Targeted intracellular delivery of molecular cargo to hypoxic human breast cancer stem cells.

Cancer stem cells (CSCs) drive tumorigenesis, are responsible for metastasis, and resist conventional therapies thus posing significant treatment challenges. CSCs reside in hypoxic tumor regions and therefore, effective therapies must target CSCs within this specific microenvironment. CSCs are characterized by limited distinguishable features, however, surface displayed phosphatidylserine (PS) appears to be characteristic of stem cells and offers a potential target.

Structural insight into rabies virus neutralization revealed by an engineered antibody scaffold.

Host-cell entry of the highly pathogenic rabies virus (RABV) is mediated by glycoprotein (G) spikes, which also comprise the primary target for the humoral immune response. RABV glycoprotein (RABV-G) displays several antigenic sites that are targeted by neutralizing monoclonal antibodies (mAbs). In this study, we determined the epitope of a potently neutralizing human mAb, CR57, which we engineered into a diabody format to facilitate crystallization.

A Coupled Model of Hydraulic Eco-Physiology and Cambial Growth - Accounting for Biophysical Limitations and Phenology Improves Stem Diameter Prediction at High Temporal Resolution.

Traditional photosynthesis-driven growth models have considerable uncertainties in predicting tree growth under changing climates, partially because sink activities are directly affected by the environment but not adequately addressed in growth modelling. Therefore, we developed a semi-mechanistic model coupling stomatal optimality, temperature control of enzymatic activities and phenology of cambial growth. Parameterized using Bayesian inference and measured data on Picea abies and Pinus sylvestris in peatland and mineral soils in Finland, the coupled model simulates transpiration and assimilation rates and stem radial dimension (SRD) simultaneously at 30 min resolution.

Modelling the Effects of Forest use Change on Brownification of Finnish Rivers under Atmospheric Pressure.

Browning of surface waters due to increased terrestrial loading of dissolved organic matter (DOM) is observed across the Northern Hemisphere. The effects influence several ecosystem services from freshwater productivity to water purification. Brownification is often explained by changes in large-scale anthropogenic pressures and ecosystem functioning (acidification, climate change, and land cover changes).

Immunometabolic cues recompose and reprogram the microenvironment around implanted biomaterials.

Circulating monocytes infiltrate and coordinate immune responses in tissues surrounding implanted biomaterials and in other inflamed tissues. Here we show that immunometabolic cues in the biomaterial microenvironment govern the trafficking of immune cells, including neutrophils and monocytes, in a manner dependent on the chemokine receptor 2 (CCR2) and the C-X3-C motif chemokine receptor 1 (CX3CR1). This affects the composition and activation states of macrophage and dendritic cell populations, ultimately orchestrating the relative composition of pro-inflammatory, transitory and anti-inflammatory CCR2, CX3CR1 and CCR2 CX3CR1 immune cell populations.

Reconciling the EU forest, biodiversity, and climate strategies.

Forests provide important ecosystem services (ESs), including climate change mitigation, local climate regulation, habitat for biodiversity, wood and non-wood products, energy, and recreation. Simultaneously, forests are increasingly affected by climate change and need to be adapted to future environmental conditions. Current legislation, including the European Union (EU) Biodiversity Strategy, EU Forest Strategy, and national laws, aims to protect forest landscapes, enhance ESs, adapt forests to climate change, and leverage forest products for climate change mitigation and the bioeconomy.

Translational Aspects of 3D and 4D Printing and Bioprinting.

Three-dimensional (3D) printed medical devices include orthopedic and craniofacial implants, surgical tools, and external prosthetics that have been directly used in patients. While the advances of additive manufacturing techniques in the production of medical devices have been on the rise, clinical translation of living cellular constructs face significant limitations in terms of regulatory affairs, process technology, and materials development. In this perspective, the current status-quo of 3D and four-dimensional (4D) (bio)printing is summarized, current advancements are discussed and the challenges that need to be addressed for improved industrial translation and clinical applications of bioprinting are highlighted.

Regulating the proinflammatory response to composite biomaterials by targeting immunometabolism.

Composite biomaterials comprising polylactide (PLA) and hydroxyapatite (HA) are applied in bone, cartilage and dental regenerative medicine, where HA confers osteoconductive properties. However, after surgical implantation, adverse immune responses to these composites can occur, which have been attributed to size and morphology of HA particles. Approaches to effectively modulate these adverse immune responses have not been described.

Magnetic Particle Imaging Reveals that Iron-Labeled Extracellular Vesicles Accumulate in Brains of Mice with Metastases.

The incidence of breast cancer remains high worldwide and is associated with a significant risk of metastasis to the brain that can be fatal; this is due, in part, to the inability of therapeutics to cross the blood-brain barrier (BBB). Extracellular vesicles (EVs) have been found to cross the BBB and further have been used to deliver drugs to tumors. EVs from different cell types appear to have different patterns of accumulation and retention as well as the efficiency of bioactive cargo delivery to recipient cells in the body.

Liprin-α1 contributes to oncogenic MAPK signaling by counteracting ERK activity.

PTPRF interacting protein alpha 1 (PPFIA1) encodes for liprin-α1, a member of the leukocyte common antigen-related protein tyrosine phosphatase (LAR-RPTPs)-interacting protein family. Liprin-α1 localizes to adhesive and invasive structures in the periphery of cancer cells, where it modulates migration and invasion in head and neck squamous cell carcinoma (HNSCC) and breast cancer. To study the possible role of liprin-α1 in anticancer drug responses, we screened a library of oncology compounds in cell lines with high endogenous PPFIA1 expression.

Polylactide Degradation Activates Immune Cells by Metabolic Reprogramming.

Polylactide (PLA) is the most widely utilized biopolymer in medicine. However, chronic inflammation and excessive fibrosis resulting from its degradation remain significant obstacles to extended clinical use. Immune cell activation has been correlated to the acidity of breakdown products, yet methods to neutralize the pH have not significantly reduced adverse responses.

Shape Anisotropy-Governed High-Performance Nanomagnetosol for In Vivo Magnetic Particle Imaging of Lungs.

Caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), coronavirus disease 2019 (COVID-19) has shown extensive lung manifestations in vulnerable individuals, putting lung imaging and monitoring at the forefront of early detection and treatment. Magnetic particle imaging (MPI) is an imaging modality, which can bring excellent contrast, sensitivity, and signal-to-noise ratios to lung imaging for the development of new theranostic approaches for respiratory diseases. Advances in MPI tracers would offer additional improvements and increase the potential for clinical translation of MPI.

Role of data uncertainty when identifying important areas for biodiversity and carbon in boreal forests.

Forest conservation plays a central role in meeting national and international biodiversity and climate targets. Biodiversity and carbon values within forests are often estimated with models, introducing uncertainty to decision making on which forest stands to protect. Here, we explore how uncertainties in forest variable estimates affect modelled biodiversity and carbon patterns, and how this in turn introduces variability in the selection of new protected areas.

Quantification of forest carbon flux and stock uncertainties under climate change and their use in regionally explicit decision making: Case study in Finland.

Uncertainties are essential, yet often neglected, information for evaluating the reliability in forest carbon balance projections used in national and regional policy planning. We analysed uncertainties in the forest net biome exchange (NBE) and carbon stocks under multiple management and climate scenarios with a process-based ecosystem model. Sampled forest initial state values, model parameters, harvest levels and global climate models (GCMs) served as inputs in Monte Carlo simulations, which covered forests of the 18 regions of mainland Finland over the period 2015-2050.

Modelling the regional potential for reaching carbon neutrality in Finland: Sustainable forestry, energy use and biodiversity protection.

The EU aims at reaching carbon neutrality by 2050 and Finland by 2035. We integrated results of three spatially distributed model systems (FRES, PREBAS, Zonation) to evaluate the potential to reach this goal at both national and regional scale in Finland, by simultaneously considering protection targets of the EU biodiversity (BD) strategy. Modelling of both anthropogenic emissions and forestry measures were carried out, and forested areas important for BD protection were identified based on spatial prioritization.

Effect of forest management choices on carbon sequestration and biodiversity at national scale.

Forest management methods and harvest intensities influence wood production, carbon sequestration and biodiversity. We devised different management scenarios by means of stakeholder analysis and incorporated them in the forest growth simulator PREBAS. To analyse impacts of harvest intensity, we used constraints on total harvest: business as usual, low harvest, intensive harvest and no harvest.

Gla-domain mediated targeting of externalized phosphatidylserine for intracellular delivery.

Phosphatidylserine (PS) is a negatively charged phospholipid normally localized to the inner leaflet of the plasma membrane of cells but is externalized onto the cell surface during apoptosis as well as in malignant and infected cells. Consequently, PS may comprise an important molecular target in diagnostics, imaging, and targeted delivery of therapeutic agents. While an array of PS-binding molecules exist, their utility has been limited by their inability to internalize diagnostic or therapeutic payloads.

How to Measure Foot Self-Care? A Methodological Review of Instruments.

Foot self-care is an important element of caring for and promoting foot health. However, little is known about the validity and reliability of existing foot self-care instruments. The purpose of this review is to describe and analyze the focus, content, and psychometric evidence of existing instruments for measuring foot self-care.

Intranasal trimeric sherpabody inhibits SARS-CoV-2 including recent immunoevasive Omicron subvariants.

The emergence of increasingly immunoevasive SARS-CoV-2 variants emphasizes the need for prophylactic strategies to complement vaccination in fighting the COVID-19 pandemic. Intranasal administration of neutralizing antibodies has shown encouraging protective potential but there remains a need for SARS-CoV-2 blocking agents that are less vulnerable to mutational viral variation and more economical to produce in large scale. Here we describe TriSb92, a highly manufacturable and stable trimeric antibody-mimetic sherpabody targeted against a conserved region of the viral spike glycoprotein.

Developmental or adult-onset deletion of neurotensin receptor-1 from dopamine neurons differentially reduces body weight.

Central neurotensin signaling via neurotensin receptor-1 (NtsR1) modulates various aspects of physiology, including suppressing feeding and promoting locomotor activity that can support weight loss. However, it remains unclear when and where NtsR1 expression contributes to control of body weight vs. other effects.

Magnetothermal Control of Temperature-Sensitive Repressors in Superparamagnetic Iron Nanoparticle-Coated .

Superparamagnetic iron oxide nanoparticles (SPIONs) are used as contrast agents in magnetic resonance imaging (MRI) and magnetic particle imaging (MPI), and resulting images can be used to guide magnetothermal heating. Alternating magnetic fields (AMF) cause local temperature increases in regions with SPIONs, and we investigated the ability of magnetic hyperthermia to regulate temperature-sensitive repressors (TSRs) of bacterial transcription. The TSR, TlpA39, was derived from a Gram-negative bacterium and used here for thermal control of reporter gene expression in Gram-positive, heating of with TlpA39 controlling bacterial luciferase expression resulted in a 14.

Tracking the fates of iron-labeled tumor cells using magnetic particle imaging.

The use of imaging to detect and monitor the movement and accumulation of cells in living subjects can provide significant insights that can improve our understanding of metastasis and guide therapeutic development. For cell tracking using Magnetic Resonance Imaging (MRI), cells are labeled with iron oxides and the effects of the iron on water provides contrast. However, due to low specificity and difficulties in quantification with MRI, other modalities and approaches need to be developed.