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CRISPR–Cas gene editing and messenger RNA-based protein replacement therapy hold tremendous potential to effectively treat disease-causing mutations with diverse cellular origin. However, it is currently impossible to rationally design nanoparticles that selectively target specific tissues. Here, we report a strategy termed selective organ targeting (SORT) wherein multiple classes of lipid nanoparticles are systematically engineered to exclusively edit extrahepatic tissues via addition of a supplemental SORT molecule. Lung-, spleen- and liver-targeted SORT lipid nanoparticles were designed to selectively edit therapeutically relevant cell types including epithelial cells, endothelial cells, B cells, T cells and hepatocytes. SORT is compatible with multiple gene editing techniques, including mRNA, Cas9 mRNA/single guide RNA and Cas9 ribonucleoprotein complexes, and is envisioned to aid the development of protein replacement and gene correction therapeutics in targeted tissues.The addition of selective organ targeting molecules to nanoparticles allows the specific targeting of extrahepatic tissues, enabling gene editing of distinct cell populations outside the liver.

Endosomal escape remains a fundamental barrier hindering the advancement of nucleic acid therapeutics. Taking inspiration from natural phospholipids that comprise biological membranes, we report the combinatorial synthesis of multi-tailed ionizable phospholipids (iPhos) capable of delivering messenger RNA or mRNA/single-guide RNA for gene editing in vivo. Optimized iPhos lipids are composed of one pH-switchable zwitterion and three hydrophobic tails, which adopt a cone shape in endosomal acidic environments to facilitate membrane hexagonal transformation and subsequent cargo release from endosomes. Structure–activity relationships reveal that iPhos chemical structure can control in vivo efficacy and organ selectivity. iPhos lipids synergistically function with various helper lipids to formulate multi-component lipid nanoparticles (called iPLNPs) for selective organ targeting. Zwitterionic, ionizable cationic and permanently cationic helper lipids enable tissue-selective mRNA delivery and CRISPR–Cas9 gene editing in spleen, liver and lungs (respectively) following intravenous administration. This rational design of functional phospholipids demonstrates substantial value for gene editing research and therapeutic applications. Ionizable phospholipid nanoparticles have been designed to efficiently destabilize endosomal membranes and mediate organ-selective mRNA delivery and CRISPR–Cas9 gene editing.

Approximately 10% of Cystic Fibrosis (CF) patients, particularly those with CF transmembrane conductance regulator ( CFTR ) gene nonsense mutations, lack effective treatments. The potential of gene correction therapy through delivery of the CRISPR/Cas system to CF-relevant organs/cells is hindered by the lack of efficient genome editor delivery carriers. Herein, we report improved Lung Selective Organ Targeting Lipid Nanoparticles (SORT LNPs) for efficient delivery of Cas9 mRNA, sgRNA, and donor ssDNA templates, enabling precise homology-directed repair-mediated gene correction in CF models. Optimized Lung SORT LNPs deliver mRNA to lung basal cells in Ai9 reporter mice. SORT LNP treatment successfully corrected the CFTR mutations in homozygous G542X mice and in patient-derived human bronchial epithelial cells with homozygous F508del mutations, leading to the restoration of CFTR protein expression and chloride transport function. This proof-of-concept study will contribute to accelerating the clinical development of mRNA LNPs for CF treatment through CRISPR/Cas gene correction. Roughly 10% of Cystic Fibrosis (CF) patients still have no effective medicine to take. Lung Selective Organ Targeting (SORT) Lipid Nanoparticles can efficiently deliver Cas9 mRNA, sgRNA, and donor ssDNA templates for precise homology-directed repair-mediated gene correction in ex vivo and in vivo CF models.

Genome editing holds great potential for cancer treatment due to the ability to precisely inactivate or repair cancer-related genes. However, delivery of CRISPR/Cas to solid tumours for efficient cancer therapy remains challenging. Here we targeted tumour tissue mechanics via a multiplexed dendrimer lipid nanoparticle (LNP) approach involving co-delivery of focal adhesion kinase (FAK) siRNA, Cas9 mRNA and sgRNA (siFAK + CRISPR-LNPs) to enable tumour delivery and enhance gene-editing efficacy. We show that gene editing was enhanced >10-fold in tumour spheroids due to increased cellular uptake and tumour penetration of nanoparticles mediated by FAK-knockdown. siFAK + CRISPR-PD-L1-LNPs reduced extracellular matrix stiffness and efficiently disrupted PD-L1 expression by CRISPR/Cas gene editing, which significantly inhibited tumour growth and metastasis in four mouse models of cancer. Overall, we provide evidence that modulating the stiffness of tumour tissue can enhance gene editing in tumours, which offers a new strategy for synergistic LNPs and other nanoparticle systems to treat cancer using gene editing. In vivo delivery of the CRISPR/Cas system is a promising cancer therapy approach, but its efficacy is hampered by low penetrability of nanoparticles in the stiff tumour tissue. Here the authors use dendrimer lipid nanoparticles to couple PD-L1 gene editing with knockdown of FAK, a protein involved in cell adhesion, showing that modulation of the mechanical properties of tumour cells leads to enhanced gene editing and tumour growth inhibition in four different animal models.

The parasites that cause malaria depend on Anopheles mosquitoes for transmission; because of this, mosquito population dynamics are a key determinant of malaria risk. Development and survival rates of both the Anopheles mosquitoes and the Plasmodium parasites that cause malaria depend on temperature, making this a potential driver of mosquito population dynamics and malaria transmission. We developed a temperature-dependent, stage-structured delayed differential equation model to better understand how climate determines risk. Including the full mosquito life cycle in the model reveals that the mosquito population abundance is more sensitive to temperature than previously thought because it is strongly influenced by the dynamics of the juvenile mosquito stages whose vital rates are also temperature-dependent. Additionally, the model predicts a peak in abundance of mosquitoes old enough to vector malaria at more accurate temperatures than previous models. Our results point to the importance of incorporating detailed vector biology into models for predicting the risk for vector borne diseases.

Two foundational questions about sustainability are “How are ecosystems and the services they provide going to change in the future?” and “How do human decisions affect these trajectories?” Answering these questions requires an ability to forecast ecological processes. Unfortunately, most ecological forecasts focus on centennial-scale climate responses, therefore neither meeting the needs of near-term (daily to decadal) environmental decision-making nor allowing comparison of specific, quantitative predictions to new observational data, one of the strongest tests of scientific theory. Near-term forecasts provide the opportunity to iteratively cycle between performing analyses and updating predictions in light of new evidence. This iterative process of gaining feedback, building experience, and correcting models and methods is critical for improving forecasts. Iterative, near-term forecasting will accelerate ecological research, make it more relevant to society, and inform sustainable decision-making under high uncertainty and adaptive management. Here, we identify the immediate scientific and societal needs, opportunities, and challenges for iterative near-term ecological forecasting. Over the past decade, data volume, variety, and accessibility have greatly increased, but challenges remain in interoperability, latency, and uncertainty quantification. Similarly, ecologists have made considerable advances in applying computational, informatic, and statistical methods, but opportunities exist for improving forecast-specific theory, methods, and cyberinfra-structure. Effective forecasting will also require changes in scientific training, culture, and institutions. The need to start forecasting is now; the time for making ecology more predictive is here, and learning by doing is the fastest route to drive the science forward.

Vector-borne parasites must succeed at three scales to persist: they must proliferate within a host, establish in vectors, and transmit back to hosts. Ecology outside the host undergoes dramatic seasonal and human-induced changes, but predicting parasite evolutionary responses requires integrating their success across scales. We develop a novel, data-driven model to titrate the evolutionary impact of ecology at multiple scales on human malaria parasites. We investigate how parasites invest in transmission versus proliferation, a life-history trait that influences disease severity and spread. We find that transmission investment controls the pattern of host infectiousness over the course of infection: a trade-off emerges between early and late infectiousness, and the optimal resolution of that trade-off depends on ecology outside the host. An expanding epidemic favors rapid proliferation, and can overwhelm the evolutionary influence of host recovery rates and mosquito population dynamics. If transmission investment and recovery rate are positively correlated, then ecology outside the host imposes potent selection for aggressive parasite proliferation at the expense of transmission. Any association between transmission investment and recovery represents a key unknown, one that is likely to influence whether the evolutionary consequences of interventions are beneficial or costly for human health.

Therapeutic genome editing of haematopoietic stem cells (HSCs) would provide long-lasting treatments for multiple diseases. However, the in vivo delivery of genetic medicines to HSCs remains challenging, especially in diseased and malignant settings. Here we report on a series of bone-marrow-homing lipid nanoparticles that deliver mRNA to a broad group of at least 14 unique cell types in the bone marrow, including healthy and diseased HSCs, leukaemic stem cells, B cells, T cells, macrophages and leukaemia cells. CRISPR/Cas and base editing is achieved in a mouse model expressing human sickle cell disease phenotypes for potential foetal haemoglobin reactivation and conversion from sickle to non-sickle alleles. Bone-marrow-homing lipid nanoparticles were also able to achieve Cre-recombinase-mediated genetic deletion in bone-marrow-engrafted leukaemic stem cells and leukaemia cells. We show evidence that diverse cell types in the bone marrow niche can be edited using bone-marrow-homing lipid nanoparticles. The ability to genetically modify haematopoietic stem cells would allow the durable treatment of a diverse range of genetic disorders but gene delivery to the bone marrow has not been achieved. Here lipid nanoparticles that target and deliver mRNA to 14 unique cells within the bone marrow are presented.

Understanding underlying transmission dynamics is necessary to effectively control an infectious disease outbreak. In the likely event that managers do not know where to target control resources because drivers of transmission are unknown, it may be desirable to tailor control strategies to a given outbreak by implementing control actions gradually in response to changes in the outbreak (adaptive) rather than all at once (fixed). Adaptive control strategies may also prevent over-reaction and thus causing unnecessary socioeconomic harm. However, it remains unclear whether the benefits of adaptive control strategies outweigh the potential of under-reacting and causing larger outbreaks. To weigh this trade-off, we used a validated national scale foot and mouth disease transmission model to compare how adaptive and fixed control strategies as well as various attributes of the control process affect outbreak size. We find that adaptive control strategies do not cost less for the vast majority of outbreaks, but infrequently result in much larger and more costly outbreaks owing to decision-making time and case reporting lags. This study emphasizes the cost of under-reacting to a disease outbreak and that minimizing decision-making time should be a key consideration when developing outbreak response guidelines.

, otherwise known as kratom, is a plant in the coffee family (Rubiaceae) native to Southeast Asia and Thailand whose leaves have been shown to cause opioid-like and stimulant responses upon ingestion. The major pharmacologically active compounds present in kratom, mitragynine and 7-hydroxymitragynine (7-HMG), are both indole alkaloids and are responsible for its opioid-like activity. While kratom is most commonly known for its affinity for mu-opioid receptors, research has shown one of its active components has effects on the same receptors to which some antipsychotics bind, such as D dopamine, serotonin (5-HT and 5-HT ), and alpha-2 adrenergic receptors displaying possible indications of kratom to be used as both antipsychotics and antidepressants. Although studies to evaluate this effect are still lacking, several online and in-person surveys note relief of depression and anxiety symptoms among those who consume kratom products, and in fact identify it as a common reason for consumption. This then highlights the dire need for further research to be conducted on kratom, its mechanism of action and the constituents that elicit these antidepressant, anxiolytic, and antipsychotic properties.