Enhanced photoelectrochemical water splitting by a 3D hierarchical sea urchin-like structure: ZnO nanorod arrays on TiO2hollow hemisphere.

A hierarchical sea urchin-like hybrid metal oxide nanostructure of ZnO nanorods deposited on TiO2porous hollow hemispheres with a thin zinc titanate interface layer is specifically designed and synthesized to form a combined type I straddling and type II staggered junctions. The HHSs, synthesized by electrospinning, facilitate light trapping and scattering. The ZnO nanorods offer a large surface area for improved surface oxidation kinetics. The interface layer of zinc titanate (ZnTiO3) between the TiO2HHSs and ZnO nanorods regulates the charge separation in a closely coupled hierarchy structure of ZnO/ZnTiO3/TiO2. The synergistic effects of the improved light trapping, charge separation, and fast surface reaction kinetics result in a superior photoconversion efficiency of 1.07% for the photoelectrochemical water splitting with an outstanding photocurrent density of 2.8 mA cm-2at 1.23 V versus RHE.

High-Precision Tailored Polymer Molecular Weights for Specific Photovoltaic Applications through Ultrasound-Induced Simultaneous Physical and Chemical Events.

It is highly challenging to reproducibly prepare semiconducting polymers with targeted molecular weight tailored for next-generation photovoltaic applications. Once such an easily accessible methodology is established, which can not only contribute to overcome the current limitation of the statistically determined nature of semiconducting polymers, but also facilitate rapid incorporation into the broad synthetic chemists' toolbox. Here, we describe a simple yet robust ultrasonication-assisted Stille polymerization for accessing semiconducting polymers with high-precision tailored molecular weights (from low to ultrahigh molecular weight ranges) while mitigating their interbatch variations. We propose that ultrasound-induced simultaneous physical and chemical events enable precise control of the semiconducting polymers' molecular weights with high reproducibility to satisfy all the optical/electrical and morphological demands of diverse types of high-performance semiconducting polymer-based devices; as demonstrated in in-depth experimental screenings in applications of both organic and perovskite photovoltaics. We believe that this methodology provides a fast development of new and existing semiconducting polymers with the highest-level performances possible on various photovoltaic devices.

Light trapping by porous TiO2 hollow hemispheres for high efficiency photoelectrochemical water splitting.

Photocatalytic water splitting has recently received increasing attention as a green fuel source. The controlled nano-geometry of the photocatalytic material can improve light harvesting. In this study, as a proof of concept, hollow hemisphere (HHS)-based films of TiO2 material were created by a conventional electrospray method and subsequently applied for photoelectrochemical (PEC) water splitting. To preserve the morphology of the HHS structure, a hydrolysis precipitation phase separation method (HPPS) was developed. As a result, the TiO2 HHS-based thin films presented a maximum PEC water splitting efficiency of ca. 0.31%, almost two times that of the photoanode formed by TiO2 nanoparticle-based films (P25). The unique morphology and porous structure of the TiO2 HHSs with reduced charge recombination and improved light absorption are responsible for the enhanced PEC performance. Light scattering by the HHS was demonstrated with total reflection internal fluorescence microscopy (TRIFM), revealing the unique light trapping phenomenon within the HHS cavity. This work paves the way for the rational design of nanostructures for photocatalysis in fields including energy, environment, and organosynthesis.

A small regulatory RNA alters Staphylococcus aureus virulence by titrating RNAIII activity.

Staphylococcus aureus is an opportunistic human and animal pathogen with an arsenal of virulence factors that are tightly regulated during bacterial infection. The latter is achieved through a sophisticated network of regulatory proteins and regulatory RNAs. Here, we describe the involvement of a novel prophage-carried small regulatory S. aureus RNA, SprY, in the control of virulence genes. An MS2-affinity purification assay reveals that SprY forms a complex in vivo with RNAIII, a major regulator of S. aureus virulence genes. SprY binds to the 13th stem-loop of RNAIII, a key functional region involved in the repression of multiple mRNA targets. mRNAs encoding the repressor of toxins Rot and the extracellular complement binding protein Ecb are among the targets whose expression is increased by SprY binding to RNAIII. Moreover, SprY decreases S. aureus hemolytic activity and virulence. Our results indicate that SprY titrates RNAIII activity by targeting a specific stem loop. Thus, we demonstrate that a prophage-encoded sRNA reduces the pathogenicity of S. aureus through RNA sponge activity.

New Dibenzocyclooctadiene Lignans and Phenolics from Kadsura heteroclite with Anti-Inflammatory Activity.

A chemical investigation of K. heteroclite led to isolation of two new dibenzocyclooctadienes (1 and 2) together with 14 known compounds (3-16) by using multiple chromatographic techniques. New compounds (1 and 2) were obtained and identified by spectroscopic methods (HR-ESI-MS, 1D and 2D NMR, and ECD) as well as by comparison of their experimental data with those reported in the literatures. All the isolates were evaluated for their ability to modulate TNF-α production in lipopolysaccharide (LPS) stimulated RAW264.7 cells. Among them, compound 5 displayed the most inhibition against tumor necrosis factor (TNF)-α production with IC50 value of 6.16±0.14 µM. Whereas, compounds (1, 3, and 6) showed the significant inhibition (IC50 values ranging from 9.41 to 14.54 µM), and compounds (2, 4, 9, 10, 13, 15, and 16) exhibited moderate inhibition (IC50 values ranging from 19.27 to 40.64 µM) toward TNF-α production, respectively.

Exploring attitude-behaviour dynamics during COVID-19: How fear of infection and working from home influence train use and the attitude toward this mode.

Research on the relationships between travel-related attitudes and travel behaviour has recently been reinvigorated by new theorizing as well as new empirical models. While traditional theories assume a rather static role of attitudes, i.e. acting as stable predispositions that cause behaviours in a unidirectional manner, recent models assume that attitudes and behaviours mutually influence each other over time. This study aims at better understanding attitude-behaviour dynamics by capitalizing on the circumstances presented by the ongoing COVID-19 pandemic. It assesses how the fear of COVID-19 infection and (the attitude towards) working-from-home influence train use as well as train use attitudes. To explore the (within-person) reciprocal relationships between these variables, random-intercept cross-lagged panel models were estimated using a 4-wave longitudinal dataset collected during the COVID-19 pandemic from a large panel of train travellers in the Netherlands. The results indicate that train use and the attitude towards train use reciprocally influence each other. Those with stronger fears of infection in one wave tend to use the train less in a subsequent wave, but higher use of the train in one wave also reduces the fear of infection in the next. We also found that working from home (WFH) and travelling by train operate as substitutes for one another. Moreover, people who work from home frequently become more fearful of infection. All the findings are consistent with cognitive dissonance theory that people develop attitudes that align with their behaviours. The paper concludes with several policy implications related to changing attitudes and promoting train use.

Food approach and avoidance appetitive traits in university students: A latent profile analysis.

Eating behaviors are influenced by many factors including appetitive traits. Few studies have utilized latent profile analysis (LPA) to examine food approach and food avoidance appetitive traits. This study utilized LPA to define cluster profile groups based on appetitive traits in undergraduate and graduate/professional students at a large University in the southwest United States. Students completed a cross-sectional online survey in fall 2020 assessing demographic information, appetitive traits via the Adult Eating Behavior Questionnaire (AEBQ), and anxiety via the Generalized Anxiety Disorder Scale (GAD-7; higher scores indicate more severe anxiety symptoms). Appetitive traits were combined into eight scales (four food approach and four food avoidance traits). Latent profile analyses were conducted to identify homogenous subgroups of participants based on AEBQ scale scores. The final sample included 1243 students (mean age = 26.5 years, 73% female, 59% White, 57% undergraduates). LPA revealed four cluster profile groups: Cluster 1 (moderate eaters: lower than mean scores for food approach and avoidance traits), Cluster 2 (food seekers and avoiders: higher than mean scores for food approach and avoidance traits), Cluster 3 (food seekers: higher than mean scores for food approach traits), and Cluster 4 (food avoiders: higher than mean scores for food avoidance traits). Distribution of age, gender, race/ethnicity, and student status differed significantly between clusters. GAD-7 score was highest in Cluster 2 (food seekers and avoiders) and lowest in Cluster 1 (moderate eaters). Among the four LPA-defined cluster profile groups, students who endorsed both food approach and avoidance traits reported more severe anxiety symptoms compared to moderate eaters, food seekers, and food avoiders. It is useful to consider clusters of appetitive traits instead of individual appetitive traits when examining associations with physical and mental health.

Public transit cuts during COVID-19 compound social vulnerability in 22 US cities.

The COVID-19 pandemic has severely impacted public transit services through plummeting ridership during the lockdown and subsequent budget cuts. This study investigates the equity impacts of reductions in accessibility due to transit service cuts during COVID-19 and their association with urban sprawl. We evaluated transit access to food and health care services across 22 US cities in three phases during 2020. We found stark socio-spatial disparities in access to basic services and employment in food and health care. Transit service cuts worsened accessibility for communities with multiple social vulnerabilities, such as neighborhoods with high rates of poverty, low-income workers, and zero-vehicle households, as well as poor neighborhoods with high concentrations of black residents. Moreover, sprawled cities experienced greater access loss during COVID-19 than compact cities. Our results point to policies and interventions to maintain social equity and sustainable urban development while benefiting diverse social groups during disruptions.

Bosentan versus nifedipine in the treatment of vasculopathy in systemic sclerosis patients: A randomized control trial.

BACKGROUND: Bosentan is effective agent in scleroderma vasculopathy. However, there are no studies evaluating effectiveness of bosentan in Vietnamese patients, where nifedipine is still the common treatment. OBJECTIVE: To compare the efficacy of bosentan versus nifedipine in scleroderma vasculopathy in Vietnamese patients. METHODS: We randomly assigned 70 patients in a 2:1 ratio to receive oral bosentan or oral nifedipine for 16 weeks, respectively. The primary outcomes were the change in Raynaud's Condition Score (RCS), appearance of new digital ulcers (DUs) and change in World Health Organization (WHO) functional class. Secondary outcomes were the change in the nailfold capillaries disease stage and systolic pulmonary arterial pressure (sPAP) value. RESULTS: At week 16, patients in bosentan group had no RCS imprvement, the mean difference was 0.8 ± 0.2 (95% CI, 0.4 to 1.1, p < 0.001) and improved WHO functional class, a mean treatment effect of 35.6% in favor of bosentan (95% CI, 13.4 to 57.7%, p < 0.05). Bosentan treatment was associated with a 58% reduction in the number of new DUs compared with nifedipine (mean ± standard error: 0.22 ± 0.42 vs 0.52 ± 0.59 new DUs, p < 0.05). sPAP was decreased by 4.1 ± 3.8 mmHg (95% CI, 3.0 to 5.3, p < 0.001) in bosentan group, versus 1.0 ± 2.9 mmHg (95% CI, -0.2 to 2.1, p > 0.05) in nifedipine group. Headache was the most common adverse event in both groups. CONCLUSIONS: Bosentan significantly limited the occurrence of new DUs, reduced symptoms of pulmonary arterial hypertension and sPAP value and all were better than nifedipine.

Anxiety is associated with appetitive traits in university students during the COVID-19 pandemic.

BACKGROUND: COVID-19 has impacted mental health globally, however, associations between anxiety and appetitive traits during the pandemic are unreported. This study evaluated anxiety symptom severity and associations with appetitive traits in students at a large public University in the U.S. during the pandemic. METHODS: Current undergraduate and graduate/professional students completed a cross-sectional survey in fall 2020. Demographic information, anxiety symptoms in the past 2 weeks assessed by the Generalized Anxiety Disorder Scale (GAD-7), and appetitive traits assessed by the Adult Eating Behavior Questionnaire (AEBQ) were evaluated. Mean scores for eight AEBQ scales (four food approach and four food avoidance traits) were calculated. Differences in mean scores were examined between participants with moderate to severe anxiety symptoms (GAD-7 score ≥ 10) and those with mild to no anxiety symptoms (GAD-7 score < 10) via independent samples t-tests and effect sizes. Associations between GAD-7 score and individual appetitive traits were also examined, adjusting for age and gender. RESULTS: Of the 1243 students who completed the survey (57% undergraduates; mean age = 26.5 years), 51.9% reported moderate to severe anxiety symptoms. Groups experiencing the highest degree of moderate to severe anxiety symptoms included transgender, gender fluid, and other-gendered participants (73.6%); the youngest age group [18-20 years (62%)]; undergraduate students (60.7%); and Hispanic/Latinx participants (57.7%). Participants with moderate to severe anxiety symptoms had higher scores for most food approach and avoidance traits but lower scores for enjoyment of food than those with mild to no anxiety symptoms. Effect sizes were largest for hunger and emotional over-eating (Cohen's d = 0.31 and 0.30, respectively). Adjusting for age and gender, GAD-7 score was significantly and positively associated with hunger, emotional over-eating, food and satiety responsiveness, and food fussiness and negatively associated with enjoyment of food. CONCLUSIONS: Over half of students at a U.S. University reported moderate to severe anxiety symptoms during COVID-19. More severe anxiety symptoms were associated with increased hunger, emotional over-eating, and food and satiety responsiveness and decreased enjoyment of food. Universities must consider strategies to address anxiety, particularly in younger students; transgender, gender fluid, and students of other genders; and across race/ethnicities keeping in mind associations with appetitive traits.

COVID-19 exacerbates unequal food access.

Inequality to food access has always been a serious problem, yet it became even more critical during the COVID-19 pandemic, which exacerbated social inequality and reshaped essential travel. This study provides a holistic view of spatio-temporal changes in food access based on observed travel data for all grocery shopping trips in Columbus, Ohio, during and after the state-wide stay-at-home period. We estimated the decline and recovery patterns of store visits during the pandemic to identify the key socio-economic and built environment determinants of food shopping patterns. The results show a disparity: during the lockdown, store visits to dollar stores declined the least, while visits to big-box stores declined the most and recovered the fastest. Visits to stores in low-income areas experienced smaller changes even during the lockdown period. A higher percentage of low-income customers was associated with lower store visits during the lockdown period. Furthermore, stores with a higher percentage of white customers declined the least and recovered faster during the reopening phase. Our study improves the understanding of the impact of the COVID-19 crisis on food access disparities and business performance. It highlights the role of COVID-19 and similar disruptions on exposing underlying social problems in the US.

A Computational Study on the Redox Reactions of Ammonia and Methylamine with Nitrogen Tetroxide.

The redox reactions of NH3 and CH3NH2 with N2O4 (NTO) have been studied by ab initio molecular orbital (MO) calculations at the UCCSD(T)∥UB3LYP/6-311+G(3df,2p) level of theory. These reactions are related to the well-known NTO-hydrazine(s) propellant systems. On the basis of the predicted potential energy surfaces, the mechanisms for these reactions were found to be similar to the hydrolysis of NTO and the hypergolic initiation reaction of the NTO-N2H4 mixture, primarily controlled by the conversion of NTO to ONONO2 via very loose transition states (with NH3 and CH3NH2 as spectators in the collision complexes) followed by the rapid attack of ONONO2 at the spectating molecules producing HNO3 and RNO (R = NH2 and CH3NH). The predicted mechanism for the NH3 reaction compares closely with its isoelectronic process NTO + H2O; similarly, the mechanism for the NTO + CH3NH2 reaction also compares closely with its isoelectronic NTO + NH2NH2 reaction. The kinetics for the formation of the final products, HNO3 + RNO (R = NH2, OH, CH3NH, and N2H3), were found to be weakly pressure-dependent at low temperatures and affected by the strengths of H-NH2 and H-OH but not in the RNH2 case. We have also compared the predicted rate constant for the oxidation of NH3 by N2O4 with that for the analogous NH3 + N2O5 recently reported by Sarkar and Bandyopadhyay [J. Phys. Chem. A. 2020, 124, 3564-3572] under troposphere conditions. The rate of the latter reaction was estimated to be 2 orders of magnitude slower than that of the N2O4 reaction under troposphere conditions.

Induction of Antitumor Immunity by Exosomes Isolated from Cryopreserved Cord Blood Monocyte-Derived Dendritic Cells.

(1) Background: Dendritic cell (DC) vaccination has shown outstanding achievements in cancer treatment, although it still has some adverse side effects. Vaccination with DC-derived exosomes has been thought to overcome the side effects of the parental DCs. (2) Method: We performed the experiments to check the ability of cryopreserved umbilical cord blood mononuclear cell-derived DCs (cryo CBMDCs) and their exosomes to prime allogeneic T cell proliferation and allogeneic peripheral blood mononuclear cell (alloPBMCs) cytotoxicity against A549 lung cancer cells. (3) Results: We found that both lung tumor cell lysate-pulsed DCs and their exosomes could induce allogeneic T cell proliferation. Moreover, alloPBMCs primed with tumor cell lysate-pulsed DCs and their exosomes have a greater cytotoxic activity against A549 cells compared to unprimed cells and cells primed with unpulsed DCs and their exosomes. (4) Conclusion: Tumor cell lysate-pulsed DCs and their exosomes should be considered to develop into a novel immunotherapeutic strategy-e.g., vaccines-for patients with lung cancer. Our results also suggested that cryo umbilical cord blood mononuclear cells source, which is a readily and available source, is effective for generation of allogeneic DCs and their exosomes will be material for vaccinating against cancer.

Association between exposure to macrolides and the development of infantile hypertrophic pyloric stenosis: a systematic review and meta-analysis.

Macrolides are bacteriostatic antibiotics with a broad spectrum of activity against Gram-positive bacteria. The aim of this study was to systematically review and meta-analyze the association between infantile hypertrophic pyloric stenosis (IHPS) and macrolides. Nine databases were searched systematically for studies with information on the association between macrolides and IHPS. We combined findings using random effects models. Our study revealed 18 articles investigating the association between macrolides and IHPS. There was a significant association between the development of IHPS and erythromycin (2.38, 1.06-5.39). The association was strong when erythromycin was used during the first 2 weeks of life (8.14, 4.29-15.45). During breastfeeding, use of macrolides showed no significant association with IHPS in infants (0.96, 0.61-1.53). IHPS was not associated with erythromycin (1.11, 0.9-1.36) or macrolides use during pregnancy (1.15, 0.98-1.36).Conclusions: There is an association between erythromycin use during infancy and developing IHPS in infants. However, no significant association was found between macrolides use during pregnancy or breastfeeding. Additional large studies are needed to further evaluate potential association with macrolide use. What is known? • Erythromycin intake in the first 2 weeks of life is associated with an increased risk of pyloric stenosis. What is New? • There is currently no evidence of significant association between macrolides use during pregnancy or breastfeeding and pyloric stenosis.

Cytotoxic Alkaloids from Leaves of Pilea aff. martinii.

Two new phenanthroquinolizidine alkaloids (1: and 2: ) and a new piperidine derivative (3: ) were isolated from the leaves of Pilea aff. martinii together with 3 known alkaloids: julandine (4: ), cryptopleurine (5: ), and 1,3,6,6-tetramethyl-5,6,7,8-tetrahydro-isoquinolin-8-one (6: ). Their structures were determined by spectral data analyses including mass spectrometry and 2-dimensional nuclear magnetic resonance data. The absolute configurations of 1: -3: were established by comparison of their experimental circular dichroism data with the calculated electronic circular dichroism spectra. The isolated compounds were evaluated for their cytotoxicity against 4 cancer cell lines: KB (mouth epidermal carcinoma cells), HepG-2 (human liver hepatocellular carcinoma cells), LU-1 (human lung adenocarcinoma cells), and MCF-7 (human breast cancer cells). The new phenanthroquinolizidine pileamartine D (2: ) showed strong and selective proliferation inhibition toward KB and HepG-2 cells with IC50 values of 25 and 27 nM, respectively. Pileamartine C (1: ), julandine (4: ), and cryptopleurine (5: ) exhibited cytotoxicity against 4 tested cancer cell lines with IC50 values less than 1 µM.

A cell transportation solution that preserves live circulating tumor cells in patient blood samples.

BACKGROUND: Circulating tumor cells (CTCs) are typically collected into CellSave fixative tubes, which kills the cells, but preserves their morphology. Currently, the clinical utility of CTCs is mostly limited to their enumeration. More detailed investigation of CTC biology can be performed on live cells, but obtaining live CTCs is technically challenging, requiring blood collection into biocompatible solutions and rapid isolation which limits transportation options. To overcome the instability of CTCs, we formulated a sugar based cell transportation solution (SBTS) that stabilizes cell viability at ambient temperature. In this study we examined the long term viability of human cancer cell lines, primary cells and CTCs in human blood samples in the SBTS for transportation purposes. METHODS: Four cell lines, 5 primary human cells and purified human PBMCs were tested to determine the viability of cells stored in the transportation solution at ambient temperature for up to 7 days. We then demonstrated viability of MCF-7 cells spiked into normal blood with SBTS and stored for up to 7 days. A pilot study was then run on blood samples from 3 patients with metastatic malignancies stored with or without SBTS for 6 days. CTCs were then purified by Ficoll separation/microfilter isolation and identified using CTC markers. Cell viability was assessed using trypan blue or CellTracker™ live cell stain. RESULTS: Our results suggest that primary/immortalized cell lines stored in SBTS remain ~90% viable for > 72 h. Further, MCF-7 cells spiked into whole blood remain viable when stored with SBTS for up to 7 days. Finally, live CTCs were isolated from cancer patient blood samples kept in SBTS at ambient temperature for 6 days. No CTCs were isolated from blood samples stored without SBTS. CONCLUSIONS: In this proof of principle pilot study we show that viability of cell lines is preserved for days using SBTS. Further, this solution can be used to store patient derived blood samples for eventual isolation of viable CTCs after days of storage. Therefore, we suggest an effective and economical transportation of cancer patient blood samples containing live CTCs can be achieved.

Adipocytes Are the Only Site of Glutamine Synthetase Expression Within the Lactating Mouse Mammary Gland.

Background: Glutamine in milk is believed to play an important role in neonatal intestinal maturation and immune function. For lactating mothers, glutamine utilization is increased to meet the demands of the enlarged intestine and milk production. However, the source of such glutamine during lactation has not been studied. Objectives: We aimed to assess the effects of lactation on the expression of glutamine synthetase (GS) in the mammary gland and other tissues of lactating mice. Methods: Mouse tissues were sampled at 4 time points: 8-wk-old (virgin, control), post-delivery day 5 (PD5, early lactation), PD15 (peak lactation), and involution (4 days after weaning at PD21). We examined the gene expression and protein concentrations of GS and the first 2 enzymes of branched-chain amino acid catabolism: branched-chain aminotransferase 2 (BCAT2) and branched-chain ketoacid dehydrogenase subunit E1α (BCKDHA). Results: The messenger RNA (mRNA) expression and protein concentrations of GS in mammary glands were significantly lower at PD5 and PD15 compared with the control but were restored at involution. Within the mammary gland, GS protein was only detected in adipocytes with no evidence of presence in mammary epithelial cells. Compared with the control, mRNA and protein concentrations of BCAT2 and BCKDHA in mammary glands significantly decreased during lactation and involution. No changes in GS protein concentrations during lactation were found in the liver, skeletal muscle, and lung. In non-mammary adipose tissue, GS protein abundance was higher during lactation compared with the virgin. Conclusions: This work shows that, within the mouse mammary gland, GS is only expressed in adipocytes and that the relative GS abundance in mammary gland sections is lower during lactation. This suggests that mammary adipocytes may be a site of glutamine synthesis in the lactating mouse. Identifying the sources of glutamine production during lactation is important for optimizing milk glutamine concentration to enhance neonatal and maternal health.

Acute acalculous cholecystitis with portal cavernoma: A case report with literature review.

Portal cavernoma cholangiopathy (PCC) refers to morphological changes in the intrahepatic, extrahepatic biliary system, along with the gallbladder (GB), induced by portal cavernoma (PC). Acute acalculous cholecystitis (AAC) represents an infrequent clinical manifestation of PCC. Given the inadequacy of documentation within medical literature, AAC may go undiagnosed among patients with PC presenting symptoms of right upper quadrant pain. The current study aims to report a case of acute acalculous cholecystitis secondary to portal cavernoma, focusing on radiological findings, with a brief review of literature.

Challenging Recurrence and Management of Squamous Cell Carcinoma in the Calcaneal Region: A Case Report.

Squamous cell carcinoma (SCC) is the second most common type of skin cancer. As ultraviolet exposure represents an important risk factor, SCC commonly occurs on the face, lips, scalp, hands, and heels. The foot is an unusual location to manifest SCC. In this report, we present a case of a 44-year-old woman with severe local recurrence of SCC in the right heel, four years after an initial excision of a primary, small lesion. For various reasons, the patient did not visit the clinic for follow-up assessment during this period. Considering the extent of the lesion and infection risk, the affected leg was amputated at one-third of the lower leg. This case report underlines the importance of educating patients about the risk of SCC and assisting them in attending follow-up visits. In addition, adequate attention should be given to foot lesions with suspicious appearance. Early detection would minimize systemic risks, including metastasis and infection, and maximize preserved function after surgical intervention.

Whole-Body Disposition and Physiologically Based Pharmacokinetic Modeling of Adeno-Associated Viruses and the Transgene Product.

To facilitate model-informed drug development (MIDD) of adeno-associated virus (AAV) therapy, here we have developed a physiologically based pharmacokinetic (PBPK) model for AAVs following preclinical investigation in mice. After 2E11 Vg/mouse dose of AAV8 and AAV9 encoding a monoclonal antibody (mAb) gene, whole-body disposition of both the vector and the transgene mAb was evaluated over 3 weeks. At steady-state, the following tissue-to-blood (T/B) concentration ratios were found for AAV8/9: ∼50 for liver; ∼10 for heart and muscle; ∼2 for brain, lung, kidney, adipose, and spleen; ≤1 for bone, skin, and pancreas. T/B values for mAb were compared with the antibody biodistribution coefficients, and five different clusters of organs were identified based on their transgene expression profile. All the biodistribution data were used to develop a novel AAV PBPK model that incorporates: (i) whole-body distribution of the vector; (ii) binding, internalization, and intracellular processing of the vector; (iii) transgene expression and secretion; and (iv) whole-body disposition of the secreted transgene product. The model was able to capture systemic and tissue PK of the vector and the transgene-produced mAb reasonably well. Pathway analysis of the PBPK model suggested that liver, muscle, and heart are the main contributors for the secreted transgene mAb. Unprecedented PK data and the novel PBPK model developed here provide the foundation for quantitative systems pharmacology (QSP) investigations of AAV-mediated gene therapies. The PBPK model can also serve as a quantitative tool for preclinical study design and preclinical-to-clinical translation of AAV-based gene therapies.