorrhage volume at T2 (ρ=-0.717, p=0.030).

Conclusions

NOX-2 seems to have a role in the development of ischemic perihematomal lesions. The association between higher ET-1 values and a lower hemorrhage volume could be related to the ET-1 vasoconstriction action on the ruptured vessel wall.
Proteomic profiling of peripheral blood mononuclear cells reveals immune dysregulation and metabolic alterations in kidney transplant recipients with COVID-19
Authors: Leite Giuseppe G. F. , Sousa Mônica Bragança , Rodrigues Larissa de Oliveira C. P. , Brunialti Milena Karina Colo , Medina-Pestana José , Butler Joe M. , Peters-Sengers Hessel , Requião-Moura Lúcio , Salomão Reinaldo
Published: September 2024

The emergence of the Coronavirus disease 2019 (COVID-19) pandemic in 2020 has profoundly impacted global health systems, particularly affecting vulnerable populations like kidney transplant recipients (KTRs).We prospectively collected blood samples from 17 PCR-confirmed COVID-19 KTR patients and 10 non-COVID-19 KTRs between May and September 2020. Using tandem mass tag-based quantitative proteomics, we characterized peripheral blood mononuclear cells (PBMCs) from KTRs alongside plasma protein biomarkers and lymphocyte counts, followed by bioinformatics analyses. Our study revealed significant proteomic alterations within PBMCs of SARS-CoV-2 infected KTRs, particularly in pathways associated with glycolysis, glucose metabolism, and neutrophil degranulation. Additionally, we observed an altered immune response marked by elevated cytokines and inflammatory mediators, coupled with decreased lymphocyte counts. Notably, patients with acute kidney injury (AKI) exhibited worse outcomes, including higher rates of ICU transfer and mechanical ventilation. Comparison of PBMC proteomic profiles between AKI and non-AKI patients highlighted distinct immune-related pathways, with AKI patients showing pronounced alterations in innate immune responses, particularly in neutrophil degranulation. Moreover, our analysis unveiled a negative correlation between T cell counts and neutrophil degranulation, suggesting potential implications for immune dysregulation in COVID-19. Our findings shed light on the complex proteomic landscape and immune responses in COVID-19-infected KTRs, emphasizing the critical need for studies focused on this population, especially in individuals with AKI. Furthermore, our observations provide valuable insights for further exploration of therapeutic interventions targeting immune dysregulation pathways in this vulnerable population.
Clinical stratification of Major Depressive Disorder in the UK Biobank: A gene-environment-brain Topological Data Analysis
Authors: Tassi Emma , Pigoni Alessandro , Turtulici Nunzio , Colombo Federica , Fortaner-Uyà Lidia , Bianchi Anna Maria , Benedetti Francesco , Fabbri Chiara , Vai Benedetta , Brambilla Paolo , Maggioni Eleonora
Published: September 2024

Major depressive disorder (MDD) is a leading cause of disability worldwide, affecting over 300 million people and posing a significant burden on healthcare systems. MDD is highly heterogeneous, with variations in symptoms, treatment response, and comorbidities that could be determined by diverse etiologic mechanisms, including genetic and neural substrates, and societal factors.

Characterizing MDD subtypes with distinct clinical manifestations could improve patient care through targeted personalized interventions. Recently, Topological Data Analysis (TDA) has emerged as a promising tool for identifying homogeneous subgroups of diverse medical conditions and key disease markers, reducing complex data into comprehensible representations and capturing essential dataset features.

Our study applied TDA to data from the UK Biobank MDD subcohort composed of 3052 samples, leveraging genetic, environmental, and neuroimaging data to stratify MDD into clinically meaningful subtypes. TDA graphs were built from unimodal and multimodal feature sets and quantitatively compared based on their capability to predict depression severity, physical comorbidities, and treatment response outcomes.

Our findings showed a key role of the environment in determining the severity of depressive symptoms. Comorbid medical conditions of MDD were best predicted by brain imaging characteristics, while brain functional patterns resulted the best predictors of treatment response profiles.

Our results suggest that considering genetic, environmental, and brain characteristics is essential to characterize the heterogeneity of MDD, providing avenues for the definition of robust markers of health outcomes in MDD.
Molecular Detection of Multi-drug resistant tuberculosis in clinical isolates from two urban centres in Malawi
Authors: Sikwese Tionge , Msosa Takondwa , Twabi Hussein , Dzunda Samuel , Chaima David , Banda Billy , Kanamazina Yusuf , Nyenje Mirriam , Musopole Alinune , Nliwasa Marriott , Ndhlovu Victor
Published: September 2024

Introduction

Suboptimal chemotherapy allowsMycobacterium tuberculosisto develop drug resistance owing to development of resistant mutants in the mycobacterial population. Early diagnosis of TB and identification of drug-resistance is of particular importance in human immunodeficiency virus (HIV)-infected individuals, as delay of therapy and subsequent development of drug-resistant TB can be devastating due to compromised immune systems.

Methodology

We conducted a cross-sectional evaluation study using presumptiveM. tuberculosispositive clinical isolates at two urban sites in Malawi (Blantyre and Lilongwe) to assess the presence of mutant genes on first and second line TB drugs using Line Probe Assay (LPA) and the gold standard drug susceptibility test (DST)

Results

For the Lilongwe site, the incidence of MDR-TB by Line Probe Assay (LPA) was found to be 14.06% (95% CI: 8%-20%) whereas that for Rif mono-resistance was 6.25% (95% CI: 2%-10%). Contrastingly, MDR-TB by DST was 23.44% (95 CI:16% - 21%) while mono-resistance was 6.25% (95% CI:2% -10). There was a substantial agreement on the detection of MDR-TB (kappa statistic was 0.75 with 95% CI of 0.62-0.88). Blantyre site, at 9.5% confidence interval, the point estimate for MDR-TB was 0% while for INH mono-resistance TB was 3.3%.

Conclusions

There is high incidence of MDR-TB among patients whose samples are sent to the Lilongwe site than previously thought. A short turnaround time to diagnosis, and the ability to simultaneously detect rifampicin and isoniazid resistance, makes LPA a reliable tool for the early detection of multidrug-resistant tuberculosis.
The impact of exercise training on the brain and cognition in T2DM, and its physiological mediators: a systematic review
Authors: Vandersmissen Jitske , Dewachter Ilse , Cuypers Koen , Hansen Dominique
Published: September 2024

Background

Type 2 diabetes (T2DM) affects brain structure and function, and is associated with an increased risk of dementia and mild cognitive impairment. It is known that exercise training has a beneficial effect on cognition and the brain, at least in healthy people, but the impact of exercise training on cognition and the brain remains to be fully elucidated in patients with T2DM.

Methods

This paper systematically reviews studies that evaluate the effect of exercise training on cognition in T2DM, and aims to indicate the most beneficial exercise modality for improving or preserving cognition in this patient group. In addition, the possible physiological mediators and targets involved in these improvements are narratively described in the second part of this review. Papers published up until the end of June 2024 were searched by means of the electronic database PubMed. Studies directly investigating the effect of any kind of exercise training on the brain or cognition in patients with T2DM, or animal models thereof, were included, with the exception of human studies assessing cognition only at one time point, and studies combining exercise training with other interventions (e.g. dietary changes, cognitive training, etc.).

Results

For the systematic part of the review, 24 papers were found to be eligible. 20 out of 24 papers (83.3%) showed a significant positive effect of exercise training on cognition in T2DM, of which four studies only showed a moderate significant effect. Four papers (16.7%) did not show a significant effect of exercise on cognition in T2DM, but two of them did show a positive trend. Similar effects were found for resistance and endurance exercise, with both possibly requiring a minimal intensity to reach cognitive improvement. In addition, BDNF, lactate, leptin, adiponectin, GSK3β, GLP-1, the AMPK/SIRT1 pathway, and the PI3K/Akt pathway were identified as plausible mediators directly from studies investigating the effect of exercise training on the brain in T2DM.

Conclusion

Overall, exercise training beneficially affects cognition and the brain in T2DM, with resistance and endurance exercise having similar effects. However, additional studies comparing the effect of different exercise intensities are needed to determine the optimal exercise intensity for cognitive improvement. Furthermore, we were able to define several mediators involved in the effect of exercise training on cognition in T2DM, but further research is necessary to unravel the entire process.

This review demonstrates a positive effect of exercise training on the brain in T2DM, but simultaneously emphasizes the need for additional studies on this topic. BDNF, lactate, leptin, adiponectin, GSK3β, GLP-1, the AMPK/SIRT1 pathway, and the PI3K/Akt pathway were identified as factors mediating the effect of exercise on the brain in T2DM.