Polymeric Nanoparticles for Drug Delivery.

The recent emergence of nanomedicine has revolutionized the therapeutic landscape and necessitated the creation of more sophisticated drug delivery systems. Polymeric nanoparticles sit at the forefront of numerous promising drug delivery designs, due to their unmatched control over physiochemical properties such as size, shape, architecture, charge, and surface functionality. Furthermore, polymeric nanoparticles have the ability to navigate various biological barriers to precisely target specific sites within the body, encapsulate a diverse range of therapeutic cargo and efficiently release this cargo in response to internal and external stimuli. However, despite these remarkable advantages, the presence of polymeric nanoparticles in wider clinical application is minimal. This review will provide a comprehensive understanding of polymeric nanoparticles as drug delivery vehicles. The biological barriers affecting drug delivery will be outlined first, followed by a comprehensive description of the various nanoparticle designs and preparation methods, beginning with the polymers on which they are based. The review will meticulously explore the current performance of polymeric nanoparticles against a myriad of diseases including cancer, viral and bacterial infections, before finally evaluating the advantages and crucial challenges that will determine their wider clinical potential in the decades to come.

A Molecular Switch between Mammalian MLL Complexes Dictates Response to Menin-MLL Inhibition.

Menin interacts with oncogenic MLL1-fusion proteins, and small molecules that disrupt these associations are in clinical trials for leukemia treatment. By integrating chromatin-focused and genome-wide CRISPR screens with genetic, pharmacologic, and biochemical approaches, we discovered a conserved molecular switch between the MLL1-Menin and MLL3/4-UTX chromatin-modifying complexes that dictates response to Menin-MLL inhibitors. MLL1-Menin safeguards leukemia survival by impeding the binding of the MLL3/4-UTX complex at a subset of target gene promoters. Disrupting the Menin-MLL1 interaction triggers UTX-dependent transcriptional activation of a tumor-suppressive program that dictates therapeutic responses in murine and human leukemia. Therapeutic reactivation of this program using CDK4/6 inhibitors mitigates treatment resistance in leukemia cells that are insensitive to Menin inhibitors. These findings shed light on novel functions of evolutionarily conserved epigenetic mediators like MLL1-Menin and MLL3/4-UTX and are relevant to understand and target molecular pathways determining therapeutic responses in ongoing clinical trials. SIGNIFICANCE: Menin-MLL inhibitors silence a canonical HOX- and MEIS1-dependent oncogenic gene expression program in leukemia. We discovered a parallel, noncanonical transcriptional program involving tumor suppressor genes that are repressed in Menin-MLL inhibitor-resistant leukemia cells but that can be reactivated upon combinatorial treatment with CDK4/6 inhibitors to augment therapy responses. This article is highlighted in the In This Issue feature, p. 1.

Quantifying the amount of physical rehabilitation received by individuals living with neurological conditions in the community: a scoping review.

BACKGROUND: Physical rehabilitation is often prescribed immediately following a neurological event or a neurological diagnosis. However, many individuals require physical rehabilitation after hospital discharge. The purpose of this scoping review was to determine the amount of physical rehabilitation that individuals living in the community with neurological conditions receive to understand current global practices and assess gaps in research and service use. METHODS: This scoping review included observational studies that 1) involved adults living with a neurological condition, and 2) quantified the amount of rehabilitation being received in the community or outpatient hospital setting. Only literature published in English was considered. MEDLINE, EMBASE, AMED, CINAHL, Cochrane Library, and PEDro databases were searched from inception. Two independent reviewers screened titles and abstracts, followed by full texts, and data extraction. Mean annual hours of rehabilitation was estimated based on the amount of rehabilitation reported in the included studies. RESULTS: Overall, 18 studies were included after screen 14,698 articles. The estimated mean annual hours of rehabilitation varied greatly (4.9 to 155.1 h), with individuals with spinal cord injury and stroke receiving the greatest number of hours. Participants typically received more physical therapy than occupational therapy (difference range: 1 to 22 h/year). Lastly, only one study included individuals with progressive neurological conditions, highlighting a research gap. DISCUSSION: The amount of rehabilitation received by individuals with neurological conditions living in the community varies greatly. With such a wide range of time spent in rehabilitation, it is likely that the amount of rehabilitation being received by most individuals in the community is insufficient to improve function and quality of life. Future work should identify the barriers to accessing rehabilitation resources in the community and how much rehabilitation is needed to observe functional improvements.

YBX1 mediates translation of oncogenic transcripts to control cell competition in AML.

Persistence of malignant clones is a major determinant of adverse outcome in patients with hematologic malignancies. Despite the fact that the majority of patients with acute myeloid leukemia (AML) achieve complete remission after chemotherapy, a large proportion of them relapse as a result of residual malignant cells. These persistent clones have a competitive advantage and can re-establish disease. Therefore, targeting strategies that specifically diminish cell competition of malignant cells while leaving normal cells unaffected are clearly warranted. Recently, our group identified YBX1 as a mediator of disease persistence in JAK2-mutated myeloproliferative neoplasms. The role of YBX1 in AML, however, remained so far elusive. Here, inactivation of YBX1 confirms its role as an essential driver of leukemia development and maintenance. We identify its ability to amplify the translation of oncogenic transcripts, including MYC, by recruitment to polysomal chains. Genetic inactivation of YBX1 disrupts this regulatory circuit and displaces oncogenic drivers from polysomes, with subsequent depletion of protein levels. As a consequence, leukemia cells show reduced proliferation and are out-competed in vitro and in vivo, while normal cells remain largely unaffected. Collectively, these data establish YBX1 as a specific dependency and therapeutic target in AML that is essential for oncogenic protein expression.

Muscle and cerebral oxygenation during cycling in chronic obstructive pulmonary disease: A scoping review.

To synthesize evidence for prefrontal cortex (PFC), quadriceps, and respiratory muscle oxygenation using near-infrared spectroscopy (NIRS) during cycling in individuals with chronic obstructive pulmonary disease (COPD). A scoping review was performed searching databases (inception-August 2020): Ovid MEDLINE, EMBASE, Cochrane Systematic Reviews, Cochrane Central Register of Controlled Clinical Trials, CINAHL, SPORTDiscus and Pedro. The search focused on COPD, cycling, and NIRS outcomes. 29 studies (541 COPD participants) were included. Compared to healthy individuals (8 studies), COPD patients at lower cycling workloads had more rapid increases in vastus lateralis (VL) deoxygenated hemoglobin (HHb); lower increases in VL total hemoglobin (tHb) and blood flow; and lower muscle tissue saturation (StO2). Heliox and bronchodilators were associated with smaller and slower increases in VL HHb. Heliox increased VL and intercostal blood flow compared to room air and supplemental oxygen in COPD patients (1 study). PFC oxygenated hemoglobin (O2Hb) increased in COPD individuals during cycling in 5 of 8 studies. Individuals with COPD and heart failure demonstrated worse VL and PFC NIRS outcomes compared to patients with only COPD-higher or more rapid increase in VL HHb and no change or decrease in PFC O2Hb. Individuals with COPD present with a mismatch between muscle oxygen delivery and utilization, characterized by more rapid increase in VL HHb, lower muscle O2Hb and lower muscle StO2. PFC O2Hb increases or tends to increase in individuals with COPD during exercise, but this relationship warrants further investigation. NIRS can be used to identify key deoxygenation thresholds during exercise to inform PFC and muscle oxygenation.

Phenotypic and transcriptomic consequences in zebrafish early-life stages following exposure to crude oil and chemical dispersant at sublethal concentrations.

To further understand the underlying mechanisms involved in the developmental toxicity of crude oil and chemically dispersed crude oil on fish early-life stages (ELS), zebrafish (Danio rerio) embryos were exposed to GM-2 chemical dispersant (DISP), low-energy water-accommodated fractions (LEWAF), and chemically enhanced WAF (CEWAF) of Merey crude oil at sublethal concentrations for 120 h. We employed the General Morphology Score (GMS) and General Teratogenic Score (GTS) systems in conjunction with high-throughput RNA-Seq analysis to evaluate the phenotypic and transcriptomic responses in zebrafish ELS. Results showed that ΣPAHs concentrations in LEWAF and CEWAF solutions were 507.63 ± 80.95 ng·L-1 and 4039.51 ± 241.26 ng·L-1, respectively. The GMS and GTS values indicated that CEWAF exposure caused more severe developmental delay and higher frequencies of teratogenic effects than LEWAF exposure. Moreover, no significant change in heart rate was observed in LEWAF treatment, while CEWAF exposure caused a significant reduction in heart rate. LEWAF and CEWAF exposure exhibited an overt change in eye area, with a reduction of 4.0% and 25.3% (relative to the control), respectively. Additionally, no obvious impact on phenotypic development was observed in zebrafish embryo-larvae following DISP exposure. Significant changes in gene expression were detected in LEWAF and CEWAF treatments, with a total of 957 and 2062 differentially expressed genes (DEGs), respectively, while DISP exposure altered only 91 DEGs. Functional enrichment analysis revealed that LEWAF and CEWAF exposure caused significant perturbations in the pathways associated with phototransduction, retinol metabolism, metabolism of xenobiotics by cytochrome P450, and immune response-related pathways. Our results provide more valid evidence to corroborate the previous suggestion that ocular impairment is an equal or possibly more sensitive biomarker than cardiotoxicity in fish ELS exposed to oil-derived PAHs. All these findings could gain further mechanistic insights into the effects of crude oil and chemical dispersant on fish ELS.

Loss of H3K36 Methyltransferase SETD2 Impairs V(D)J Recombination during Lymphoid Development.

Repair of DNA double-stranded breaks (DSBs) during lymphocyte development is essential for V(D)J recombination and forms the basis of immunoglobulin variable region diversity. Understanding of this process in lymphogenesis has historically been centered on the study of RAG1/2 recombinases and a set of classical non-homologous end-joining factors. Much less has been reported regarding the role of chromatin modifications on this process. Here, we show a role for the non-redundant histone H3 lysine methyltransferase, Setd2, and its modification of lysine-36 trimethylation (H3K36me3), in the processing and joining of DNA ends during V(D)J recombination. Loss leads to mis-repair of Rag-induced DNA DSBs, especially when combined with loss of Atm kinase activity. Furthermore, loss reduces immune repertoire and a severe block in lymphogenesis as well as causes post-mitotic neuronal apoptosis. Together, these studies are suggestive of an important role of Setd2/H3K36me3 in these two mammalian developmental processes that are influenced by double-stranded break repair.

Exposure to water-accommodated fractions of two different crude oils alters morphology, cardiac function and swim bladder development in early-life stages of zebrafish.

The present study investigated the developmental toxicity of water-accommodated fractions (WAFs) of Oman crude oil (OCO) and Merey crude oil (MCO) on zebrafish (Danio rerio) in early-life stages (ELS). Based on total petroleum hydrocarbons (TPH), LC50 values manifested that OCO WAF was 1.2-fold more lethal to zebrafish embryos than MCO WAF. As for hatching rate, EC50 value for OCO WAF was 5.7-fold lower than that for MCO WAF. To evaluate the sublethal morphological effects, semi-quantitative extended general morphological score (GMS) and general teratogenic score (GTS) systems were adopted. The GMS and GTS scores indicated that the WAFs caused remarkable developmental delay and high frequencies of malformation in a dose-dependent manner. Additionally, OCO and MCO WAFs exposure exhibited severe bradycardia (reduced heart rate) and overt reduction of stroke volume, with a concomitant decrease in the cardiac output. Meanwhile, the WAFs also induced dose-dependent down-regulated expressions of several key functional genes of excitation-contraction coupling in cardiomyocytes, including ryr2, atp2a2a, atp2a2b, ncx1h, and kcnh2. For key gene markers of swim bladder development, results showed that high dose of TPH induced significant down-regulation of hb9 and anxa5 with no obvious change of acta2, suggesting that the WAFs could affect the specification and development of epithelium and outer mesothelium of swim bladder in zebrafish ELS. A strong negative relationship between the failure of swim bladder inflation and cardiac dysfunction via cardiac output was found. All these findings provide novel insights into the complicated mechanisms of the developmental toxicity of crude oil on fish in ELS.

Transgenerational effects of heavy fuel oil on the sea urchin Strongylocentrotus intermedius considering oxidative stress biomarkers.

Stranding of oil onto a coastline after an oil spill threatens the health of marine benthic organisms. Here, the transgenerational effects of exposure to stranded heavy fuel oil (HFO) on the sea urchin Strongylocentrotus intermedius were assessed. The column containing gravel coated with HFO was prepared in the laboratory to simulate HFO-contaminated gravel shorelines. Adult sea urchins were exposed for 21 days to either a HFO-oiled gravel column at the oil loading of 3000 µg oil/g gravel or a non-HFO-oiled gravel column (as the control treatment) and then offspring were either exposed to HFO or ambient seawater conditions. The sublethal exposure to HFO for 21 days induced polycyclic aromatic hydrocarbons (PAHs) accumulation in gonads, accompanied by increased levels of oxidative lipid, protein and DNA damage and a reduction in total antioxidant capacity. Analysis of gametes indicated that both maternal and paternal exposure could result in the transfer of PAHs and DNA damage to their offspring. Parental (maternal, paternal or both) exposure to HFO caused increases in malformation rates of offspring compared to those from control parents under ambient seawater condition. Continued HFO exposure in the offspring resulted in further increased malformation rates compared with those reared in ambient seawater, as well as oxidative lipid, protein and DNA damage. Furthermore, mother exposure history reduced the total antioxidant capacity of larvae to response to continued HFO exposure. Overall, the results suggest an increased sensitivity to toxic effects of HFO in larvae from exposed both parents compared with those from control parents in S. intermedius, which may consequently affect the recruitment and population maintenance.

Toxicity of Water-Accommodated Fractions (WAF), Chemically Enhanced WAF (CEWAF) of Oman Crude Oil and Dispersant to Early-Life Stages of Zebrafish (Danio rerio).

This study focused on comparing the lethal and sublethal toxicity of water-accommodated fractions (WAF) and chemically enhanced WAF (CEWAF) of crude oil to zebrafish (Danio rerio) on early life stages (ELS). Results showed that the addition of GM-2 dispersant caused an increase in the levels of total petroleum hydrocarbons (TPHs) and total priority polycyclic aromatic hydrocarbons (ΣPAHs). Based on ΣPAHs, the LC20 estimates for WAF and CEWAF were 4.88 µg L-1 and 1.19 µg L-1, respectively, indicating that CEWAF was approximately four times more toxic. CEWAF exposure caused markedly lower hatching rates and higher malformation frequencies than WAF. Meanwhile, the general morphology score (GMS) values in CEWAF were about fourfold lower than that in WAF, indicating that CEWAF exposure induced more significant developmental delay. The results suggested that chemical dispersant enhanced the toxicity of crude oil to zebrafish on ELS and its application could increase the exposure of fishes to crude oil.

Parental exposure to heavy fuel oil induces developmental toxicity in offspring of the sea urchin Strongylocentrotus intermedius.

The present study investigated the toxic effects of parental (maternal/paternal) exposure to heavy fuel oil (HFO) on the adult reproductive state, gamete quality and development of the offspring of the sea urchin Strongylocentrotus intermedius. Adult sea urchins were exposed to effluents from HFO-oiled gravel columns for 7 days to simulate an oil-contaminated gravel shore, and then gametes of adult sea urchins were used to produce embryos to determine developmental toxicity. For adult sea urchins, no significant difference in the somatic size and weight was found between the various oil loadings tested, while the gonad weight and gonad index were significantly decreased at higher oil loadings. The spawning ability of adults and fecundity of females significantly decreased. For gametes, no effect was observed on the egg size and fertilization success in any of the groups. However, a significant increase in the percentage of anomalies in the offspring was observed and then quantified by an integrative toxicity index (ITI) at 24 and 48 h post fertilization. The offspring from exposed parents showed higher ITI values with more malformed embryos. The results confirmed that parental exposure to HFO can cause adverse effects on the offspring and consequently affect the recruitment and population maintenance of sea urchins.

Preparation of ordered N-doped mesoporous carbon materials via a polymer-ionic liquid assembly.

Here we report a facile and effective strategy for the preparation of ordered mesoporous carbon materials with a high-nitrogen-content (8.1 at%) coating layer through a polymer-ionic liquid assembly strategy. The prepared N-doped mesoporous carbon materials demonstrated enhanced CO2 adsorption capacity (2.29 mmol g-1) compared with non-doped carbon (1.84 mmol g-1).

Surface binding of polypyrrole on porous silicon hollow nanospheres for Li-ion battery anodes with high structure stability.

Uniform porous silicon hollow nano-spheres are prepared without any sacrificial templates through a magnesio-thermic reduction of mesoporous silica hollow nanospheres and surface modified by the following in situ chemical polymerization of polypyrrole. The porous hollow structure and polypyrrole coating contribute significantly to the excellent structure stability and high electrochemical performance of the nanocomposite.

A novel classification method based on ICA and ELM: a case study in lie detection.

The classification of EEG tasks has drawn much attention in recent years. In this paper, a novel classification model based on independent component analysis (ICA) and Extreme learning machine (ELM) is proposed to detect lying. Firstly, ICA and its topography information were used to automatically identify the P300 ICs. Then, time and frequency-domain features were extracted from the reconstructed P3 waveforms. Finally, two classes of feature samples were used to train ELM, Back-propagation network (BPNN) and support vector machine (SVM) classifiers for comparison. The optimal number of P3 ICs and the values of classifier parameter were optimized by the cross-validation procedures. Experimental results show that the presented method (ICA_ELM) achieves the highest training accuracy of 95.40% with extremely less training and testing time on detecting P3 components for the guilty and the innocent subjects. The results indicate that the proposed method can be applied in lie detection.