Single-Cell Transcriptional Profile Construction of Rat Pituitary Glands before and after Sexual Maturation and Identification of Novel Marker Spp1 in Gonadotropes.

The mammalian pituitary gland drives highly conserved physiological processes such as somatic cell growth, pubertal transformation, fertility, and metabolism by secreting a variety of hormones. Recently, single-cell transcriptomics techniques have been used in pituitary gland research. However, more studies have focused on adult pituitary gland tissues from different species or different sexes, and no research has yet resolved cellular differences in pituitary gland tissue before and after sexual maturation. Here, we identified a total of 15 cell clusters and constructed single-cell transcriptional profiles of rats before and after sexual maturation. Furthermore, focusing on the gonadotrope cluster, 106 genes were found to be differentially expressed before and after sexual maturation. It was verified that Spp1, which is specifically expressed in gonadotrope cells, could serve as a novel marker for this cell cluster and has a promotional effect on the synthesis and secretion of follicle-stimulating hormone. The results provide a new resource for further resolving the regulatory mechanism of pituitary gland development and pituitary hormone synthesis and secretion.

Fabrication of Carbon Dots with Singlet Oxygen Generation and Their Potential Photodynamic Therapy Applications.

Due to the unique chemical and biomedical properties of carbon dots (CDs), they have increasingly obtained the attention in many research fields, for example, bioimaging, fluorescence sensing, and drug delivery, etc. Recently, it was found that, under light excitation, CDs can also be exploited as a novel photosensitizer to prepare reactive oxygen species (ROS), which expand their applications in the field of photodynamic therapy for cancer treatment. Nevertheless, the high cost and complex fabrication approach of CDs significantly limit their applications. To address this issue, bottom-up routes usually utilize sustainable and inexpensive carbon precursor as starting materials, employed N,N-dimethylformamide (DMF) or ethanol as an environmental-friendly solvent. Bottom-up approach was energy efficient, and the purification process was relatively simple by dialysis. Therefore, carbon dots (CDs) were facilely fabricated in a one-pot solvothermal process using 1-aminoanthraquinone as a precursor, and their application as photosensitizers for in vitro antitumor cells, especially photodynamic therapy (PDT) was established. Then the photophysical and nanoscale dimensions properties of the fabricated CDs were characterized via TEM, UV-visible, fluorescence, and FT-IR spectroscopy. The synthesized N-doped CDs can easily dissolve in water, possess very low biotoxicity, yellow-light emission (maximum peak at 587 nm). More importantly, PDT studies demonstrated that the obtained CDs possess a high singlet oxygen yield of 35%, and exhibit significant phototoxicity to cancer cells upon 635 nm laser irradiation. These studies highlight that N-doped CDs can be facilely synthesized from only one precursor, and are a potentially novel theranostic agent for in vivo PDT.

Monocyte-Derived Macrophages Aggravate Cardiac Dysfunction After Ischemic Stroke in Mice.

BACKGROUND: Cardiac damage induced by ischemic stroke, such as arrhythmia, cardiac dysfunction, and even cardiac arrest, is referred to as cerebral-cardiac syndrome (CCS). Cardiac macrophages are reported to be closely associated with stroke-induced cardiac damage. However, the role of macrophage subsets in CCS is still unclear due to their heterogeneity. Sympathetic nerves play a significant role in regulating macrophages in cardiovascular disease. However, the role of macrophage subsets and sympathetic nerves in CCS is still unclear. METHODS AND RESULTS: In this study, a middle cerebral artery occlusion mouse model was used to simulate ischemic stroke. ECG and echocardiography were used to assess cardiac function. We used Cx3cr1GFPCcr2RFP mice and NLRP3-deficient mice in combination with Smart-seq2 RNA sequencing to confirm the role of macrophage subsets in CCS. We demonstrated that ischemic stroke-induced cardiac damage is characterized by severe cardiac dysfunction and robust infiltration of monocyte-derived macrophages into the heart. Subsequently, we identified that cardiac monocyte-derived macrophages displayed a proinflammatory profile. We also observed that cardiac dysfunction was rescued in ischemic stroke mice by blocking macrophage infiltration using a CCR2 antagonist and NLRP3-deficient mice. In addition, a cardiac sympathetic nerve retrograde tracer and a sympathectomy method were used to explore the relationship between sympathetic nerves and cardiac macrophages. We found that cardiac sympathetic nerves are significantly activated after ischemic stroke, which contributes to the infiltration of monocyte-derived macrophages and subsequent cardiac dysfunction. CONCLUSIONS: Our findings suggest a potential pathogenesis of CCS involving the cardiac sympathetic nerve-monocyte-derived macrophage axis.

PKIB, a Novel Target for Cancer Therapy.

The serine-threonine kinase protein kinase A (PKA) is a cyclic AMP (cAMP)-dependent intracellular protein with multiple roles in cellular biology including metabolic and transcription regulation functions. The cAMP-dependent protein kinase inhibitor ß (PKIB) is one of three known endogenous protein kinase inhibitors of PKA. The role of PKIB is not yet fully understood. Hormonal signaling is correlated with increased PKIB expression through genetic regulation, and increasing PKIB expression is associated with decreased cancer patient prognosis. Additionally, PKIB impacts cancer cell behavior through two mechanisms; the first is the nuclear modulation of transcriptional activation and the second is the regulation of oncogenic AKT signaling. The limited research into PKIB indicates the oncogenic potential of PKIB in various cancers. However, some studies suggest a role of PKIB in non-cancerous disease states. This review aims to summarize the current literature and background of PKIB regarding cancer and related issues. In particular, we will focus on cancer development and therapeutic possibilities, which are of paramount interest in PKIB oncology research.

Weight management personas of breast cancer patients undergoing chemotherapy in China: a multi-method study.

BACKGROUND: Mobile health (mHealth) may be an ideal solution for breast cancer (BC) patients in China to access weight management interventions. User retention and engagement are the main challenges faced by mHealth applications. A user persona, which is a user-centered design process, can lead to the development of mHealth that is more acceptable to the needs of target users. This study aimed to investigate the variety of experiences in weight management and the behavioral preferences of BC patients receiving chemotherapy to develop users' personal information and persona development for the design and implementation of mHealth interventions. METHODS: Sixteen individual semi-structured in-depth interviews were conducted with BC patients receiving chemotherapy. We employed the thematic analysis method to analyze the interview transcripts in NVivo 11 software. The themes obtained from the analysis were used as the subdomains of personas. A proforma was designed to extract each participant's experience in each subdomain. Patients who exhibited similar experience in subdomains were grouped into a persona using affinity diagrams. The personas were named according to their prominent features. A questionnaire survey was conducted to validate the personas and to test whether the personas that were generated from the qualitative interview data were applicable to the Chinese population with BC. RESULTS: Four themes were identified as subdomains of weight management personas: the perception of weight management while undergoing chemotherapy, symptoms and emotional disturbance, changes in diet and exercise, and health literacy and information seeking. Five personas were ultimately obtained: (1) positive weight controllers, (2) patients who were inactive due to fatigue, (3) young patients who avoided communication, (4) overweight patients with treatment priority, and (5) patients who engaged in irregular exercise. Finally, the quantitative study showed that 51.58% of patients chose one of these five personas to represent themselves in weight management. None of the patient reported selecting options that were not explicitly outlined in the questionnaire and provided personalized descriptions of their weight management characteristics. CONCLUSIONS: The selected personas were developed from in-depth interviews on biopsychosocial areas. They highlight different weight management patterns in Chinese BC patients and provide implications for both the design of mHealth systems and traditional interventions.

CAR-based immunotherapy for breast cancer: peculiarities, ongoing investigations, and future strategies.

Surgery, chemotherapy, and endocrine therapy have improved the overall survival and postoperative recurrence rates of Luminal A, Luminal B, and HER2-positive breast cancers but treatment modalities for triple-negative breast cancer (TNBC) with poor prognosis remain limited. The effective application of the rapidly developing chimeric antigen receptor (CAR)-T cell therapy in hematological tumors provides new ideas for the treatment of breast cancer. Choosing suitable and specific targets is crucial for applying CAR-T therapy for breast cancer treatment. In this paper, we summarize CAR-T therapy's effective targets and potential targets in different subtypes based on the existing research progress, especially for TNBC. CAR-based immunotherapy has resulted in advancements in the treatment of breast cancer. CAR-macrophages, CAR-NK cells, and CAR-mesenchymal stem cells (MSCs) may be more effective and safer for treating solid tumors, such as breast cancer. However, the tumor microenvironment (TME) of breast tumors and the side effects of CAR-T therapy pose challenges to CAR-based immunotherapy. CAR-T cells and CAR-NK cells-derived exosomes are advantageous in tumor therapy. Exosomes carrying CAR for breast cancer immunotherapy are of immense research value and may provide a treatment modality with good treatment effects. In this review, we provide an overview of the development and challenges of CAR-based immunotherapy in treating different subtypes of breast cancer and discuss the progress of CAR-expressing exosomes for breast cancer treatment. We elaborate on the development of CAR-T cells in TNBC therapy and the prospects of using CAR-macrophages, CAR-NK cells, and CAR-MSCs for treating breast cancer.

Genome engineering with Cas9 and AAV repair templates generates frequent concatemeric insertions of viral vectors.

CRISPR-Cas9 paired with adeno-associated virus serotype 6 (AAV6) is among the most efficient tools for producing targeted gene knockins. Here, we report that this system can lead to frequent concatemeric insertions of the viral vector genome at the target site that are difficult to detect. Such errors can cause adverse and unreliable phenotypes that are antithetical to the goal of precision genome engineering. The concatemeric knockins occurred regardless of locus, vector concentration, cell line or cell type, including human pluripotent and hematopoietic stem cells. Although these highly abundant errors were found in more than half of the edited cells, they could not be readily detected by common analytical methods. We describe strategies to detect and thoroughly characterize the concatemeric viral vector insertions, and we highlight analytical pitfalls that mask their prevalence. We then describe strategies to prevent the concatemeric inserts by cutting the vector genome after transduction. This approach is compatible with established gene editing pipelines, enabling robust genetic knockins that are safer, more reliable and more reproducible.

Genetic dissection of ten photosynthesis-related traits based on InDel- and SNP-GWAS in soybean.

KEY MESSAGE: A total of 416 InDels and 112 SNPs were significantly associated with soybean photosynthesis-related traits. GmIWS1 and GmCDC48 might be related to chlorophyll fluorescence and gas-exchange parameters, respectively. Photosynthesis is one of the main factors determining crop yield. A better understanding of the genetic architecture for photosynthesis is of great significance for soybean yield improvement. Our previous studies identified 5,410,112 single nucleotide polymorphisms (SNPs) from the resequencing data of 219 natural soybean accessions. Here, we identified 634,106 insertions and deletions (InDels) from these 219 accessions and used these InDel variations to perform principal component and linkage disequilibrium analysis of this population. The genome-wide association study (GWAS) were conducted on six chlorophyll fluorescence parameters (chlorophyll content, light energy absorbed per reaction center, quantum yield for electron transport, probability that a trapped exciton moves an electron into the electron transport chain beyond primary quinone acceptor, maximum quantum yield of photosystem II primary photochemistry in the dark-adapted state, performance index on absorption basis) and four gas-exchange parameters (intercellular carbon dioxide concentration, stomatal conductance, net photosynthesis rate, transpiration rate) and revealed 416 significant InDels and 112 significant SNPs. Based on GWAS results, GmIWS1 (encoding a transcription elongation factor) and GmCDC48 (encoding a cell division cycle protein) with the highest expression in the mapping region were determined as the candidate genes responsible for chlorophyll fluorescence and gas-exchange parameters, respectively. Further identification of favorable haplotypes with higher photosynthesis, seed weight and seed yield were carried out for GmIWS1 and GmCDC48. Overall, this study revealed the natural variations and candidate genes underlying the photosynthesis-related traits based on abundant phenotypic and genetic data, providing valuable insights into the genetic mechanisms controlling photosynthesis and yield in soybean.

Effects of different oil additives on water resistance of corn starch straws.

To investigate the effect of oil additives on improving the water resistance of corn starch straws, corn oil (CO), soybean oil (SO), rapeseed oil (RO), peanut oil (PO), lard (LD) and coconut oil (CCO) were chosen and compared the structure and properties of starch straws with different oil additives. Corn starch straws (CS), and starch straws supplemented with CO, SO, RO, PO, LD and CCO were prepared by thermoplastic extrusion. The results showed that the incorporation of oils effectively enhanced the water resistance of starch straws such as water absorption, water solubility and water swelling performance. Meanwhile, the flexural strength of starch straws significantly increased. There was no significant linear relationship among starch chain length, oil unsaturation and straw performance. Among seven starch straws, S-SO had the strongest hydrogen bond interaction (3289 cm-1) and relaxation time (0.96 ms). The S-CO had the highest relative crystallinity (16.82 %) and degree of double helix (1.535), hence resulting in the lowest water absorption and solubility values, the highest flexural strength (23.43 MPa), the highest ΔT value (9.93 °C) and ΔH value (4.79 J/g). S-RO had the highest thermal transition temperatures.

The relationship between lactate dehydrogenase to albumin ratio and all-cause mortality during ICU stays in patients with sepsis: A retrospective cohort study with propensity score matching.

Background: Sepsis is a prevalent and severe medical condition which is frequently observed in the intensive care unit (ICU). Although numerous biomarkers have been identified to predict the prognosis of sepsis, the lactate dehydrogenase to albumin ratio (LDH/ALB ratio) has not been extensively investigated. The principal objective of this study is to assess the relationship between LDH/ALB ratio and all-cause mortality in patients with sepsis. Methods: This study included all adult critically ill patients with sepsis from the Medical Information Mart for Intensive Care IV (MIMIC-IV, version 2.0) database. Propensity score matching (PSM) analysis was conducted to mitigate bias, and Kaplan-Meier curves were performed to evaluate the cumulative survival across different groups. The association between the LDH/ALB ratio and mortality was examined through restricted cubic spline (RCS) analysis and Cox regression analysis. The robustness of the findings was confirmed through subgroup analyses. Additionally, the prognostic capability of the LDH/ALB ratio was further evaluated using receiver operating characteristic (ROC) curve analysis. Results: There were 6059 adult patients with sepsis enrolled in the final analysis. RCS revealed a non-linear relationship between the LDH/ALB ratio and an increased risk of ICU all-cause mortality (χ2 = 46.900, P < 0.001). Following PSM analysis, 1553 matched pairs were obtained. As comparison to the low LDH/ALB ratio group, the mortality rate in the high LDH/ALB ratio group was significantly higher (P < 0.001). Kaplan-Meier curves, both before and after PSM, revealed that the ICU cumulative survival rate for patients with sepsis was significantly lower in the high LDH/ALB ratio group compared to the low LDH/ALB ratio group (χ2 = 93.360, P < 0.001; χ2 = 14.400, P < 0.001). Even after adjusting for a range of potential confounders, multivariate Cox regression analysis indicated that an elevated LDH/ALB ratio was a significant predictor of all-cause mortality in these patients. ROC curve analysis demonstrated that the LDH/ALB ratio had an area under the ROC curve (AUC) of 0.688 for predicting ICU mortality, with a sensitivity of 69.2% and a specificity of 58.6%. Conclusions: An elevated LDH/ALB ratio (≥10.57) was associated with all-cause mortality in critically ill patients with sepsis, and it might serve as a prognostic marker. Clinicians should pay closer attention to sepsis patients presenting with an LDH/ALB ratio of 10.57 or higher.

Combined transplantation of hiPSC-NSC and hMSC ameliorated neuroinflammation and promoted neuroregeneration in acute spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) is a serious clinical condition that has pathological changes such as increased neuroinflammation and nerve tissue damage, which eventually manifests as fibrosis of the injured segment and the development of a spinal cord cavity leading to loss of function. Cell-based therapy, such as mesenchymal stem cells (MSCs) and neural stem cells (NSCs) are promising treatment strategies for spinal cord injury via immunological regulation and neural replacement respectively. However, therapeutic efficacy is rare reported on combined transplantation of MSC and NSC in acute mice spinal cord injury even the potential reinforcement might be foreseen. Therefore, this study was conducted to investigate the safety and efficacy of co-transplanting of MSC and NSC sheets into an SCI mice model on the locomotor function and pathological changes of injured spinal cord. METHODS: To evaluate the therapeutic effects of combination cells, acute SCI mice model were established and combined transplantation of hiPSC-NSCs and hMSCs into the lesion site immediately after the injury. Basso mouse scale was used to perform the open-field tests of hind limb motor function at days post-operation (dpo) 1, 3, 5, and 7 after SCI and every week after surgery. Spinal cord and serum samples were collected at dpo 7, 14, and 28 to detect inflammatory and neurotrophic factors. Hematoxylin-eosin (H&E) staining, masson staining and transmission electron microscopy were used to evaluate the morphological changes, fibrosis area and ultrastructure of the spinal cord. RESULT: M&N transplantation reduced fibrosis formation and the inflammation level while promoting the secretion of nerve growth factor and brain-derived neurotrophic factor. We observed significant reduction in damaged tissue and cavity area, with dramatic improvement in the M&N group. Compared with the Con group, the M&N group exhibited significantly improved behaviors, particularly limb coordination. CONCLUSION: Combined transplantation of hiPSC-NSC and hMSC could significantly ameliorate neuroinflammation, promote neuroregeneration, and decrease spinal fibrosis degree in safe and effective pattern, which would be indicated as a novel potential cell treatment option.

DDX20 positively regulates the interferon pathway to inhibit viral infection.

The DEAD-box (DDX) family comprises RNA helicases characterized by the conserved sequence D(Asp)-E(Glu)-A(Ala)-D(Asp), participating in various RNA metabolism processes. Some DDX family members have been identified for their crucial roles in viral infections. In this study, RNAi library screening of the DDX family unveiled the antiviral activity of DDX20. Knockdown of DDX20 enhanced the replication of viruses such as vesicular stomatitis virus (VSV) and herpes simplex virus type I (HSV-1), while overexpression of DDX20 significantly diminished the replication level of these viruses. Mechanistically, DDX20 elevated the phosphorylation level of IRF3 induced by external stimuli by facilitating the interaction between TBK1 and IRF3, thereby promoting the expression of IFN-ß. The increased IFN-ß production, in turn, upregulated the expression of interferon-stimulated genes (ISGs), including Cig5 and IFIT1, thereby exerting the antiviral effect. Finally, in an in vivo infection study, Ddx20 gene-deficient mice exhibited increased susceptibility to viral infection. This study provides new evidence that DDX20 positively modulates the interferon pathway and restricts viral infection.

Workshop environment heterogeneity shaped the microbiome and metabolome profiles during Xiasha round of Jiangxiangxing Baijiu.

Workshop with different fermentation years plays an essential role in the yield and quality of Baijiu. In actual production, the quality of base Baijiu in newly built workshop is inferior to the older one. In this study, the microbiota of workshop environment and fermentation process from two workshops namely N (ferment 2 years) and O (ferment 20 years) and flavor compounds were studied during Xiasha round. Results showed workshop O accumulated more environmental microorganisms and fungi including P. kudriavzevii, Wickerhamomyces anomalus and Saccharomyces sp mainly came from ground. Yeasts including Pichia, Cyberlindnera, Wickerhamomyces and Candida were responsible for flavor substances formation in O while Saccharopolyspora was in N. This study for the first time explored the reasons for the brewing differences among N and O workshop from perspectives of workshop environment, microbial community and flavor substances, providing new ideas for guiding production as well as improvement of Baijiu quality.

Synthesis, and Insecticidal Activities of Propargyloxy-Diphenyl Oxide-Sulfonamide Derivatives.

Agricultural pests are the primary contributing factor to crop yield reduction, particularly in underdeveloped regions. Despite the significant efficacy of pesticides in pest control, their extensive use has led to the drug-fast of insecticide resistance. Developing of new environmentally friendly plant-based pesticides is an urgent necessity. In this study, a series of diaryl ether compounds containing propargyloxy and sulfonamide groups were designed. The synthesis of these 36 compounds primarily relied on nuclear magnetic resonance for structure determination, while single-crystal X-ray diffraction was employed for certain compounds. Meanwhile, the insecticidal activities against Mythimna separata were also assessed. Some of the compounds exhibited significantly enhanced activity, the LC50 value of the highest activity compound TD8 (0.231 mg/mL) demonstrating respective increases by 100-fold compared to the plant pesticide celangulin V (23.9 mg/mL), and a 5-fold increase with the positive control L-1 (1.261 mg/mL). The interaction between the target compound and the target, as well as the consistency of the target, were verified through symptomological analysis and molecular docking. The structure-activity relationships were also conducted. This study offered a novel trajectory for the advancement and formulation of future pesticides.

Diversifying the benzenesulfonamide scaffold for potential V-ATPase inhibitors: synthesis and insecticidal activity evaluation.

Celangulin V is a natural ß-dihydroagarofuran derivative isolated from Celastrus angulatus which shows insecticidal activity in many agricultural pests. Using celangulin V as a molecular probe, we find out a new pesticide target: subunit H of V-ATPase. To explore the potential application of this novel target, lead sulfonamides have been found through virtual screening. Combined with the previous work, 46 sulfonamide derivatives are designed and synthesized. All target compounds are first screened for their insecticidal activities against Mythimna separata. The results of bioassay reveal that most of the designed compounds exhibit significant insecticidal activities against third-instar larvae of M. separata under the concentration of 10 mg/mL, and compound 8.4 shows the highest activity with LC50 value of 1.72 mg/mL, 15-fold smaller than that of celangulin V (25.89 mg/mL). Molecular docking results further indicated that compound 8.4 might serve as a potential inhibitor of the subunit H of V-ATPase. This study provides a potential sulfonamide candidate compound for the M. separata control.

The Myb73-GDPD2-GA2ox1 transcriptional regulatory module confers phosphate deficiency tolerance in soybean.

Phosphorus is indispensable in agricultural production. An increasing food supply requires more efficient use of phosphate due to limited phosphate resources. However, how crops regulate phosphate efficiency remains largely unknown. Here, we identified a major quantitative trait locus, qPE19, that controls seven low-phosphate (LP)-related traits in soybean (Glycine max) through linkage mapping and genome-wide association studies. We identified the gene responsible for qPE19 as GLYCEROPHOSPHORYL DIESTER PHOSPHODIESTERASE2 (GmGDPD2), and haplotype 5 represents the optimal allele favoring LP tolerance. Overexpression of GmGDPD2 significantly affects hormone signaling and improves root architecture, phosphate efficiency and yield-related traits; conversely, CRISPR/Cas9-edited plants show decreases in these traits. GmMyb73 negatively regulates GmGDPD2 by directly binding to its promoter, thus GmMyb73 negatively regulates LP tolerance. GmGDPD2 physically interacts with GA 2-oxidase 1 (GmGA2ox1) in the plasma membrane, and overexpressing GmGA2ox1 enhances LP-associated traits, similar to GmGDPD2 overexpression. Analysis of double mutants for GmGDPD2 and GmGA2ox1 demonstrated that GmGDPD2 regulates LP tolerance likely by influencing auxin and gibberellin dose-associated cell division in root. These results reveal a regulatory module that plays a major role in regulating LP tolerance in soybean and is expected to be utilized to develop phosphate-efficient varieties to enhance soybean production, particularly in phosphate-deficient soils.

Divergent Geminal Alkynylation-Allylation and Acylation-Allylation of Carbenes: Evolution and Roles of Two Transition-Metal Catalysts.

Cooperative bimetallic catalysis to access novel reactivities is a powerful strategy for reaction development in transition-metal-catalyzed chemistry. Particularly, elucidation of the evolution of two transition-metal catalysts and understanding their roles in dual catalysis are among the most fundamental goals for bimetallic catalysis. Herein, a novel three-component reaction of a terminal alkyne, a diazo ester, and an allylic carbonate was successfully developed via cooperative Cu/Rh catalysis with Xantphos as the ligand, providing a highly efficient strategy to access 1,5-enynes with an all-carbon quaternary center that can be used as immediate synthetic precursors for complex cyclic molecules. Notably, a Meyer-Schuster rearrangement was involved in the reactions using propargylic alcohols, resulting in an unprecedented acylation-allylation of carbenes. Mechanistic studies suggested that in the course of the reaction Cu(I) species might aggregate to some types of Cu clusters and nanoparticles (NPs), while the Rh(II)2 precursor can dissociate to mono-Rh species, wherein Cu NPs are proposed to be responsible for the alkynylation of carbenes and work in cooperation with Xantphos-coordinated dirhodium(II) or Rh(I)-catalyzed allylic alkylation.

The Contributions of the Endolysosomal Compartment and Autophagy to APOEɛ4 Allele-Mediated Increase in Alzheimer's Disease Risk.

Apolipoprotein E4 (APOE4), although yet-to-be fully understood, increases the risk and lowers the age of onset of Alzheimer's disease (AD), which is the major cause of dementia among elderly individuals. The endosome-lysosome and autophagy pathways, which are necessary for homeostasis in both neurons and glia, are dysregulated even in early AD. Nonetheless, the contributory roles of these pathways to developing AD-related pathologies in APOE4 individuals and models are unclear. Therefore, this review summarizes the dysregulations in the endosome-lysosome and autophagy pathways in APOE4 individuals and non-human models, and how these anomalies contribute to developing AD-relevant pathologies. The available literature suggests that APOE4 causes endosomal enlargement, increases endosomal acidification, impairs endosomal recycling, and downregulates exosome production. APOE4 impairs autophagy initiation and inhibits basal autophagy and autophagy flux. APOE4 promotes lysosome formation and trafficking and causes ApoE to accumulate in lysosomes. APOE4-mediated changes in the endosome, autophagosome and lysosome could promote AD-related features including Aß accumulation, tau hyperphosphorylation, glial dysfunction, lipid dyshomeostasis, and synaptic defects. ApoE4 protein could mediate APOE4-mediated endosome-lysosome-autophagy changes. ApoE4 impairs vesicle recycling and endosome trafficking, impairs the synthesis of autophagy genes, resists being dissociated from its receptors and degradation, and forms a stable folding intermediate that could disrupt lysosome structure. Drugs such as molecular correctors that target ApoE4 molecular structure and enhance autophagy may ameliorate the endosome-lysosome-autophagy-mediated increase in AD risk in APOE4 individuals.

Lipophilic arsenic compounds in the cultured green alga Chlamydomonas reinhardtii.

In this study, arsenic (As) speciation was investigated in the freshwater alga Chlamydomonas reinhardtii treated with 20 µg/L arsenate using fractionation as well as ICP-MS/ESI-MS analyses and was compared with the known As metabolite profile of wild-grown Saccharina latissima. While the total As accumulation in C. reinhardtii was about 85% lower than in S. latissima, the relative percentage of arsenolipids was significantly higher in C. reinhardtii (57.0% vs. 5.01%). As-containing hydrocarbons and phospholipids dominated the hydrophobic As profile in S. latissima, but no As-containing hydrocarbons were detectable in C. reinhardtii. Instead for the first time, an arsenoriboside-containing phytol (AsSugPhytol) was found to dominate the hydrophobic arsenicals of C. reinhardtii. Interestingly, this compound and its relatives had so far been only found in green marine microalgae, open sea plankton (mixed assemblage), and sediments but not in brown or red macroalgae. This compound family might therefore relate to differences in the arsenic metabolism between the algae phyla.

Secreted Particle Information Transfer (SPIT) - A Cellular Platform for In Vivo Genetic Engineering.

A multitude of tools now exist that allow us to precisely manipulate the human genome in a myriad of different ways. However, successful delivery of these tools to the cells of human patients remains a major barrier to their clinical implementation. Here we introduce a new cellular approach for in vivo genetic engineering, Secreted Particle Information Transfer (SPIT) that utilizes human cells as delivery vectors for in vivo genetic engineering. We demonstrate the application of SPIT for cell-cell delivery of Cre recombinase and CRISPR-Cas9 enzymes, we show that genetic logic can be incorporated into SPIT and present the first demonstration of human cells as a delivery platform for in vivo genetic engineering in immunocompetent mice. We successfully applied SPIT to genetically modify multiple organs and tissue stem cells in vivo including the liver, spleen, intestines, peripheral blood, and bone marrow. We anticipate that by harnessing the large packaging capacity of a human cell's nucleus, the ability of human cells to engraft into patients' long term and the capacity of human cells for complex genetic programming, that SPIT will become a paradigm shifting approach for in vivo genetic engineering.