bluuebunny/crossref_metadata_2025 huggingface dataset:
Sclerostin blockade inhibits bone resorption through PDGF receptor signaling in osteoblast lineage cells
Authors: Thouverey Cyril , Apostolides Pierre , Brun Julia , Caverzasio Joseph , Ferrari Serge
Published: September 2023

While sclerostin-neutralizing antibodies (Scl-Ab) transiently stimulate bone formation by activating Wnt signaling in osteoblast lineage cells, they exert sustained inhibition of bone resorption, suggesting an alternate signaling pathway by which Scl-Ab control osteoclast activity. Since sclerostin can activate platelet-derived growth factor receptors (PDGFRs) in osteoblast lineage cells in vitro and PDGFR signaling in these cells induces bone resorption through M-CSF secretion, we hypothesized that the prolonged anti-catabolic effect of Scl-Ab could result from PDGFR inhibition. We show here that inhibition of PDGFR signaling in osteoblast lineage cells is sufficient and necessary to mediate prolonged Scl-Ab effect on M-CSF secretion and osteoclast activity in mice. Indeed, sclerostin co-activates PDGFRs independently of Wnt/β-catenin signaling inhibition, by forming a ternary complex with LRP6 and PDGFRs in pre-osteoblasts. In turn, Scl-Ab prevents sclerostin-mediated co-activation of PDGFR signaling and consequent M-CSF up-regulation in pre-osteoblast cultures, thereby inhibiting osteoclast activity in pre-osteoblast/osteoclast co-culture assays. These results provide a new potential mechanism explaining the dissociation between anabolic and anti-resorptive effects of long-term Scl-Ab.
Ligand requirements for immunoreceptor triggering
Authors: Barton Michael I. , Paterson Rachel L. , Denham Eleanor M. , Goyette Jesse , van der Merwe P. Anton
Published: September 2023

Leukocytes interact with other cells using cell surface receptors. The largest group of such receptors are non-catalytic tyrosine phosphorylated receptors (NTRs), also called immunoreceptors. NTR signalling requires phosphorylation of cytoplasmic tyrosine residues by SRC-family tyrosine kinases. How ligand binding to NTRs induces this phosphorylation, also called NTR triggering, remains controversial, with roles suggested for size-based segregation, clustering, and mechanical force. Here we exploit a recently developed cell-surface generic ligand system to explore the ligand requirements for NTR triggering. We examine the effect of varying the ligand’s length, mobility and valency on the activation of representative members of four NTR families: SIRPβ1, Siglec 14, NKp44 and TREM-1. Increasing the ligand length impairs activation via NTRs, despite enhancing cell-cell conjugation, while varying ligand mobility has little effect on either conjugation or activation. Increasing the valency of the ligand, while enhancing cell-cell conjugation, does not enhance activation at equivalent levels of conjugation. These findings are more consistent with a role for size-based segregation, rather than mechanical force or clustering, in NTR triggering, suggesting a role for the kinetic-segregation model.
Regulation of human interferon signaling by transposon exonization
Authors: Pasquesi Giulia Irene Maria , Allen Holly , Ivancevic Atma , Barbachano-Guerrero Arturo , Joyner Olivia , Guo Kejun , Simpson David M. , Gapin Keala , Horton Isabella , Nguyen Lily , Yang Qing , Warren Cody J. , Florea Liliana D. , Bitler Benjamin G. , Santiago Mario L. , Sawyer Sara L. , Chuong Edward B.
Published: September 2023

Summary

Innate immune signaling is essential for clearing pathogens and damaged cells, and must be tightly regulated to avoid excessive inflammation or autoimmunity. Here, we found that the alternative splicing of exons derived from transposable elements is a key mechanism controlling immune signaling in human cells. By analyzing long-read transcriptome datasets, we identified numerous transposon exonization events predicted to generate functional protein variants of immune genes, including the type I interferon receptor IFNAR2. We demonstrated that the transposon-derived isoform of IFNAR2 is more highly expressed than the canonical isoform in almost all tissues, and functions as a decoy receptor that potently inhibits interferon signaling including in cells infected with SARS-CoV-2. Our findings uncover a primate-specific axis controlling interferon signaling and show how a transposon exonization event can be co-opted for immune regulation.
Snow Buntings, an arctic cold-specialist passerine, risk overheating under intense activity even at low air temperatures
Authors: O’Connor Ryan S. , Love Oliver P. , Regimbald Lyette , Gerson Alexander R. , Elliott Kyle H. , Hargreaves Anna L. , Vézina François
Published: September 2023

Birds maintain some of the highest body temperatures (Tb) among endothermic animals. Often deemed a selective advantage for heat tolerance, high Tbalso limits the capacity to increase Tbbefore reaching lethal levels. Recent thermal modelling suggests that sustained effort in Arctic birds might be restricted at mild air temperatures (Ta) during energetically demanding life history stages, which may force reductions in activity to avoid overheating, with expected negative impacts on reproductive performance. Consequently, understanding how Arctic birds will cope with increasing Tahas become an urgent concern. We examined within-individual changes in Tbin response to an experimental increase in activity in outdoor captive Arctic cold-specialised snow buntings (Plectrophenax nivalis), exposed to naturally varying Tafrom -15 to 36 °C. Calm buntings exhibited a modal Tbrange from 39.9 – 42.6 °C. However, we detected a dramatic increase in Tbwithin minutes of shifting birds to active flight, with strong evidence for a positive effect of Taon Tb(slope = 0.04 °C/°C). Importantly, by Taof 9 °C, flying buntings were already generating Tb≥ 45°C, approaching the upper thermal limits of organismal performance (i.e., Tb= 45 - 47 °C). Under scenarios of elevated Tb, buntings must increase rates of evaporative water loss and/or reduce activity to avoid overheating. With known limited evaporative heat dissipation capacities, we argue buntings operating at peak energy levels will increasingly rely on behavioral thermoregulatory strategies (i.e., reducing activity) to regulate Tb, at the potential detriment to nestling growth and survival.
Magnetically Powered Microwheel Thrombolysis of Occlusive Thrombi in Zebrafish
Authors: Pontius M. Hao Hao , Ku Chia-Jui , Osmond Matthew , Disharoon Dante , Liu Yang , Marr David W.M. , Neeves Keith B. , Shavit Jordan A.
Published: September 2023

Tissue plasminogen activator (tPA) is the only FDA approved treatment for ischemic stroke but carries significant risks, including major hemorrhage. Additional options are needed, especially in small vessel thrombi which account for ∼25% of ischemic strokes. We have previously shown that tPA-functionalized colloidal microparticles can be assembled into microwheels (µwheels) and manipulated under the control of applied magnetic fields to enable rapid thrombolysis of fibrin gels in microfluidic models of thrombosis. Providing a living microfluidic analog, transparent zebrafish larvae have a highly conserved coagulation cascade that enables studies of hemostasis and thrombosis in the context of intact vasculature, clotting factors, and blood cells. Here we show that tPA-functionalized µwheels can perform rapid and targeted recanalizationin vivo. This effect requires both tPA and µwheels, as minimal to no recanalization is achieved with tPA alone, µwheels alone, or tPA-functionalized microparticles in the absence of a magnetic field. We evaluated tPA-µwheels in CRISPR-generated plasminogen (plg) heterozygous and homozygous mutants and confirmed that tPA-µwheels are dose-dependent on plasminogen for lysis. We have found that magnetically powered µwheels as a targeted tPA delivery system are dramatically more efficient at plasmin-mediated thrombolysis than systemic deliveryin vivo. Further development of this system in fish and mammalian models could enable a less invasive strategy for alleviating ischemia that is safer than directed thrombectomy or systemic infusion of tPA.
Sclerotic prostate cancer bone metastasis: woven bone lesions with a twist
Authors: Eltit-Guersetti Felipe , Wang Qiong , Jung Naomi , Munshan Sheryl , Xie Dennis , Xu Samuel , Mojtahedzadeh Bita , Liu Danmei , Corey Eva , True Lawrence D , Morrissey Colm , Wang Rizhi , Cox Michael E.
Published: September 2023

Bone metastasis (BM) are the most severe and prevalent consequences of prostate cancer (PC) affecting more than 80% of patients with advanced PC. PCBM generate pain, pathological fractures, and paralysis. As modern therapies increase survival, more patients are suffering from these catastrophic consequences of PCBM. Radiographically, PCBM are predominantly osteosclerotic, but the mechanisms of abnormal bone formation, and how this “more and new” bone is related to fractures is unclear. In this study, we conducted a comprehensive analysis on a cohort of 76 cadaveric PCBM samples and 12 from non-PC donors as control. We used μ-CT to determine three-dimensional organization and quantify bone characteristics, quantitative backscattering electron microscopy to characterize mineral content and details in bone structure, nano indentation to determine mechanical properties, and we finalize with histological and immunohistochemical analysis of bone structure and composition. We define 4 phenotypes of PCBM, osteolytic, mixed lytic-sclerotic, and two subgroups of osteosclerotic lesions, those with residual trabeculae, and others without residual trabeculae. The osteosclerotic lesions are characterized by the presence of abnormal bone within the trabeculae surfaces and intertrabecular spaces. This abnormal bone is characterized by higher lacunae density, abnormal lacunae morphology and orientation. However, we observed no significant difference between this irregular bone and residual trabeculae in terms of mineral content, hardness, and elastic modulus at micron-scale. The collagen matrix of this abnormal bone presents with irregular organization and is accompanied by increased proteoglycan and phosphorylated glycoprotein content. These characteristics suggests the presence of woven bone in PCBM. However, the lack of subsequent bone remodelling, absence of lamellar bone deposition on its surface, absence of markers of matrix vesicles but evidence of alkaline phosphatase dominated mineralization and collagen-III structure, set up differences from woven bone, while the role of PC cells in inducing this irregular bone phenotype remains unclear.
Oligodendroglia generate vascular mural cells and neurons in the adult mouse brain
Authors: Yu Qingting , Yang Kairan , Fan Zhouling , Huang Maojiao , Xu Ting , Yang Yanzhuo , Yang Zuisu , He Xiaosong , Yuan Falei
Published: September 2023

BACKGROUND

Oligodendroglia encompass oligodendrocyte precursor cells (OPCs) and oligodendrocytes (OLs). In the grey matter of the cortex, nearly all OPCs divide slowly, yet they don’t differentiate solely into mature OLs, leaving the exact role of these OPCs in the grey matter enigmatic.

METHODS

Oligodendroglia, including OPCs, were traced using the Sox10 Cre-ERT2reporter mice. We compared the effect of tamoxifen dissolved in different solvents on the fate of Sox10 cells. We also compared the effect of tamoxifen dosage on the fate of Sox10 cells. The differentiation of labeled red fluorescent protein (RFP) cells was analyzed using immunofluorescence staining.

RESULTS

Two groups of RFP cells, type A Sox10 (Sox10-A) cells, and type B Sox10 (Sox10-B) cells, were identified in the cortex, striatum, hippocampus, thalamus, and hypothalamus. Sox10-A cells differentiate into platelet-derived growth factor receptor-β (PDGFRβ)+, CD13+ pericytes, and smooth muscle myosin heavy chain 11 (MYH11) + smooth muscle cells when the mice received ethanol or high-dose tamoxifen. Sox10-B cells transform into glutamatergic neurons when the mice received high-dose tamoxifen. Sox10-B cells include perineurona OPCs and OLs.

CONCLUSIONS

This investigation provides evidence that a substantial proportion of oligodendroglia in the grey matter serve as mural cell precursors and neuronal precursors. These two phenomena may contribute to our understanding of neurodegenerative diseases.

Graphic abstract
Developing a safe 15-hour preservation protocol of donor kidneys using normothermic machine perfusion
Authors: Stone John P , Cowey William R , Bowers Corban JT , Stewart Amy F , Armstrong Erin R , Clancy Marc , Entwistle Timothy R , Pozo Jorge del , Amin Kavit , Fildes James E
Published: September 2023

Introduction

Background

Normothermic machine perfusion (NMP) offers a superior alternative to existing hypothermic preservation strategies but is currently limited to 1-3 hours. Extending the time a kidney can be sustained using this technology could electivise transplantation, and enable physiological assessments of renal function. We aimed to develop a protocol that allows the safe preservation of donor kidneys for 12 hours using this technique.

Methods

Porcine kidneys (n=20) were retrieved and flushed with 1L preservation solution before being stored on ice. Following a cold ischaemic time of 3.5 hours, kidneys were placed onto a NMP circuit and perfused for 12 hours. Renal haemodynamics, biochemistry and urine output were recorded and analysed. At the end of perfusion, kidneys were scored based on the clinical assessment score and their suitability for transplant determined. Biopsies were collected at the end for histological assessment.

Results

All kidneys were successfully perfused with immediate recordable renal blood flow (RBF). RBF continually improved over the course of the perfusions, peaking at 12 hours, and negatively correlated with intra-renal resistance. Perfusate sodium concentrations remained stable and within physiological parameters. Sodium bicarbonate increased over time with a corresponding decrease in lactate concentrations, demonstrating active renal gluconeogenesis and Cori cycle processes. Urine production began immediately in all kidneys and was sustained throughout, indicating active renal function. Under the clinical perfusion assessment score, all kidneys received a score of 1 and would be considered suitable for transplantation. Histological assessment revealed kidneys were injury free with REMUZZI scores of 0 in all samples.

Conclusion

We have developed an NMP protocol that safely preserves donor kidneys for over 15 hours. Successful perfusion was achieved with stable haemodynamics, blood-perfusate biochemistry, and maintained urine output. Importantly, kidneys remained in optimal health, with no evidence of injury. This protocol may enable the electivisation of transplantation, while reducing ischaemic injury associated with static cold storage.
Bumblebee occupancy responds to complex interactions between local and landscape land use, climatic niche properties and climate change
Authors: Newbold Tim , Kerr Jeremy , Soroye Peter , Williams Jessica J.
Published: September 2023

Insect biodiversity is changing rapidly, driven by a complex suite of pressures, foremost among which are human land use, land-use intensification, and increasingly climate change. Bumblebees deliver important pollination services to wild plants and human crops, but we lack large-scale empirical evidence on how land use and climate change interact to drive bumblebee biodiversity changes. We assess bumblebee occupancy responses to interactive effects of land use and climate pressures across North America and Western Europe. Occupancy increases with landscape natural habitat and decreases with the duration of human use of landscapes. Responses to historical climate warming are negative in natural habitats but positive in human land uses, while human land use reduces occupancy most in the centre of species’ temperature niches. We estimate that the combined pressures have reduced bumblebee occupancy by 61% across sampled natural habitats, and 65% across human land uses, suggesting that treating present-day natural habitats as an undisturbed reference is misleading. Our results can inform efforts to conserve bumblebee biodiversity in the face of ongoing land-use changes and accelerating climatic changes.

One-sentence summary

Land use and climate change interact to drive large declines in bumblebee occupancy in both natural and human-modified habitats
Powerful and accurate detection of temporal gene expression patterns from multi-sample multi-stage single cell transcriptomics data with TDEseq
Authors: Fan Yue , Li Lei , Sun Shiquan
Published: September 2023

We present a non-parametric statistical method called TDEseq that takes full advantage of smoothing splines basis functions to account for the dependence of multiple time points, and uses hierarchical structure linear additive mixed models to model the correlated cells within an individual. As a result, TDEseq demonstrates powerful performance in identifying four potential temporal expression patterns within a specific cell type. Extensive simulation studies and the analysis of four published scRNA-seq datasets show that TDEseq can produce well-calibrated p-values and up to 20% power gain over the existing methods for detecting temporal gene expression patterns.
TAPIR: a T-cell receptor language model for predicting rare and novel targets
Authors: Fast Ethan , Dhar Manjima , Chen Binbin
Published: September 2023

T-cell receptors (TCRs) are involved in most human diseases, but linking their sequences with their targets remains an unsolved grand challenge in the field. In this study, we present TAPIR (T-cell receptor and Peptide Interaction Recognizer), a T-cell receptor (TCR) language model that predicts TCR-target interactions, with a focus on novel and rare targets. TAPIR employs deep convolutional neural network (CNN) encoders to process TCR and target sequences across flexible representations (e.g., beta-chain only, unknown MHC allele, etc.) and learns patterns of interactivity via several training tasks. This flexibility allows TAPIR to train on more than 50k either paired (alpha and beta chain) or unpaired TCRs (just alpha or beta chain) from public and proprietary databases against 1933 unique targets. TAPIR demonstrates state-of-the-art performance when predicting TCR interactivity against common benchmark targets and is the first method to demonstrate strong performance when predicting TCR interactivity against novel targets, where no examples are provided in training. TAPIR is also capable of predicting TCR interaction against MHC alleles in the absence of target information. Leveraging these capabilities, we apply TAPIR to cancer patient TCR repertoires and identify and validate a novel and potent anti-cancer T-cell receptor against a shared cancer neoantigen target (PIK3CA H1047L). We further show how TAPIR, when extended with a generative neural network, is capable of directly designing T-cell receptor sequences that interact with a target of interest.
UNNT: A novel Utility for comparing Neural Net and Tree-based models
Authors: Gutta Venkata Vineeth , Ganakammal Satish Ranganathan , Jones Sara , Beyers Matthew , Chandrasekaran Sunita
Published: September 2023

Using deep learning in cancer research to tackle scientific challenges is becoming an increasingly popular technique. Advances in enhanced data generation, machine learning algorithms, and compute infrastructure have led to an acceleration in the use of deep learning in various domains of cancer research such as drug response problems. In our study, we explored tree-based models to improve the accuracy of a single drug response model and demonstrate that tree-based models such as XGBoost have advantages over deep learning models, such as a convolutional neural network (CNN), for single drug response problems. However, comparing models is not a trivial task. To make training and comparing CNNs and XGBoost (eXtreme Gradient Boosting) more accessible to users, we developed an open-source library called UNNT (A novel Utility for comparing Neural Net and Tree-based models). The case studies, in this manuscript, focus on cancer drug response datasets however the application can be used on datasets from other domains, such as chemistry.

Author summary

Advancement in data science, machine learning (ML), and artificial intelligence (AI) methods has enabled extraction of meaningful information from large and complex datasets that has assisted in better understanding, diagnosing, and treating cancer. The understanding of the drug response domain in cancer research has been accelerated with developing ML models to aid in predicting the effectiveness of the drugs based on a specific genomic molecular feature. In this study we developed a novel robust framework called UNNT (A novel Utility for comparing Neural Net and Tree-based models) that trains and compares deep learning method such as CNN and tree-based method such as XGBoost on the user input dataset. We applied this software to single drug response problem in cancer to identify the best performing ML method based on the National Cancer Institute 60 (NCI60) dataset. In addition, we studied the computational aspects of training each of these models where our results show that neither is evidently superior on both CPUs and GPUs while training. This shows that when both models have similar error rates for a dataset the hardware available determines the model choice for training as discussed in tables 7 and 11. UNNT:https://github.com/vgutta/UNNT.git
Tuning Interdomain Conjugation Towardin situPopulation Modification in Yeast
Authors: Stindt Kevin R , McClean Megan N
Published: September 2023

The ability to modify and control natural and engineered microbiomes is essential for biotechnology and biomedicine. Fungi are critical members of most microbiomes, yet technology for modifying the fungal members of a microbiome has lagged far behind that for bacteria. Interdomain conjugation (IDC) is a promising approach, as DNA transfer from bacterial cells to yeast enablesin situmodification. While such genetic transfers have been known to naturally occur in a wide range of eukaryotes, and are thought to contribute to their evolution, IDC has been understudied as a technique to control fungal or fungal-bacterial consortia. One major obstacle to widespread use of IDC is its limited efficiency. In this work, we utilize interactions between genetically tractableEscherichia coliandSaccharomyces cerevisiaeto control the incidence of IDC. We test the landscape of population interactions between the bacterial donors and yeast recipients to find that bacterial commensalism leads to maximized IDC, both in culture and in mixed colonies. We demonstrate the capacity of cell-to-cell binding via mannoproteins to assist both IDC incidence and bacterial commensalism in culture, and model how these tunable controls can predictably yield a range of IDC outcomes. Further, we demonstrate that these lessons can be utilized to lastingly alter a recipient yeast population, by both “rescuing” a poor-growing recipient population and collapsing a stable population via a novel IDC-mediated CRISPR/Cas9 system.
Plant diversity darkspots for global collection priorities
Authors: Ondo Ian , Dhanjal-Adams Kiran L. , Pironon Samuel , Silvestro Daniele , Colli-Silva Matheus , Deklerck Victor , Grace Olwen M. , Monro Alexandre K. , Nicolson Nicky , Walker Barnaby , Antonelli Alexandre
Published: September 2023

More than 15% of all vascular plant species may remain scientifically undescribed, and many of the >340,000 described species have no or few geographic records documenting their distribution. Identifying and understanding taxonomic and geographic knowledge shortfalls is key to prioritising future collection and conservation efforts.

Using extensive data for 343,523 vascular plant species and time-to-event analyses, we conducted multiple tests related to plant taxonomic and geographic data shortfalls, and identified 32 global diversity darkspots (regions predicted to lack most information about their species diversity and distribution). We defined priority regions for future collection according to several socio-economic and environmental scenarios.

Most plant diversity darkspots are found within biodiversity hotspots, except New Guinea. We identify New Guinea, the Philippines, Borneo, Myanmar, India, Turkey, Colombia, Ecuador, and Peru, as global collection priorities under all environmental and socio-economic conditions considered.

Our study provides a framework to accelerate plant species documentation for the implementation of conservation actions. As digitisation of the world’s herbaria progresses, collection and conservation priorities may soon be identifiable at finer scales.
GPR35 inhibits TRPA1-mediated colonic afferent hypersensitivity through suppression of Substance P release
Authors: Gupta Rohit A , Higham James P , Urriola-Muñoz Paulina , Barker Katie H , Paine Luke , Ghooraroo Joshua , Hockley James RF , Rahman Taufiq , Smith Ewan St John , Brown Alistair JH , Suzuki Rie , Bulmer David C
Published: September 2023

The development of non-opioid analgesics for the treatment of chronic abdominal pain is a pressing area of unmet clinical need. To address this, we examined the expression of Gi/o-coupled receptors in colonic sensory neurons, which, like opioid receptors, have the potential to inhibit nociceptor activation due to their inhibitory G protein coupling. This led to the identification of the orphan receptor GPR35 as a visceral analgesic drug target due to its marked co-expression with TRPA1, a mediator of noxious mechanotransduction in the bowel. Consistent within silicodocking studies which identified binding sites for the mast cell stabiliser cromolyn and phosphodiesterase inhibitor zaprinast at GPR35, we demonstrated, using GPR35 knockout mice, that the antinociceptive effects of these drugs on TRPA1-mediated colonic nociceptor activation and mechanosensitisation were GPR35-dependent. Further work showed these antinociceptive effects occurred through the inhibition of substance P (SP) release. This confirmed both the pronociceptive effect of SP on colonic afferents, and the contribution of SP to TRPA1-mediated colonic nociceptor activation and sensitisation. We also found that TRPA1-induced contraction of the colon was mediated by SP signalling and could be inhibited by cromolyn in a GPR35-dependent manner. Our data identify GPR35, through its inhibition of SP-mediated colonic contractility and nociceptor activation and sensitisation, as a putative mechanism for the reported clinical efficacy of cromolyn in the treatment of irritable bowel syndrome. These findings highlight the potential utility of GPR35 agonists to deliver non-opioid analgesia for the treatment of abdominal pain associated with gastrointestinal diseases such as irritable bowel syndrome and inflammatory bowel disease.
Extracellular matrix scaffold-assisted tumor vaccines induce tumor regression and long-term immune memory
Authors: Pal Sanjay , Chaudhari Rohan , Baurceanu Iris , Hill Brenna J. , Nagy Bethany A. , Wolf Matthew T.
Published: September 2023

Injectable scaffold delivery is an immune engineering strategy to enhance the efficacy and reliability of cancer vaccine immunotherapy. The composition and structure of the biomaterial scaffold determines both vaccine release kinetics and inherent immune stimulation via the scaffold host response. Extracellular matrix (ECM) scaffolds prepared from decellularized tissues initiate an acute alternative inflammatory response following implantation, which facilitates wound healing following tumor resection and promotes local cancer immune surveillance. However, it remains unknown whether this environment is compatible with generating protective anti-tumor cytotoxic immunity with local immunotherapy delivery. Here, we engineered an ECM scaffold-assisted therapeutic cancer vaccine that maintained an immune microenvironment consistent with tissue reconstruction. Immune adjuvants MPLA, GM-CSF, and CDA were screened in a cancer vaccine formulated for decellularized small intestinal submucosa (SIS) ECM scaffold co-delivery. Though MPLA and GM-CSF showed the greatest increase in local myeloid cell infiltration, we found that the STING pathway adjuvant CDA was the most potent inducer of cytotoxic immunity with SIS-ECM scaffold delivery. Further, CDA did not diminish hallmark ECM immune responses needed in wound healing such as highIl4cytokine expression. SIS scaffold delivery enhanced therapeutic vaccine efficacy using CDA and the antigen ovalbumin, curing greater than 50% of established EG.7 tumors in young mice and 75% in 24-week-old mature mice, compared to soluble components alone (0% cured). SIS-ECM scaffold assisted vaccination extended antigen exposure, was dependent on CD8+cytotoxic T cells, and generated long term anti-tumor memory at least 7 months post-vaccination in both young and mature-aged mice. This study shows that an ECM scaffold is a promising delivery vehicle to enhance cancer vaccine efficacy while being orthogonal to characteristics of pro-healing immune hallmarks.
Soybean RIN4 represents a mechanistic link between plant immune and symbiotic signaling
Authors: Tóth Katalin , Kim Daewon , Cho Sung-Hwan , Nguyen Cuong T. , Nguyen Tran H. N. , Hartanto Christopher , Michno Jean-Michel , Stec Adrian O. , Stupar Robert M. , Stacey Gary
Published: September 2023

The legume-rhizobium symbiosis represents a unique and beneficial interaction between legumes and nitrogen-fixing soil bacteria, called rhizobia. The initiation and development of this symbiosis is complex and begins with recognition of key molecular signals, produced by the plant and its symbiont, which determine symbiotic compatibility. Current data suggest that the invading symbiont initially triggers plant immune responses that are subsequently suppressed. Hence, there is growing evidence that features of plant immunity may be relevant to symbiotic establishment. RIN4 is a key immune regulator in plants, regulating basal immunity and it is also targeted by pathogen effector proteins that either confer susceptibility or resistance, depending on the presence of the appropriate resistance protein. Surprisingly, we found that RIN4 was rapidly phosphorylated upon rhizobial inoculation of soybean root hairs. RNAi silencing and mutant studies indicate that RIN4 expression is essential for effective nodulation of soybean. RIN4 phosphorylation occurs within a fifteen amino acid motif, which is highly conserved within the Fabales (legumes) and Rosales orders, that comprise species capable of nitrogen-fixing endosymbiosis with rhizobia. RIN4 proteins mutated in this conserved phosphorylation site failed to support efficient soybean nodulation. Phosphorylation of this site is mediated by the symbiotic receptor-like kinase, SymRK, a well-studied member of the symbiotic signaling pathway. The data implicate RIN4 phosphorylation as a key mediator of rhizobial compatibility, interconnecting symbiotic and immune signaling pathways.

Significance

The nitrogen fixing legume-rhizobium symbiosis is a cornerstone of sustainable agriculture, with ongoing efforts to transfer this unique ability to non-leguminous crop plants. Plants are surrounded by a myriad of microbes in the soil, and, therefore, require constant surveillance in order to distinguish between a pathogen or symbiont. Plants monitor for specific molecular signals that indicate pathogen or symbiont presence. We show that RIN4, a key immune regulator, plays an essential role in promoting the development of the symbiotic nitrogen-fixing relationship between soybean and its compatible symbiontBradyrhizobium japonicum. Therefore, RIN4 is likely a key player in mediating the appropriate response upon infection by friend or foe.
Lipid network of plasma extracellular vesicles reveals sex-based differences in the lipidomic profile from patients with alcohol use disorder
Authors: Perpiñá-Clérigues Carla , Mellado Susana , Galiana-Roselló Cristina , Fernández-Regueras María , Marcos Miguel , García-García Francisco , Pascual María
Published: September 2023

Alcohol use disorder (AUD) is one of the most common psychiatric disorders, and the consumption of this substance is considered one of the main causes of preventable deaths worldwide. Lipids play a crucial functional role in cell membranes, however little is known about the role of lipids containing extracellular vesicles (EVs), as regulatory molecules and biomarkers. In this study, a highly sensitive lipidomic strategy is employed to characterize plasma EV lipid species from individuals with AUD, to evaluate differential functional roles and enzymatic activity networks to improve the knowledge of lipid metabolism in the alcohol consumption. Plasma EV lipids from female and male patients with AUD and healthy individuals were analyzed to obtain lipid differential abundance, as well as biological interpretation of LINEX2lipidomics data, evaluating enzymatic dysregulation through an enrichment algorithm. Our results showed for the first time that females with AUD exhibit greater substrate-product changes in LPC and PC lipids, as well as phospholipases and acyltransferases activity, potentially linked to cancer progression and neuroinflammation. Conversely, males with AUD showed dysregulation in Cer and SM lipid, involving sphingomyelinases, sphingomyelin phosphodiesterase, and sphingomyelin synthase, which could be related with hepatotoxicity. Notably, females with AUD showed LION-terms associated with “positive intrinsic curvature”, while males exhibited “negative intrinsic curvature, contributing to vesicle fusion processes. These methodological developments allow a better understanding of lipid metabolism and its regulatory mechanisms, which contributes not only to identify novel lipid targets, but also the discovery of sex-specific clinical biomarkers in the AUD.
Evolutionary origin of morphologically cryptic species imprints co-occurrence and sympatry patterns
Authors: Delić Teo , Borko Špela , Premate Ester , Rexhepi Behare , Alther Roman , Knüsel Mara , Malard Florian , Weber Dieter , Stoch Fabio , Flot Jean-François , Fišer Cene , Altermatt Florian
Published: September 2023

Aim

Morphologically cryptic species are an important part of global biodiversity, yet it remains unclear how these species contribute to and integrate into communities at different geographic scales. It is especially unclear at which scales they co-occur, and if and how their ranges overlap. To adequately protect biodiversity, an accurate understanding of the underlying processes and adequate level of protection is needed, in particularly for often overlooked cryptic species.

Question

We analyzed patterns of syntopies (local co-occurrences) and sympatries (range overlap) to test how the evolutionary origin of cryptic species shapes biodiversity patterns at different geographic scales. We hypothesized i) that syntopies are more common among phylogenetically deeply divergent cryptic species than among close relatives, and ii) that sympatries are an outcome of phylogenetic relatedness and dispersal, with range size as a proxy of dispersal ability.

Location

Western Europe.

Taxon

Subterranean amphipod crustaceans of the polyphyleticNiphargus rhenorhodanensisspecies complex.

Methods

Unilocus species delimitations (PTP, ASAP), calibrated multilocus phylogenetic analyses, co-occurrence analyses using a probabilistic model, generalized linear models (GLM).

Results

The studied species complex comprises 37–48 molecular operational taxonomic units (MOTUs) from nine different clades. Syntopies are random or less frequent than expected, implying an insufficient between-MOTU differentiation allowing stable coexistence. GLM suggested that age of divergence does not predict species sympatries, although they emerge more frequently among MOTUs from different clades. By contrast, sympatries emerge when at least one MOTU disperses over a large geographic range. Biodiversity rich regions were found at the foothills of the Alps, the Jura and the Central Massif, regardless the inference method.

Main conclusions

Biodiversity patterns of the herein studied species complex are driven mainly by dispersal and reflect geographic circumstances of speciation. While species richness on a local scale may be the outcome of competition and dispersal, regional biodiversity patterns emerged through biogeographic history on a clade-level.
Rapid degeneration and neurochemical plasticity of the lateral geniculate nucleus following lesions of the primary visual cortex in marmoset monkeys
Authors: Ma Gaoyuan , Chan Jonathan M. , Worthy Katrina H. , Rosa Marcello G.P. , Atapour Nafiseh
Published: September 2023

Lesions of the primary visual cortex (V1) cause retrograde neuronal degeneration, volume loss and neurochemical changes in the lateral geniculate nucleus (LGN). Here we characterise the timing of these processes, by comparing the LGN of adult marmoset monkeys following various recovery times after unilateral V1 lesions. Observations in NeuN-stained sections obtained from animals with very short (3 days) recoveries showed that the volume and neuronal density in the LGN ipsilateral to the lesions were similar to those in the contralateral hemispheres. However, neuronal density in the LGN lesion projection zones (LPZ) dropped rapidly thereafter, with a loss of ∼50% of the population occurring within a month of the lesions. This level of neuronal loss was then sustained for the remainder of the range of recovery times, up to >3 years post-lesion. In comparison, shrinkage of the LGN progressed more gradually, not reaching a stable value until 6 months post lesion. We also determined the time course of the expression of the calcium-binding protein calbindin (CB) in magnocellular (M) and parvocellular (P) layer neurons, a recently described form of neurochemical plasticity triggered by V1 lesions. We found that CB expression could be detected in surviving M and P neurons as early as 1 month after a lesion, with the percentage of neurons showing this neurochemical phenotype showing subtle changes over 6 months. Our study shows that there is a limited time window for any possible interventions aimed at reducing secondary neuronal loss in the visual afferent pathways following damage to V1.
Comparative cardiotoxicity assessment of bisphenol chemicals and estradiol using human induced pluripotent stem cell-derived cardiomyocytes
Authors: Cooper Blake L. , Salameh Shatha , Posnack Nikki Gillum
Published: September 2023

Background

Bisphenol A (BPA) is commonly used to manufacture consumer and medical-grade plastics. Due to health concerns, BPA substitutes are being incorporated – including bisphenol S (BPS) and bisphenol F (BPF) – without a comprehensive understanding of their toxicological profile.

Objective

Previous studies suggest that bisphenol chemicals perturb cardiac electrophysiology in a manner that is similar to 17β-estradiol (E2). We aimed to compare the effects of E2 with BPA, BPF, and BPS using human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM).

Methods

Cardiac parameters were evaluated using microelectrode array (MEA) technology and live-cell fluorescent imaging at baseline and in response to chemical exposure (0.001-100 μM).

Results

Cardiac metrics remained relatively stable after exposure to nanomolar concentrations (1-1,000 nM) of E2, BPA, BPF, or BPS. At higher micromolar concentrations, chemical exposures resulted in a decrease in the depolarizing spike amplitude, shorter field potential and action potential duration, shorter calcium transient duration, and decrease in hiPSC-CM contractility (E2>BPA>BPF >> BPS). Cardiomyocyte physiology was largely undisturbed by BPS exposure. BPA-induced effects were exaggerated when co-administered with an L-type calcium channel antagonist (verapamil) or E2 - and reduced when co-administered with an L-type calcium channel agonist (Bay K8644) or an estrogen receptor alpha antagonist (MPP). E2-induced effects generally mirrored those of BPA, but were not exaggerated by co-administration with an L-type calcium channel antagonist.

Discussion

Collectively across multiple cardiac endpoints, E2 was the most potent and BPS was the least potent disruptor of hiPSC-CM function. Although the observed cardiac effects of E2 and BPA were similar, a few distinct differences suggest that these chemicals may act (in part) through different mechanisms. hiPSC-CM are a useful model for screening cardiotoxic chemicals, nevertheless, the describedin vitrofindings should be validated using a more complexex vivoand/orin vivomodel.
Heat stress at the bicellular stage inhibits sperm cell development and their transport into pollen tubes
Authors: Li Xingli , Bruckmann Astrid , Dresselhaus Thomas , Begcy Kevin
Published: September 2023

For a successful double fertilization process in flowering plants (angiosperms), pollen tubes each deliver two non-motile sperm cells towards female gametes (egg and central cell, respectively). Heatwaves especially during the reproduction period are threatening male gametophyte (pollen) development, which results in severe yield losses. By using maize as a crop and grass model system, we found strong seed set reduction when moderate heat stress was applied for two days during the uni- and bicellular stages of pollen development. We show that heat stress accelerates pollen development and impairs pollen germination capabilities, when applied at the unicellular stage. Heat stress at the bicellular stage impairs sperm cell development and their transport into pollen tubes. To understand the course of the latter defects, we used marker lines and analyzed the transcriptomes of isolated sperm cells. While heat stress also affects the expression of genes involved in transcription, RNA processing and translation, especially genes in DNA replication and the cell cycle were mis-regulated. This includes centromeric histone CENH3 and α-tubulin. Most mis-regulated genes are involved in transition from metaphase to anaphase during pollen mitosis II (PM II). Heat stress activates spindle assembly check point and meta-to anaphase transition genes in sperm cells. In summary, mis-regulation of the identified genes during heat stress at the bicellular stage explains sperm cell development and transport defects ultimately leading to sterility.
Complex relationship among vessel diameter, shear stress and blood pressure controlling vessel pruning during angiogenesis
Authors: Kumar Vivek , Kumar Prashant , Hikita Takao , Ding Mingqian , Kametani Yukinori , Nakayama Masanori , Hasegawa Yosuke
Published: September 2023

Blood vessel pruning during angiogenesis is the optimization process of the branching pattern to improve the transport properties of a vascular network. Recent studies show that part of endothelial cells (ECs) subjected to lower shear stress migrate toward vessels with higher shear stress in opposition to the blood flow for vessel regression. While dynamic changes of blood flow and local mechano-stress could coordinately modulate EC migration for vessel regression within the closed circulatory system, the effect of complexity of haemodynamic forces and vessel properties on vessel pruning remains elusive. Here, we reconstructed a 3-dimentsional (3D) vessel structure from 2D confocal images of the growing vessels in the mouse retina, and numerically obtained the local information of blood flow, shear stress and blood pressure in the vasculature. Moreover, we developed a predictive model for vessel pruning based on machine learning. We found that the combination of shear stress and blood pressure with vessel radius was tightly corelated to vessel pruning sites. Our results highlighted that orchestrated contribution of local haemodynamic parameters was important for the vessel pruning.

Authors Summary

Blood vessel networks formed by angiogenic vessel growth subsequently undergo extensive vascular remodeling process by regression of selected vascular branches. Optimization of the branching pattern in the vasculature is critical to ensure sufficient blood supply throughout the entire tissue. Recent studies have highlighted a strong relationship between the vessel remodeling and the shear stress acting on the vessel wall. However, its detailed mechanisms remain elusive due to the difficulties of estimating local haemodynamic parameters and relating them to vessel remodeling.

Here, we have numerically simulated local haemodynamic parameters within the vascular network of the postnatal day 6 (P6) mouse retinal vasculature. Then, the relationship among the local shear stress, blood pressure, and vessel radius with the vessel pruning was examined. Moreover, we developed a predictive model for the vessel pruning based on the local haemodynamic parameters by a machine learning technique. Importantly, our results indicate that the combination of shear stress and blood pressure with vessel radius is tightly correlated to vessel pruning sites.

Given the ongoing clinical approach to suppress tumor growth via blood vessel normalization, our results provide important knowledge for developing future medicine such as nanomedicine based on drug delivery systems.
Detection of prodromal Parkinson’s disease using a urine proteomics panel and machine learning
Authors: Hällqvist Jenny , Schreglmann Sebastian R. , Kulcsarova Kristina , Skorvanek Matej , Feketeova Eva , Rizig Mie , Mollenhauer Brit , Turano Paola , Bacalini Maria Giulia , Francheschi Claudio , Wood Nicholas , Bhatia Kailash P. , Mills Kevin
Published: September 2023

Parkinson’s disease is a progressive neurodegenerative disorder and idiopathic REM-sleep behaviour disorder (iRBD) has been identified as its single most specific early symptom. To facilitate the screening of individuals at high risk to develop Parkinson’s disease, we developed a multiplexed panel of urine proteomics using machine learning and targeted mass spectrometry to detect iRBD. Random urine samples from clinically and genetically well characterized patients with iRBD, idiopathic and hereditary forms of Parkinson’s disease, and matching controls, collected in two academic centres, were analysed in a standardized way.

First, a biomarker discovery and exploratory comparison of samples from randomly selected idiopathic Parkinson’s patients and age/sex-matched healthy controls were proteomically profiled and quantified (> 2500 proteins). The most differentially expressed biomarkers were combined into a high-throughput, multiplexed assay using targeted proteomics designed for use of tandem mass spectrometers for potential translation into clinical practise. This was then validated on independent patient and control samples (n=184). After detecting a major influence of sex on the proteome, we focused subsequent analyses on the larger group of available male samples (n= 114) and report results based on iRBD (n= 14), idiopathic (n= 35) and young-onset Parkinson’s disease (n= 15), carriers of LRRK2 (n= 10), PARKIN-gene mutations (n= 5), and healthy control subjects (n= 35). After establishing excellent compatibility between the two study sites, orthogonal partial least squares discriminant analysis (OPLS-DA) excluded a relevant effect of aging, but detected significant differences between iRBD and healthy controls (ANOVA-CVP= 0.002), as well as the combination of iPD/iRBD and healthy controls (ANOVA-CVP= 0.01).

Uni- and multivariate analyses detected a shared expression pattern for the protein biomarkers UBC, NCAM1, MIEN1, SPP2, REG1B, ITIH2, BCHE and C3 between iRBD and idiopathic Parkinson’s disease. Utilizing split train/test-datasets in a multiple-regression classifier model resulted in a mean accuracy of 78% to detect iRBD, matching iRBD’s conversion rate to Parkinson’s disease. Hierarchical clustering revealed greater similarities in urine proteomic changes between iRBD and idiopathic than monogenic Parkinson’s disease. Several proteins identified correlated either with clinical severity (e.g. VCAM1, MSN, HPX), or risk for future conversion to Parkinson’s disease (VCAM1, MSN, MYO10, HSPAIL).

This demonstrates the power of machine learning and urine biomarkers to identify iRBD patients. As we develop new therapies and interventions, the ability to detect individuals at-risk of neurodegeneration in very early disease stage will be invaluable for treatment success.