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Published at 19th of November 2020 03:00:12 AM
But she couldn't say anything, for if she did, they wouldn't allow her to stay .
Feng Liu smacked the table in frustration . "Feng Wu is so arrogant! She's crossed the line! I really hope that someone can teach her a lesson!"
An idea struck Dugu Yamo, and she turned to Zuo Qingyu . "By the way, Qingyu, when is your sister coming back?"
Needless to say, she was talking about Zuo Qingluan .
Zuo Qingyu smiled . "I don't think my sister will come back before she becomes a Spiritual Lord . "
"But isn't she worried?" Dugu Yamo looked at Zuo Qingyu . "Feng Wu is hitting on His Royal Highness!"
Zuo Qingyu chuckled . "Why are you worried? How can some girl like Feng Wu compare with my sister? She's too petty to even put my sister's shoes on for her . "
Feng Liu smacked the table . "That's right! Feng Wu is nothing compared with Sister Qingluan!"
Zuo Qingyu waved her hands and smiled . "Even if Feng Wu is lucky enough for His Royal Highness to be interested in her, she'll be a concubine at most . What can she possibly do in front of my sister, His Royal Highness's official wife?"
The others agreed with her, but still felt jealous .
It was either Feng Wu or Zuo Qingluan – why couldn't it be one of them?
Just then, Zuo Qingyu heard the sounds of a small commotion outside .
His Royal Highness?
"Is His Royal Highness here at World Tower?" Zuo Qingyu was excited!
Although her sister and His Royal Highness were meant for each other, no one said that a sister-in-law had to remain a sister-in-law . It would be so nice if she and her sister could marry the same person .
Zuo Qingyu had always had that fantasy, so she rushed out as soon as she heard that Jun Linyuan was here .
Why did all the girls here hold so many grudges against Feng Wu? Why had they become allies?
It was because of His Royal Highness, their common goal, and Feng Wu, their common enemy .
Hence, Zuo Qingyu wasn't the only one who rushed out .
What about Feng Wu? What was she doing at the moment?
She was so anxious!
Jun Linyuan!
Where was Jun Linyuan at the moment?
Feng Wu had searched everywhere, including all the places Jun Linyuan liked to visit .
Could he be at the Feng manor?
Feng Wu ran back to Fallen Star Yard as fast as she could .
Chaoge was startled when she saw Feng Wu return . "Xiao Wu, did His Royal Highness hit you?"
Elated, Feng Wu took Chaoge's arm . "No, he didn't . Was His Royal Highness here?"
Chaoge nodded . "Yes, he was here only just then, and stood next to the wall, looking all angry . He also kicked our wall before he left —"
Chaoge pointed at what was left of the wall after Jun Linyuan kicked it . "That's the third time! The wall's been destroyed three times!"
The broken wall was the last thing Feng Wu cared about . "Where's Jun Linyuan now?"
Chaoge gave her a sympathetic look . "Xiao Wu, His Royal Highness was so mad and so intimidating . I don't think we should interact with him anymore…"
Feng Wu felt like screaming .


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Baptism is a joyous occasion not only for a family but for the church community as well. We, at St. Joseph, are thrilled to be a part of your family's preparation and celebration.
Baptism for infants (birth to seven years) does involve preparation. At our parish, the preparation begins with a meeting involving at least one parent with the pastoral assistant responsible for baptism. At the meeting families will receive all of the required forms necessary for baptism and a schedule for baptism classes.
To schedule a baptism meeting with Tracy Joy, email firstname.lastname@example.com, or call 360-823-2833.
For children over the age of seven and adults, baptism is completed through RCIA.
To schedule an RCIA meeting with Frances Farrell, email email@example.com, or call 360-823-2833.

subset: commoncrawl


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How can we help you?
We invite you to get in touch via a free, no-obligation initial consultation.
Check out our Christmas Hours
is our take on what is currently happening in the mortgage market. Our views
are often cited in several national publications, including; BBC News, The
Times, Telegraph, City AM, FT Adviser and Daily Mail, as well as a number of
key trade publications, so this should keep you ahead of the curve. If you have
any questions on any of these stories, or would like further information,
please do not hesitate to get in touch.
Borrower self-build loans comparatively cheap
Rates for self-build products have not changed significantly relative to the rest of the market where rates have increased at their fastest rate since 2012 in the six months to May. Self-build now appears to be a rather effective way to borrow both on a property to build from the ground up or also one that needs heavy refurbishment.
More lender innovation needed for existing borrowers to improve home energy performance
Amid a cost-of-living crisis and squeezed household budgets, we have had clients both on the buy to let and residential homeowner side of the coin expressing concerns regarding cash flow to improve home energy performance and EPC ratings. We believe lenders need to do more to ensure existing borrowers can easily access funds to improve their property's EPC rating. Mortgage lender CHL released a refurbishment product range last week showcasing product innovation designed to improve EPC ratings and we'd love to see more of this.


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In Arizona, you are going to melt for most of the months of the summer if you don't have a swimming pool. Chances are you don't want to stay indoors year-round, right? If that's the case, you will want to talk with the swimming pool contractors in Scottsdale, Arizona from SwimRight Pool & Spa Service about 5 ways to have more fun in your swimming pool.
If you've been working with us for a while or if you're a new swimming pool owner we can help with pool maintenance and service and you can spend your free time swimming and not cleaning, you know that time spent in a pool helps the summer be more bearable.
5 ways to have more fun in your swimming pool
Are there activities you and your family thoroughly enjoy? Are there some you wish you could do, but don't have the accessories or equipment? Here are a few ideas to have more fun.
- When is the last time you threw a party that wasn't just an impromptu gathering? Plan a party with a theme, invite friends and make a day — and night of it! Whip up your favorite foods. Have a grill master cook off and enjoy the fruits of the grilling labor! Or just order a pizza and kick back and relax!
- You may not think that exercise is fun, but when you're in the pool it doesn't feel like exercise. Even if you're swimming laps, it is more fun than jogging or working out at the gym, right? Swimming is a "sneaky" way to exercise!
- Invest in a high quality raft and float away your stress. Grab a book, your favorite beverage and lounge for a while. Being in and around the water is relaxing no matter what you do.
- Buy some in-pool games like a volleyball net or an in pool basketball set. Pool noodles and beachballs never go out of style!
- Check your budget and if you have the funds, do some upgrades. Add a slide or a diving board. Why not add a fountain or even a rock waterfall. How about a major upgrade to add in a swim up spa.
Swimming rarely goes out of style and in Arizona you can swim almost all year, so take some time and decide whether you want to to a pool upgrade and give us a call!


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Facilitating drug delivery in the central nervous system by opening the blood-cerebrospinal fluid barrier with a single low energy shockwave pulse
Fluids and Barriers of the CNS volume 19, Article number: 3 (2022)
The blood-cerebrospinal fluid (CSF) barrier (BCSFB) is critically important to the pathophysiology of the central nervous system (CNS). However, this barrier prevents the safe transmission of beneficial drugs from the blood to the CSF and thus the spinal cord and brain, limiting their effectiveness in treating a variety of CNS diseases.
This study demonstrates a method on SD rats for reversible and site-specific opening of the BCSFB via a noninvasive, low-energy focused shockwave (FSW) pulse (energy flux density 0.03 mJ/mm2) with SonoVue microbubbles (2 × 106 MBs/kg), posing a low risk of injury.
By opening the BCSFB, the concentrations of certain CNS-impermeable indicators (70 kDa Evans blue and 500 kDa FITC-dextran) and drugs (penicillin G, doxorubicin, and bevacizumab) could be significantly elevated in the CSF around both the brain and the spinal cord. Moreover, glioblastoma model rats treated by doxorubicin with this FSW-induced BCSFB (FSW-BCSFB) opening technique also survived significantly longer than untreated controls.
This is the first study to demonstrate and validate a method for noninvasively and selectively opening the BCSFB to enhance drug delivery into CSF circulation. Potential applications may include treatments for neurodegenerative diseases, CNS infections, brain tumors, and leptomeningeal carcinomatosis.
The brain is a unique organ in that is highly protected from the periphery by two major barriers, the blood–brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB). However, the mechanisms by which the BBB and the BCSFB protect the brain/CSF from pathogens and toxins also block drug delivery [1, 2]. However, BCSFB and BBB are different from their functional and morphological domains. Issues related to how to open the BBB have been widely explored over the past decade. However, research on opening the BCSFB and its importance to CSF circulation and brain disorders is still relatively limited [3].
It is possible to achieve widespread drug delivery to the whole brain by opening the BCSFB instead of the BBB. Pharmacologically regulated BBB opening has been shown to provide a wide drug delivery area and a long delivery window; however, this long window poses a high risk of infection. On the other hand, high-intensity focused ultrasound (HIFU), a method commonly used to open the BBB, can provide a shorter delivery window, reducing the risk of infection but limiting the area to which drugs can be delivered [4].
BCSFB opening addresses the limitations of both pharmacological and HIFU-based BBB opening, providing a short opening period and a wide drug delivery area in the brain or the central nervous system (CNS) in general [5]. Currently, drug delivery to CSF is primarily achieved in five ways: (i) intracerebroventricular (ICV) or intrathecal drug infusion, with direct drug injection/infusion into the CSF [6]; (ii) the use of an anti-transferrin receptor (TfR) antibody (OX-26 anti-rat TfR) to transport medication across the BCSFB into the CSF [7]; (iii) delivery from the olfactory region into the olfactory bulb via trigeminal and olfactory neurons, followed by absorption into the lamina propria and then entry into the CSF [8]; (iv) dosing with John Cunningham virus (JCV); and (v) treatment with drug-loaded biodegradable nanoparticles that enhance the adoptive transfer ability of the BCSFB [9, 10]. However, when used for the delivery of therapeutic drugs, these methods are limited by low efficiency, invasiveness, or the development of immunogenic reactions [11]. Thus, an efficient and noninvasive method to effectively control the permeability of the BCSFB is urgently needed.
Previous research on the use of mechanical waves to transport drugs into the CSF circulation mainly applied focused ultrasound to induce opening of the blood-spinal cord barrier (BSCB) [12]. As its name implies, the BSCB exists in the spinal cord and is functionally and morphologically similar to the BBB [13]. Unfortunately, the use of focused ultrasound to open the BSCB may not only be hampered by the complicated bony structure around, but also may induce spinal cord injury, resulting in permanent motor and sensory disability [14]. If mechanical waves are to be used to open one of the blood–brain barriers, they must be applied to a location to which risk of damage would be minimal and/or would have little adverse effect on patient function. Our focused shockwave pulse (FSW)-BCSFB opening method is applied to the lateral ventricle region, which is considered a non-eloquent and safe region [15]. Furthermore, with our technique, CSF circulates from the lateral ventricle area to the spinal cord area, which is reversed for the BSCB opening technique. In our previous study, we have shown that even at severe epileptic attacks, our FSW-BCSFB opening method could still provide a lower Racine's scale, inflammation, oxidative stress, apoptosis, and zero mortality way to alleviate epilepsy [16].
This study investigates the feasibility of applying a single low-energy extracorporeal focused shockwave pulse (FSW) with microbubbles to open the BCSFB for the delivery of large-molecule model drugs or therapeutics into CSF circulation. One of advantage for applying FSW is the lower total acoustic energy. Figure 1 shows the pulsing characteristics of the FSW device (Fig. 1a) used in the current study, the pulsed high-intensity focused ultrasound (HIFU) device, a preferred device to induce BBB opening (Fig. 1b), and the HIFU instrument to ablate tissue (Fig. 1c). Using the single low energy FSW pulse, the total energy required for BBB opening under the conditions shown in Fig. 1 is about 1/60,000 times that of by using pulsed HIFU. Moreover, the low energy FSW is only 1/7,000,000 of that for HIFU ablation. Furthermore, as FSW generates negligible heat, its application, exploiting acoustic related biological effects, would not be limited by tissue heating or related adverse effects [16,17,18,19].
In this study, we hypothesize that (i) FSW-based BCSFB opening will enhance drug passage; (ii) FSW exposure will induce BCSFB opening in specific brain regions with abundant choroid plexus (CP); and (iii) once drugs cross the BCSFB into the CSF circulation, they will remain long enough to maintain therapeutically sufficient drug concentrations. In this study, the location and efficiency of in vivo drug delivery were determined by measuring the fluorescence intensity of model drugs in the brain with an in vivo imaging system (IVIS) and by directly measuring the amounts of drugs in the CSF. Chemotherapeutic agents, at the same concentrations we achieved in the CSF, were tested for their ability to suppress the growth of selected CNS-targeted tumor cells in vitro. Finally, the feasibility and treatment efficacy of the FSW drug delivery technique were evaluated in a glioma rat model.
Materials and methods
Animals, materials and instruments
This study was approved by the ethics committee of the Laboratory Animal Center at the National Taiwan University College of Medicine (Approval No. 20170091 for the use of rats) and adhered to the experimental animal care guidelines. All rats (adult Sprague Dawley rats between 9 and 10 weeks of age) were obtained from the National Laboratory Animal Center (Taipei, Taiwan), fed a standard diet and housed in a temperature- and humidity-controlled room (19–23 °C; 40–70%, respectively) under a 12/12-h light–dark cycle. For more details, please refer to the supporting information.
FSW-BCSFB opening and brain mapping
The commercial shockwave device and the FSW probe positioning platform were set up identically to those previously reported by Kung [19]. FSW with microbubbles was implemented following the established technique for single low-energy extracorporeal FSW pulses, which can minimize damage to the brain within a safe operating range [20]: single pulse (energy flux density 0.03 mJ/mm2) with SonoVue microbubbles (2 × 106 MBs/kg).
To find the ideal location to open the BCSFB by FSW, we first selected different points in the rat brain where CP is abundant (Fig. 2a, b). The IVIS was then used to analyze the fluorescence signal distribution of the injected indicator for each brain slice to map good FSW treatment sites in the brain to improve experimental repeatability and accuracy.
Once the rats were treated by FSW (single pulse, intensity level 0.1, peak negative pressure − 4.2 MPa; energy flux density 0.03 mJ/mm2) with microbubbles (2 × 106 MBs/kg), 50 mg of either 70 kDa or 500 kDa FITC-dextran was administered via the tail vein. Three hours after FITC-dextran administration, the rats were sacrificed by a CO2 euthanasia instrument (followed the BU ASC guidelines for carbon dioxide euthanasia for rats and mice), and subsequent to a formaldehyde fixation process, their brains were sliced from locations S1 to S9 (shown in Fig. 3a) using brain matrices. The brain slices were then immediately placed into an IVIS scanning chamber to measure the fluorescence intensity of FITC-dextran, which was used to create a brain map for FSW-BCSFB opening. All IVIS data in the proposed research were analyzed using Living Image 3.1 (Caliper Life Sciences, Waltham, US).
Duration of FSW-BCSFB opening and FSW-BBB opening
After determining the FSW triggering positions with a higher probability for FSW-BCSFB opening than FSW-BBB opening in subsection 'FSW-BCSFB opening and brain mapping', we evaluated the duration of FSW-UCA-induced BCSFB and BBB opening. Twenty rats each were treated with FSW-UCA at time 0 at positions suitable for opening the BCSFB (position C. on Fig. 3a) and BBB (position G on Fig. 3a). Then, 0.5 ml of 3% Evans blue was infused 0.5, 1, 2, and 3 h (with five rats at each time point for the two positions) after time 0. Then, samples of CSF were obtained 3.5 h after time 0, after which the rats were sacrificed. In addition, five rats were designated as the blank group and were not treated with FSW-UCA.
Histopathologic sections and immunohistochemistry
To confirm the crossing of FITC-dextran across the BCSFB following the FSW treatments, after IVIS scanning, sliced rat brains were immersed in a 10% formaldehyde solution for 24 h. Subsequently, the sliced specimens were embedded in paraffin and subjected to immunohistochemistry to visualize FITC-dextran within the nuclei of the neurons. All 4-μm serial paraffin sections were deparaffinized by EZ prep (Ventana Medical Systems Inc., Tucson, AZ, USA). The slides were incubated with anti-FITC (FITC-11) at a 1:50 dilution for 30 min at 37 °C using the automated Ventana Benchmark XT (Ventana Medical Systems Inc.). Labeling was visualized with the UltraView DAB Detection Kit according to the manufacturer's protocol. All sections were counterstained with hematoxylin in Ventana reagent. After staining, all slides were analyzed using a Ventana Dp200 slide scanner with the corresponding software, Ventana Image Viewer v3.2 Advanced.
Duration of drug retention in the CSF circulation
To determine how long FITC-dextran can remain in the CSF circulation, rats were treated by FSW-UCA method and sacrificed 24, 72, and 120 h after FSW treatment, and brain slices were processed according to the procedure described in subsection 'FSW-BCSFB opening and brain mapping'. The brain slices were then placed into the IVIS scanning chamber to measure FITC-dextran fluorescence intensity, i.e., the concentration distribution of the delivered drug in the CSF circulation.
Efficiency of FSW-based drug delivery into the CSF
To evaluate the effectiveness of FSW in facilitating drug delivery into CSF circulation, the CSF concentrations of three indicators (Evans blue and 70 and 500 kDa FITC-dextran) and three clinical drugs (penicillin G, DOX, and BEV) were measured and compared before and after FSW treatment. Generally, these drugs have difficulty reaching the brain across the BBB or BCSFB under regular conditions [21]. Three hours after FSW-UCA treatment, samples of CSF were collected from the cisterna magna of the treated rats based on the protocols of a previous study [16, 22]. For more details, please refer to the Additional file 1.
Efficiency of FSW-based delivery of drugs into the CSF with multiple FSW stimulations
To evaluate the possibility of applying multiple FSW stimulations to increase drug concentrations in the CSF, we applied FSW treatment at different positions or iterations under the following conditions: (i) C: a single FSW pulse at position C; (ii) C10: 10 FSW pulses at position C; (iii) A-B-C: a single FSW pulse each at positions A, B and C; and (iv) CL-CR: a single FSW pulse at position C for each hemisphere. The FSW pulses were administered at the same intensity level of 0.1 for all conditions. The indicator was 3% Evans blue (dissolved in 0.9% saline). Other conditions were identical to those listed in the previous subsections.
Tumor cell viability
The procedures in the previous sections were used to determine the concentrations of both DOX and BEV in the CSF with and without FSW stimulation in vivo. Here, we investigated whether these concentrations of chemotherapeutic agents were sufficiently high to suppress the growth of three CNS-targeted tumor cell lines in vitro.
We used the different CSF concentrations of DOX and BEV obtained in the in vivo studies to C6, MDA, and MDA META cells in vitro and tested the viability of the cells using an alamarBlue assay. The advantages of alamarBlue include its technical simplicity, the absence of radioisotopes, its versatile detectability, the lack of a need to perform extraction, and its excellent reproducibility and sensitivity [26]. For more details, please refer to the Additional file 1.
Application of the FSW-BCSFB opening technique in treating a glioma-bearing model
To evaluate the ability of our FSW-BCSFB opening technique to suppress tumor growth in vivo, the C6 glioma cell line was chosen to establish a brain tumor model. The rat C6 glioma cell line was transfected with the luciferase (LUC) gene and maintained following procedures described previously [31, 32]. The cells were then implanted in the rat brain according to the following modified procedure [25, 33]: (1) rats were anesthetized using 3% isoflurane in oxygen; (2) the caudo-putamen of each rat brain (0.5 mm anterior and 2.0 mm lateral to the bregma; 5 mm deep) was stereotactically injected with 105 C6-LUC glioma cells in 5 µl using a Hamilton syringe within 15 min; and (3) the skull hole was sealed with bone wax, and the wound was rinsed with iodinated alcohol.
As shown in Fig. 8a, DOX (5 mg/kg) was infused through the tail vein with or without FSW treatment at position C on days 7, 10 and 13 following tumor cell injection using the procedures mentioned in subsection 'FSW-BCSFB opening and brain mapping'. The rats were injected with 200 μl (100 mg/kg) of d-luciferin via the tail vein and then imaged by the IVIS to monitor treatment response (tumor size) on days 10, 13, 16 and 20 [32]. The following IVIS parameters were used: field of view B (6.5 × 6.5 cm), 1-min exposure time, medium binning, and f/stop = 1.
Statistical analysis
Statistical analysis was performed using SPSS version 26. All data were expressed as mean ± standard deviation (SD) of at least five independent samples (N). In group comparisons, overall survival was calculated by the Kaplan–Meier method and the log-rank test was used to compare the survival curves. Other statistical evaluations were carried out with one-way ANOVA and post-hoc analysis (Tukey). A p-value of less than 0.05 was considered significant.
FSW-BCSFB opening
We sought to assess the ability of the FSW technique to open the BCSFB by measuring the distribution of FITC-dextran through FSW stimulation at different points in the brain. We stained histological sections obtained at S3 with anti-FITC (DAB) and hematoxylin (blue) to evaluate rats that were and were not treated with an FSW pulse at position C and found a strong anti-FITC immunochromatographic reaction in areas around the third ventricle (Fig. 3b) and the gray matter around the central canal (Fig. 3d) only in the group treated with FSW pulses.
Figure 3c shows fluorescence images of histological sections S7–S9. After the BCSFB was opened by FSW, a strong fluorescence signal was observed around the center of the spinal cord in the FSW-UCA treatment group, but a similar signal was not observed in the control group. The immunoreactive sites depicted in the above images were all adjacent to regions of abundant CP and high CSF circulation. These results indicate that this FSW-based technique can indeed open the BCSFB and deliver drugs into the CSF circulation.
Figure 3e shows the H&E stains of position C (S4) and position E (S6). On position E, bleeding was found on cerebellum region 3 h after the FSW-treatment. However, no red cell extravasation, cell death or any hemorrhage were found on position C.
Additionally, Fig. 3f shows fluorescence images of each histological section after FSW treatment at position G for two different rats. The fluorescence is local since the FITC indicator cannot enter the CSF circulation.
Figure 3g illustrates the duration of BCSFB and BBB opening via evaluation of the concentration of an indicator, Evans blue, in sections 'FSW-BCSFB opening and brain mapping' and 'Duration of FSW-BCSFB opening and FSW-BBB opening' respectively following FSW treatment at position C and FSW treatment at position G, along with the concentration in a control animal (no FSW treatment). The concentration of Evans blue in the CSF was significantly higher following FSW-BCSFB opening than FSW-BBB opening. The concentration shown for the FSW-BCSFB technique corresponds to an opening duration of approximately 1–2 h. Besides, the mortality rate 3 h after FSW stimulation at positions E and F were respectively 60% and 70%, while that for the rest was 0%.
Brain mapping by FSW delivery of FITC-dextran across the BCSFB
Figure 4a shows fluorescence images of brain sections S1–S6 at 3 h after FSW treatment at different positions (A–E) or after control treatment (no FSW treatment group). Figure 4b shows the normalized fluorescence intensity by two standard fluorescent cards for injections of 70 kDa FITC-dextran, while Fig. 4d shows the normalized fluorescence intensity by two standard fluorescent cards for injections of 500 kDa FITC-dextran. It can be clearly seen that the fluorescence intensities are higher in the brain regions and sections closer to the FSW stimulation areas, although the differences are not consistently significant between the two weights of FITC-dextran. For example, the total fluorescence flux of both 70 and 500 kDa FITC-dextran was higher at position B in brain slices S2 and/or S3 since position B is closer to the area captured by S2. The accumulated fluorescence intensities of all brain sections (Fig. 4c, e) were not significantly different except for that produced following treatment at position E.
Following stimulation of the left hemisphere by the FSW technique, the fluorescence signal for 70 kDa FITC-dextran could still be clearly seen in the contralateral hemisphere (Fig. 4a), indicating that the distribution was not limited to the stimulated area. This indicates that the proposed FSW treatment technique can open the BCSFB and deliver the indicator into the CSF circulation.
Duration of indicator retention in the CSF circulation
Figure 5a shows fluorescence images for the brain histological sections harvested after 24, 72, and 120 h. The fluorescence intensity distributions were more uniform than those in Fig. 4a, and the strong signals around the stimulation points shown in Fig. 4a were absent. Figure 5b shows quantitative measurements of fluorescence intensity 3, 24, 72, and 120 h after FSW treatment. By normalizing the values by the intensity at 3 h, the intensity values at 24, 72, and 120 h were respectively 46.31%, 19.29%, and 9.38% with 70 kDa FITC-dextran and 55.40%, 25.42%, and 9.17% with 500 kDa FITC-dextran. Based on these results, the half-life of the fluorescence signal strength was approximately 24 h. Furthermore, significant differences in signal strength were seen only after 72 h. Therefore, this FSW-BCSFB opening provides a method to deliver drugs into the CSF circulation, with above 50% of drug concentrations at T0 (FSW-treatment) for around 24 h.
Efficiency of FSW-based drug delivery into the CSF
Tables 1 and 2 compares CSF drug concentrations with and without FSW treatment. The numbers indicate the percentage of drug in CSF relative to that in the blood. As can be seen, the drug concentrations in the CSF following FSW treatment differed significantly from those in the CSF without FSW treatment (Table 1). These results bolster the findings made for FITC-dextran and illustrate that the FSW treatment technique is beneficial for different kinds of drugs.
Figure 6a shows histological sections after the application of FSW at different positions and iterations. In addition, the BCSFB and BBB opening regions (the blue-stained areas), indicated by red arrows, are at similar locations to the high FLUX-LUX intensity locations at different FSW positions in Fig. 4a. Figure 6a shows H & E stains on S4 of Fig. 6a, in which, the blue arrows indicate the locations of the red blood cell extravasations (on A-B-C and CL-CR groups), and the black arrow indicate the bleeding (in C10 group). Unfortunately, the brain bleeding rat was dead within 3 h after the FSW-treatment. In the current study, the mortalities of the C, C10, A-B-C, and CL-CR groups were respectively 0%, 20%, 0%, and 0% (Table 2). Despite these groups showing a 3- to 4.5-fold increase in CSF drug concentration (Table 2), a single shockwave pulse is still recommended for BCSFB opening to avoid the unexpected brain bleeding.
Tumor cell viability
Figure 7 shows the viability of C6, MDA META, and MDA cells cultured with DOX or BEV at the in vivo CSF concentration of each drug corresponding to rats with (FSW) or without (Con) shockwave treatment. For the cells cultured with DOX, the viabilities in the FSW group were significantly different from those in the control group for all three cell line types. For the cells cultured with BEV, the cell viability of the FSW group was significantly different from that of the control group for only the C6 cell line. Furthermore, at the studied concentration, DOX showed good tumor cell suppression in all three cell lines.
Application in treating a glioma-bearing model
Figure 8b shows brain tumor (C6 cells) growth following DOX injection monitored by measuring luciferase activity using the IVIS imaging system. The FSW and control groups showed major differences in fluorescence intensity after the first treatment. However, the FSW and Sham groups started to show significant differences after the second treatment. Figure 8c shows an analysis of animal survival via Kaplan–Meier curves. Compared with the control group, the FSW group, but not the Sham group, showed a significant difference in survival (*p < 0.05). However, the difference between the Sham and FSW groups was not significant. This indicates that the proposed FSW-BCSFB opening method can significantly improve the antitumor efficacy of DOX in the glioblastoma model.
The BCSFB is regarded as the gatekeeper of blood circulation into the CSF space. By stimulating specific areas of the brain using a single FSW pulse with microbubbles, we not only temporarily opened the BCSFB to facilitate the delivery of therapeutics into the brain via the CSF circulation, but also achieved therapeutic concentrations of DOX that suppressed the growth of glioblastoma multiforme tumors in an in vivo model. Our results indicate that this technique has potential for treating various CNS disorders by opening the BCSFB and increasing drug concentrations in the CSF circulation.
The BCSFB is formed by epithelial cells of the CP located primarily in the four ventricles of the brain. The CP epithelium, which forms the BCSFB, is a unique single layer of epithelial cells situated at the interface between the blood and CSF. In contrast to the structures of the BBB, the BCSFB is formed by tight junctions between CP epithelial cells instead of endothelial cells, restricting the movement of molecules leaking from fenestrated capillaries into the CSF. By analyzing the distal diffusion of fluorescence to different parts of the brain and spinal cord, our study demonstrated a site-specific strategy for opening the BCSFB by FSW. We found that by stimulating the rat brain at different positions with the same FSW intensity, the BCSFB could be opened in positions near the lateral ventricles (positions A–D), areas with abundant CP (Fig. 3e), but not at the brain parenchyma (position G) (Fig. 3f). At this moment, we still can not obtain high-power enough pictures and evidences of FSW-disrupted choroid plexus. The permeable choroid plexus may be caused by whether the acoustic-pressure disruption or tight junction opening such as TRPV4 channel or other mechanism [34].
Additionally, the fluorescence following stimulation at position G was found only locally, suggesting that only the BBB was opened, not the BCSFB. The comparison of indicator concentrations in the CSF (Fig. 3g) provided additional evidence of the high correlation between FSW position and BCSFB opening.
Conventionally, as compared with ultrasound, shockwave is believed to have higher potential to tissue damages while applying on brains. However, as shown in our previous study, the fine-tuned single low energy FSW pulse shows improved control of cavitation without detectable hemorrhage or apoptosis, and a lower inflammation, apoptosis, and free radical generation [reactive oxygen species (ROS) and reactive nitrogen species (RNS)] in the brain [16, 19]. The single low energy FSW pulse may provide an alternative way to deliver drugs into brains, and may benefit future neuro-oncology and neuropharmacology research and applications.
Common methods of FSW- and HIFU-based BBB opening provide a time window of 1 h or less and deliver drugs to only a thin region (approximately 2 mm3) of the rat brain. Even with a 72-h time window, HIFU-BBB opening can deliver drugs to only approximately 30 mm3 of the rat brain [16, 20, 35]. In contrast, by inducing BCSFB opening in suitable positions, our FSW-BCSFB opening technique could provide not only a method to deliver drugs into the CSF circulation (nearly the whole rat brain and spinal cord) but also provides a 1- to 2-h time window for drug administration.
In this study, the operating parameters of the FSW-BCSFB opening technique were identical to those of the FSW-induced BBB opening technique reported in our previous study [16, 20]. However, the FSW stimulation positions were different. In our previous research, the FSW focus was intentionally positioned 5 mm beneath the scalp surface, 3 mm caudal, and 3 mm right or left of the bregma of the rat skull [16, 19, 20]. Thus, the maximal pressure area was positioned at the cortex of the rat brain for BBB opening. Here, the positions for FSW-BCSFB stimulation are beside the blue area in Fig. 2, especially near the CP-rich area. Limited by the need to control the intensity level and energy of the FSW pulses, the precise threshold for FSW-BCSFB opening is unknown. However, the data obtained in this study supports the concept that FSW can be used to selectively manipulate the permeability of the BBB and BCSFB.
It is worth noting that stimulation at areas close to the fragile cerebellum and brain stem area (E and F) may result in mortality. The mortality rate 3 h after FSW stimulation at positions E and F were respectively 60% and 70%, while that for the rest was 0%, probably because positions E and F are located near the cerebellum and brain stem, which are essential to many vital functions [36].
CSF circulates in the ventricles and the subarachnoid space, and plays an essential role in CNS homeostasis, including protection, waste clearance, and nutrient transport. Recent studies have demonstrated that a back-and-forth movement of the CSF is produced by respiratory and cardiac pulsations surrounding small penetrating arteries, providing exchanges between the CSF and interstitial fluid of the brain parenchyma. The pathway consists of a para-arterial influx route for CSF to enter the brain parenchyma [37]. Moreover, drugs delivered into the CSF can diffuse into the brain parenchyma and contact brain cells. A recent study demonstrated the possibility of using focused ultrasound to facilitate the CSF drainage through the glymphatic pathway from periarterial to perivenous CSF spaces [38, 39]. The technique shown in this study not only enhances the transport of drugs across the BCSFB and the BBB but also has the potential to push drugs further through ventricle and glymphatic pathways to brain cells due to the pulsating nature of the mechanical waves.
Several CNS disorders have been found to spread via the subarachnoid spaces and CSF. Among them, leptomeningeal carcinomatosis (LC), consisting of tumor cells that metastasize throughout the CSF space to the CNS, is the most devastating and terminal type and is frequently seen in lung cancer and breast cancer patients [40]. Intrathecal administration of antitumor agents such as trastuzumab, which has poor CNS penetration following intravascular infusion, has shown efficacy in patients with HER2-positive breast cancer with LC [41]. Our technique may provide a less invasive alternative for the treatment of LC; through the use of a multiple stimulation strategy (for example, the A-B-C or the CL-CR strategy shown in Fig. 6), the concentration of treatment drugs could be controlled.
Comparing the accumulated fluorescence intensity (Fig. 4c, e) of both 70 and 500 kDa FITC-dextran, no significant difference was observed after FSW stimulation at positions A–D. This may be due to the wide distribution of the CSF in the CNS. Once a drug enters the CSF circulation, it can circulate in the whole CSF system, and its half-life is longer than that in the blood circulation [42]. Stimulation at position E produced significantly higher concentrations of FITC fluorescence, but the increased likelihood of mortality makes it a poor choice for FSW treatment.
The molecules sucrose (360 Da) and inulin (5 kDa) slowly cross the CP to enter the CSF with a CSF/blood ratio (CBR) of approximately 10% [43], and the protein transthyretin (55 kDa) can cross the CSF barrier with a 5.6% CBR. However, other molecules (> 55 kDa), such as albumin (67 kDa), IgG (150 kDa), and IgM (900 kDa), have respective CSF/blood ratios of only 0.49%, 0.22% and 0.03% [44, 45]. Besides, as shown in Fig. 4, the FSW-BCSFB opening technique can enhance the BCSFB permeability to even large molecules to deliver drugs into the CSF circulation. Furthermore, regardless of the FSW stimulation position, once the BCSFB is opened, the indicator is distributed in the CSF circulation from the brain ventricles to the spinal cord. This method can also provide a one-day half-life of drug delivery, as shown in Fig. 5b. Therefore, this method could not only allow the delivery of molecules ten-times larger than normally allowed through the BCSFB channel for future drug delivery, but also keep drugs in the CSF circulation for at least one day.
In this study, the animal species is SD rat. The species differences in brain size will bring concerns such as the relative distance from CSF to deep brain structures in rats and humans. However, based on previous studies, those brains on the higher-level species are with higher folding brain structure. Once, the drugs are delivered into the ventricles, the subarachnoid space, or the parenchyma, they will be much easier to be delivered into the whole brain since the glymphatic pathways in the gyrencephalic brain [46, 47]. Moreover, for the current FSW technique, the penetration depth is adjustable from 0.5 cm to around 15.0 cm using different gel pads according to actual needs.
The in vivo DOX concentrations in the CSF following FSW treatment showed a good suppressive ability against all three cancer cell lines tested in vitro (Fig. 7), C6, MDA META, and MDA, probably due to the interaction of DOX with tumor cell DNA by direct intercalation and inhibition of macromolecular biosynthesis. In contrast, the suppressive effect of BEV was poor, since BEV can exert its effect only by inhibiting vascular endothelial growth factor A (VEGF-A) and angiogenesis. Under the in vitro experimental mechanism described here, BEV was unable to exert its antiangiogenic ability [48, 49]. Furthermore, the FSW-BCSFB opening technique combined with DOX shows potential in the suppression of both orthotopic and metastatic brain tumors.
The results in Fig. 8 suggest that our FSW technique can be combined with DOX to suppress glioblastoma tumors in a rat model. Significant tumor suppression could be seen on day 13 or after the 2nd FSW treatment. Significant survival improvement was also seen between the FSW and control groups. There was no significant survival improvement between the FSW and sham groups, which may be caused from the limited rat number. Referred to the Fig. 8b, that already showed the significant improvement on the GBM cell growth rate between the FSW and sham groups. On the other hand, in Fig. 8b, the reason why the signal of the control group dropped after day 13 is probably due to excessive tumor size and internal necrosis when the GBM cells grew too fast to obtain enough nutrition [50].
This is the first study to demonstrate that the BCSFB can be noninvasively opened in selected brain regions by a single FSW pulse with microbubbles. Though we cannot perfectly avoid BBB opening, we successfully show that the positions of FSW stimulation, i.e., near choroid plexus, enhance the probability of BCSFB opening. BCSFB opening allowed significant increase in the concentrations of certain CNS-impermeable indicators as well as medications such as penicillin G, DOX, and BEV into the CSF, brain and spinal cord region. Moreover, the increased CSF concentrations of DOX were found to be effective for the in vitro suppression of glioblastoma multiforme (C6), breast tumor (MDA) and MDA brain metastasis (MDA META) cells. Furthermore, FSW-treated glioblastoma bearing animals displayed significantly longer survival than untreated animals. These results suggest that FSW treatment could be an alternative way to combat CNS disorders by opening the BCSFB and enhancing the therapeutic efficiency of medication through entry into the CSF circulation. This innovative approach may benefit future treatments for neurodegenerative disorders, CNS infection, brain tumors, and leptomeningeal carcinomatosis.
Availability of data and materials
The datasets analyzed during the current study are available from the corresponding author on request.
Blood–brain barrier
Blood-cerebrospinal fluid barrier
Glioblastoma multiforme cells
Focused shockwave pulse
Glioblastoma multiforme
In vivo imaging system
Breast tumor cells
MDA brain metastasis cells
Ultrasound Contrast Agents
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We thank Dr. Yen-Shen Lu (NTUH) for providing the MDA META cell line. We thank Miss Tz-Yi Wen (UC Davis) for improving the English writing of this paper.
This work was supported by Grants 105-2923-B-002-001-MY3 (Caribbbou ANR-NSC project) and 108-2314-B-002-164 from the Ministry of Science and Technology (Taiwan), by Grants 107-M3989 and 109-M4670 from the National Taiwan University Hospital, by Grants BN-108-PP-003 and BN-109-PP-03 from the National Health Research Institutes of the Republic of China (Taiwan), and by Grant 109-53 from the Good Liver Foundation (Taiwan).
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Authors and Affiliations
YK designed and developed the system and performed the major experiments. WHL and YHH provided the biotechnological analysis information. APHH, KYC, CHW, MYH, and WSC directed the research. YK and WSC wrote the manuscript. All authors read and approved the final manuscript.
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This study was approved by the ethics committee of the Laboratory Animal Center at the National Taiwan University College of Medicine (Approval No. 20170091 for the use of rats) and adhered to the experimental animal care guidelines.
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The authors declare no competing interests.
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Additional file 1.
Material and method details.
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Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
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Kung, Y., Chen, KY., Liao, WH. et al. Facilitating drug delivery in the central nervous system by opening the blood-cerebrospinal fluid barrier with a single low energy shockwave pulse. Fluids Barriers CNS 19, 3 (2022). https://doi.org/10.1186/s12987-021-00303-x
DOI: https://doi.org/10.1186/s12987-021-00303-x


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Recognized by the distinctive white ring around its eyes, the Adélie penguin is only one of two species of penguin whose only home is Antarctica. While Adélie numbers have been observed to decline in some regions amid a changing climate, the truth is surprisingly little is known about the penguins' actual distribution along Antarctica's coastline. A 2015 land-and-air survey explored previously unreported colonies of Adélie here, in a cluster of ice-choked islands called the Danger Islands.
The discovery could mark an important technological turning point in species tracking that would have clear implications for preserving biodiversity.
Researchers conducted their survey from aboard a research vessel and on the grounds of several of the Danger Islands—only one of which had ever been inspected for Adélie penguins. They counted nests [manually], [from panoramic photos], and [from imagery captured by drones].
In all, the team tallied 751,527 pairs of Adélie penguins in the Danger Islands. That's more than the rest of the Antarctic Peninsula combined! And at a region scale, the new count boosts the previous population estimate by nearly 70%.
The researchers compared their findings with aerial imagery captured in the 1950s and satellite imagery gathered since the 90s. The analysis revealed that, overall, Adélie numbers have remained roughly stable, in stark contrast to the declines observed along the Western Antarctic Peninsula. These findings are consistent with recent modeling work showing that the warming pattern of the peninsula has perhaps spared the Danger Islands from large environmental changes—at least from a penguin's perspective.
That conclusion, of course, is limited by the lack of imagery between the late 1950s and 1990. But it points to the potential power of medium-resolution satellite imagery. Combined with drone-based photography, such imagery could enable researchers to discovery further penguin colonies and chart their biogeography over time.
Additionally, the results make a strong case for increased species protection in the Danger Islands. The islands are large and likely to remain a vital hotspot for avian abundance under
projected climate change. As such, the team argues that they deserve special consideration in the negotiation and design of Marine Protected Areas in this region.


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What to know
- Meta has added the ability to make video calls using your cartoon avatar on Instagram and the Facebook Messenger app.
- Users can create their avatars from the Edit Profile section on Instagram, and the more options (hamburger icon) section on Facebook.
- To use your avatar, simply initiate a video call and tap on the avatar icon on the left.
- If you have different avatars on the two platforms, sync your avatar by syncing the two profiles from the Account Center. The default avatar will be the one created on the app you're currently using.
Meta's avatar creation system may have blown hot and cold amongst users. But that hasn't stopped Meta from pushing avatars to its platforms for those who like their digital doubles to take over when the need arises. First seen in VR applications, these cartoon-like avatars can now be used for video calling as well, across both Instagram and Facebook.
If you're looking to give it a go, here's everything you need to know to create your very own avatar and make video calls on Instagram and Facebook Messenger with them.
How to create a cartoon avatar?
If you're new to Meta's avatars, here's a primer on how you can create one to use on video calls on Instagram and Messenger.
Note: Those who have already created their cartoon avatars can skip this section.
On Instagram
Open the Instagram app and tap on your profile icon at the bottom right corner.
Tap on Edit profile.
Tap on Edit picture or avatar.
Tap on the avatar tab to switch to it.
Here, tap on Create Avatar.
Choose your avatar's skin tone, hairstyle, outfits, etc. Once done, tap on Done.
Tap on Save Changes.
On Facebook
To create an avatar on Facebook, tap on the hamburger icon at the top right corner.
Select See more.
Tap on Avatars.
Then go through the same process as before to customize your avatar and click on Done.
Once done, exit the avatar creation page.
You're now ready to make video calls using your avatar on Instagram and Facebook.
How to make video calls using your avatar on Instagram and Facebook?
Now, let's see how you can use these avatars while video calling.
On Instagram
Firstly, open the Chats section from the top right corner.
Select a user to start video calling.
Tap on the Video call icon at the top right corner.
While the call is ongoing, tap on the avatar icon on the left (first from the top).
Note: If you see the avatar icon loading, keep your face well within the camera for it to complete loading. Once it's done, you will see your avatar appear.
On Facebook
The steps to making a video call on the Facebook Messenger app are the same. Simply select a friend to video call.
And tap on the video call icon at the top right corner.
Tap on the avatar icon on the left to use it.
And begin your video call with your avatar.
How to sync your avatar across profiles?
Even though both Facebook and Instagram allow you to create different avatars for each platform, you can use the avatar created on one to use on a video call on another platform.
You will have to sync your profile and your avatar first. To do so, open the app whose avatar you want to use, for example, Instagram. Tap on the hamburger icon for more options.
Select Settings and privacy.
Tap on Accounts Centre.
Tap on Profiles.
Then select the platform other than the one you're on (Facebook in our example).
Tap on it again.
Toggle on Sync profile info.
Tap on Sync profile info.
Once synced, the avatar created on the platform you're on (Instagram in our example) will become your default avatar. You can make sure of it by tapping on Avatar.
And see that the Sync avatar is toggled on.
Let's take a look at a few commonly asked questions about using avatars to make video calls on Facebook Messenger and Instagram.
Can Instagram avatars be used on Facebook?
Yes, you can use the avatar created on Instagram on Facebook as well. To do so, make sure to sync the two profiles on the Instagram app. This will make your Instagram avatar your default avatar which can be used on both Instagram and Facebook.
How do you make an animated avatar on Instagram?
To make an animated avatar on Instagram, go to the edit profile section of the app and select the avatar (next to your profile image). Then follow the steps to create the animated avatar.
Meta's known to closely integrate features across different platforms, and the introduction of video calling using your avatar is no different. We hope this guide helped you bring your avatar to life on video calls on Instagram as well as the Facebook Messenger app. Until next time!


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- Dec 5, 2020 1:00 pm
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Whether it's pest control, makeup, or solar panels, we've all come in contact with a multi-level marketing business, or MLM for short. Many of these companies get a bad rap for their recruitment model and often-aggressive selling techniques. They make us think of the pushy door-to-door salesman who comes around trying to sell us pest control or a new internet provider for ridiculous prices. But are they all bad? And what should you know if you're interested in working for one of these companies? Joining us this morning is Ashley Smith, an attorney from Salt Lake City, here with us to discuss multi-level marketing businesses and how to determine if they're a good fit for you.


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Hannah has been a joy to work with - she is so helpful and supportive, with the most wonderful approach.
Hannah has a great deal of experience in dealing with cases involving companies and trust arrangements. Many of Hannah's clients have assets abroad as well as in the UK. Hannah is able to work with other lawyers across different jurisdictions in order to ensure the client has all necessary information to make an informed decision as to how best to resolve their matter.
Hannah has a client focused and pragmatic approach to dealing with her cases. She is committed to delivering an effective and tailored result for each client's case. Hannah is a member of Resolution and is therefore committed to dealing with matters in a conciliatory and non-confrontational manner whenever possible. Hannah, however, is mindful that litigation is sometimes unavoidable and is experienced and unperturbed by dealing with cases in this way.
Hannah Field is a practical lawyer who gives clear advice to clients. She is excellent at exploiting good points in cases, but always advises clients where the pitfalls are in their case.
Hannah has experience of advising individuals from a broad range of backgrounds and adapts her approach in order to meet the individual needs of her client. Her patient and sympathetic approach allows her clients to make informed and practical decisions, supporting them through what can often be a very difficult situation.
She is a trained collaborative lawyer and always considers the options available to her clients for resolving matters including all methods of dispute resolution. She sees herself as a facilitator and part of her client's team working together to achieve the best outcome possible in each situation.
There were times when I could have made mistakes if I followed my emotions, however when I listened to Hannah's advice it was always the right thing to do. She had the ability to calm me down and make me see sense.
Hannah's highlights
Family law podcast series
Practical help and things to think about when sorting out arrangements for your children


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Are you on the quest for a best vegan mayo recipe that is creamy, versatile and egg free and will fool even the biggest mayo lovers? Look no further because you've come to the right place! In this comprehensive guide, we will unveil the secrets to creating the creamiest, most irresistible vegan mayo recipe you've ever tasted. Whether you're a seasoned plant-based eater or simply exploring dairy-free alternatives, this article is your go-to resource for detailed instructions, helpful tips, and answers to frequently asked questions. Get ready to embark on a flavor-packed journey as we show you how to make the perfect vegan mayo that will take your culinary creations to new heights!
Ingredients For Best Vegan Mayo Recipe:
Before we dive into the step-by-step instructions, let's gather all the ingredients you'll need for this delectable vegan mayo recipe creation:
- ½ cup of warm unsweetened soy milk
- 1 cup of canola oil or any other cooking oil of your choice
- 1 tablespoon of vinegar
- ½ teaspoon of salt
- ¼ tablespoon of garlic powder
- ¼ tablespoon of smoked paprika
It's crucial to use unsweetened soy milk and warm it up to aid in the emulsification process. With these ingredients ready, let's move on to the detailed instructions that will help you achieve mayo perfection!
Instructions for Best Vegan Mayo Recipe:
- Blend It Up: In a high-speed blender, immersion blender or food processor, combine the warm soy milk, canola oil, vinegar, salt, garlic powder, and smoked paprika. Start the blender on low speed and gradually increase it to high. Blend the ingredients for about 1-2 minutes until the mixture begins to thicken.
- Emulsify to Perfection: As the blender runs on high speed, watch in amazement as the ingredients magically transform into a thick and creamy mayo consistency. This emulsification process is what gives vegan mayo recipe its signature texture. Be patient and keep blending until you achieve the desired creamy consistency.
- Taste and Adjust: Now it's time to put your taste buds to work! Take a spoonful of your homemade vegan mayo recipe and savor the flavors. Is it tangy enough? Does it need more salt or acidity? Adjust the seasonings to your liking, adding a pinch more salt or a splash more vinegar as needed. Remember, customization is key!
- Store and Chill: Transfer the creamy vegan mayo into a clean jar or airtight container. Seal it tightly and refrigerate for at least 30 minutes to allow the flavors to meld together. Your homemade vegan mayo will stay fresh for up to one week, ready to enhance your culinary creations.
Tips for Perfection for Best Vegan Mayo Recipe:
Creating the best vegan mayo recipe requires a little finesse. Here are some tips to ensure your mayo turns out creamy and flavorful every time:
- Use warm soy milk: Warming up the soy milk helps with the emulsification process, allowing the oil and milk to blend more seamlessly. Ensure that the soy milk is warm but not scalding hot before adding it to the blender.
- Experiment with oils: While the recipe suggests canola oil, feel free to explore different cooking oils to find your preferred flavor. Olive oil, avocado oil, or even a combination of oils can add unique characteristics to your mayo. Each oil will lend its own distinct taste, so don't be afraid to get creative!
- Add seasonings and spices: Vegan mayo is a blank canvas for flavor experimentation. Enhance the taste by adding additional seasonings or spices. A pinch of cayenne pepper can add a subtle heat, while herbs like dill, basil, or chives can bring a fresh and vibrant touch to your mayo. Feel free to get creative and customize your vegan mayo recipe with your favorite flavors.
- Control the consistency: If your mayo turns out too thick, you can gradually add a small amount of warm water or more soy milk to thin it out. On the other hand, if it's too thin, blend in a tablespoon of oil at a time until you achieve the desired thickness. Adjust the consistency to your liking, keeping in mind the intended use of the mayo.
- Keep it chilled: To maintain the freshness and quality of your homemade vegan mayo, always store it in an airtight container in the refrigerator. This will ensure that it stays at the optimal temperature and remains safe to consume. Before each use, give the mayo a good stir to ensure that the ingredients are well incorporated.
With these tips in mind, you're well on your way to becoming a vegan mayo pro!
Alternative Variations for Vegan Mayo Recipe:
While the classic vegan mayo recipe is already a winner, why not explore alternative variations to add even more excitement to your culinary creations? Here are some delicious ideas to take your vegan mayo recipe game to the next level:
- Aquafaba Wonder: Replace the soy milk with aquafaba, the liquid found in canned chickpeas. Whip the aquafaba until frothy, then incorporate it into the remaining ingredients. This variation creates a lighter and fluffier mayo with a unique flavor profile.
- Oil-Free Delight: Looking for a healthier alternative? Swap out the oil altogether and use soaked cashews or silken tofu instead. Blend these ingredients with the other seasonings to create a creamy and oil-free vegan mayo recipe. You can also experiment with mashed avocado for a rich and creamy twist.
- Zesty Lemon Herb: Add a burst of freshness by incorporating lemon zest and freshly squeezed lemon juice into your mayo. Finely chop your favorite herbs, such as parsley, dill, or basil, and mix them in. This variation adds a bright and citrusy note to your mayo, perfect for summery salads and sandwiches.
- Spicy Chipotle Kick: Craving some heat? Blend in a spoonful of chipotle peppers in adobo sauce or a pinch of cayenne pepper to give your mayo a spicy kick. This variation pairs exceptionally well with vegan burgers, tacos, and wraps.
Feel free to get creative and experiment with different variations. The beauty of homemade vegan mayo is the ability to customize it to suit your taste preferences and culinary needs.
Suggested Pairings for Best Vegan Mayo Recipe:
Now that you have the perfect vegan mayo recipe at your disposal, it's time to explore some mouthwatering ways to enjoy it:
- Classic Sandwiches: Spread a generous layer of your homemade vegan mayo on your favorite bread along with crisp lettuce, juicy tomato slices, avocado, and your choice of plant-based protein. Whether it's a classic veggie sandwich, a tempeh Reuben, or a vegan chicken salad, the creamy mayo will bring all the flavors together in perfect harmony.
- Dip and Devour: Transform your vegan mayo into a delectable dip for an array of snacks. Dip crispy sweet potato fries, crunchy onion rings, or fresh vegetable sticks into the creamy goodness. It's the perfect accompaniment for snacking or party appetizers.
- Salads and Dressings: Mix your vegan mayo into homemade potato salad, coleslaw, or pasta salad for a creamy and tangy twist. The mayo will coat each ingredient with velvety goodness, making your salads incredibly flavorful. You can also use your mayo as a base to create a variety of dressings for salads. Add some lemon juice, Dijon mustard, and a touch of maple syrup for a tangy vinaigrette or experiment with herbs and spices to create your own signature dressing.
- Savory Sauces: Your vegan mayo recipe can be the star of savory sauces. Create a luscious vegan aioli by adding minced garlic, lemon juice, and a pinch of cayenne pepper to your mayo. This versatile sauce is perfect for dipping roasted potatoes, drizzling over grilled vegetables, or spreading on sandwiches.
- Burger Bliss: Take your veggie burgers to the next level by slathering them with a generous amount of vegan mayo. The creamy texture and rich flavors will elevate the burger experience and create a mouthwatering symphony of tastes.
- Wraps and Rolls: Add a dollop of vegan mayo to your wraps and rolls for an extra creamy and flavorful touch. Whether it's a falafel wrap, a veggie burrito, or a sushi roll, the mayo will enhance the overall taste and make each bite a delightful experience.
- Dipping Sauces: Get creative with vegan mayo-based dipping sauces. Mix in some sriracha or hot sauce for a spicy kick, or add herbs and spices like dill, basil, or smoked paprika for unique flavor combinations. Use these sauces to dip vegetables, tofu bites, or breaded mushrooms.
- Craving Curiosity: Vegan mayo can be a fantastic base for exploring various flavors and cuisines. Experiment with adding different spices, herbs, or seasonings to create a mayo that reflects your favorite cuisine, such as a smoky chipotle mayo for Mexican-inspired dishes or a zesty lemon and herb mayo for Mediterranean flavors.
Feel free to let your imagination run wild and discover new pairings that excite your taste buds. The creamy and versatile nature of vegan mayo makes it the perfect companion for a wide range of dishes.
FAQs (Frequently Asked Questions) for Best Vegan Mayo Recipe:
Q: How can I make my vegan mayo taste more like regular mayo?
A: If you're aiming to replicate the taste of traditional mayo, you can add a touch of sweetness, such as maple syrup or agave nectar, along with a hint of apple cider vinegar. Adjust the quantities to find the perfect balance that closely mimics the flavor you desire.
Q: Can I use this recipe to make vegan tartar sauce?
A: Absolutely! This vegan mayo recipe serves as an excellent base for creating a tangy and flavorful vegan tartar sauce. Simply add finely chopped pickles, capers, minced onion, a squeeze of lemon juice, and a dash of dill to the mayo, and you'll have a delightful condiment that pairs perfectly with vegan fish alternatives or as a dip for fries.
Q: Can I make a vegan mayo recipe without oil?
A: Yes, you can! If you prefer an oil-free version, substitute the oil with soaked cashews, silken tofu, or mashed avocado. Blend these alternatives with the other ingredients to create a creamy and oil-free vegan mayo.
Q: How long can I store homemade vegan mayo?
A: Properly stored in an airtight container in the refrigerator, homemade vegan mayo can typically be kept for up to one week. However, always trust your senses and discard it if you notice any changes in texture, odor, or taste.
Q: Can I freeze vegan mayo?
A: It is not recommended to freeze vegan mayo as it can affect the texture and result in separation when thawed. It's best to make smaller batches to ensure optimal freshness and quality.
Q: How can I make my vegan mayo taste tangier?
A: To make your vegan mayo tangier, you can increase the amount of vinegar or add a splash of lemon juice. Start with small increments and taste the mayo as you go, adjusting the acidity to your preference. Remember to balance the tanginess with the other flavors, and feel free to experiment with different types of vinegar, such as apple cider vinegar or white wine vinegar, for unique taste profiles.
Q: Can I use a different type of plant-based milk instead of soy milk?
A: Potentially! There have been success stories of people using almond milk and cashew milk for their vegan mayo recipes. Soy milk is naturally high in lecithin, which is an emulsifier. When substituting soy milk, you will need to choose another vegan milk that also contains lecithin. Without lecithin, your vegan mayo will separate and won't thicken.
Q: How can I make my vegan mayo thicker or thinner?
A: Adjusting the thickness of your vegan mayo is easy. If you prefer a thicker consistency, you can add more oil gradually while blending until you reach the desired thickness. On the other hand, if you want a thinner mayo, you can incorporate a small amount of plant-based milk or warm water while blending until you achieve the desired consistency. Remember to make these adjustments gradually to maintain control over the thickness of your mayo.
Q: Can I add other ingredients like herbs or spices to customize my vegan mayo?
A: Absolutely! Customizing your vegan mayo with herbs and spices is a fantastic way to add extra flavor. You can experiment with adding minced garlic, chopped fresh herbs like parsley, basil, or dill, or spices like paprika, cayenne pepper, or even curry powder. These additions will infuse your mayo with unique and exciting flavors that will take your culinary creations to new heights.
Q: How can I make my vegan mayo taste more like a specific cuisine?
A: To infuse your vegan mayo with the flavors of a specific cuisine, you can incorporate seasonings and spices commonly used in that cuisine. For example, if you want a Mexican-inspired mayo, add cumin, chili powder, and lime juice. For a Mediterranean twist, try adding lemon zest, oregano, and a pinch of sumac. Experiment with different combinations of spices and seasonings to create a mayo that complements your desired cuisine.
Q: Can I use this vegan mayo recipe as a substitute for regular mayo in recipes?
A: Absolutely! This vegan mayo recipe can be used as a one-to-one substitute for regular mayo in most recipes. Whether you're making creamy salad dressings, potato salad, coleslaw, or even baking vegan cakes and muffins, this mayo will provide the same rich and creamy texture. So go ahead and explore the endless possibilities of incorporating your homemade vegan mayo into your favorite recipes!
Congratulations! You have now mastered the art of creating the ultimate vegan mayo that is creamy, versatile, and egg-free. With this comprehensive guide, you possess the knowledge and skills to whip up a batch of homemade vegan mayo recipe that will elevate your plant-based dishes to new heights. From sandwiches and wraps to dips, dressings, and sauces, your vegan mayo will add a burst of flavor and creaminess to your culinary creations. The best part? You have the freedom to customize your mayo with alternative variations, herbs, spices, and seasonings to suit your taste preferences and explore various cuisines.
So, gather your ingredients, put on your chef's hat, and enjoy the process of creating your own creamy, plant-based masterpiece. Say goodbye to store-bought mayo and embrace the deliciousness of homemade vegan mayo. Your taste buds and the animals will thank you for it. Happy mayo-making!
Other Recipes to Try:
PrintThe Ultimate Vegan Mayo Recipe That Tastes Just Like Real Mayo (No Egg!)
- Prep Time: 5
- Total Time: 5 minutes
1 cup of warm unsweetened soy milk
1 cup of canola oil or any other cooking oil of your choice
1 tablespoon of vinegar
½ teaspoon of salt
¼ tablespoon of garlic powder
¼ tablespoon of smoked paprika
- In a high-speed blender, immersion blender or food processor, combine the warm soy milk, canola oil, vinegar, salt, garlic powder, and smoked paprika. Start the blender on low speed and gradually increase it to high. Blend the ingredients for about 1-2 minutes until the mixture begins to thicken.
- As the blender runs on high speed, watch in amazement as the ingredients magically transform into a thick and creamy mayo consistency. This emulsification process is what gives vegan mayo its signature texture. Be patient and keep blending until you achieve the desired creamy consistency.
- Transfer the creamy vegan mayo into a clean jar or airtight container. Seal it tightly and refrigerate for at least 30 minutes to allow the flavors to meld together. Your homemade vegan mayo will stay fresh for up to one week, ready to enhance your culinary creations.
Keywords: vegan mayo recipe


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When you are in your weakest form, that's when you will realise
the ones who will be there for you.You need to have bad days in your life for you to find out who are the real people and not.
Tough times will reveal the real colours of the people who aren't supportive since the beginning.
Download the HelloTalk app to join the conversation.


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Project WILD
Educator Workshop
Course Details
Project WILD is a curriculum companion that has a wide array of activities and lessons tailored to teaching and learning outside.
Project WILD is based on educational standards, developed by scientists, and reviewed and field tested by educators. The interdisciplinary Canadian Project WILD guide features 121 complete lesson plans about wildlife and the environment that can each be adapted for any age, grade level or subject and every participant will leave with their own copy! Mathematics lessons, writing assignments, art lessons and more can be found in the pages of the Project WILD resource Manual.
Course Schedule
What it's all about
With the Project WILD activity guide, you'll explore topics and concepts such as:
Carrying capacity
Food webs
Life stages and life cycles
Renewable and non-renewable resources
Symbiosis, commensalism, mutualism and parasitism
And much more!
Why you'll love it
Project WILD helps learners develop the awareness, knowledge, skills and commitment needed to make informed decisions and to take constructive action for wildlife, habitat and the environment.
Activities are designed to be infused into mandated curriculum subjects such as art, health, language arts, math, music, physical education, science and social studies.
The guide can be used by both classroom teachers and non-formal educators, including resource specialists, conservation officers, camp counsellors and Scout and Guide leaders.
The guide contains all the information needed to successfully plan and run each activity (objectives, method, background, list of materials, procedures, evaluation suggestions, activity extensions, key vocabulary, etc.).
Ready to go WILD? Project WILD activity guides can be obtained by participating in an introductory workshop where you will become a certified WILD Educator.
Cancellation Policy
We operate our courses rain or shine, UNLESS our guide(s) deem it unsafe due to lightning or heavy rains and/or unsafe water conditions such as high waves or strong winds. We typically adjust the course to remain safe. We MAY cancel tours due to low enrolment if we have less than 4 participants.
In light of this, any cancelations initiated by Wilderland Adventure Co. will be fully refunded.
Cancelations initiated by participants are subject to the following terms:
1. Cancelations made more than 21 days in advance of the tour start date are fully refundable.
2. Cancellations made 21 to 14 days in advance of the course start date will forfeit a $25 cancellation fee, and will receive refund of remaining balance paid.
3. Cancellations made less than 14 days in advance of the course start date will forfeit any balance payments made.


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There are a few things that you can do to try and stop your dog from licking a raw spot. One thing that you can try is to put a bandage on the raw spot. You can also try putting a bitter apple on the raw spot. You can also try spraying the area with bitter apple spray.
What can I put on my dogs raw skin?
There are a few things that can be put on a dog's raw skin. Some people prefer to use a cream, while others use a paste or powder. Some people also like to use a bandage.
What to put on dogs skin to stop licking?
There are a few things you can put on your dog's skin to stop them from licking. Some people recommend using lip balm, vaseline, or petroleum jelly. Others simply recommend keeping the dog away from areas they like to lick and rewarding them with treats when they stop.
What your dog is trying to warn about if they lick their paws Dr Marty?
If your dog licks their paws, it could mean that they have something on their paws that they don't want you to see. It could be something small like a piece of grass or a bug, or it could be something bigger, like a snake. If your dog is licking their paws a lot, it might mean that they are feeling anxious or scared.
Is excessive licking a sign of pain in dogs?
There is no definitive answer to this question as it can depend on the individual dog and what triggers their licking behavior. Some dogs may lick excessively when they are in pain, while others may do so as a way of calming themselves. If your dog is licking excessively and it is causing them discomfort or distress, you should speak to a veterinarian about the possibility of treating their pain.
How do you treat a dog's lick spot?
There are a few things you can do to treat a dog's lick spot. You can use a squirt bottle filled with water or apple cider vinegar to mist the area and then rub it in. You can also try using a pet toy that has been dipped in chicken broth or tomato sauce.
What to put on a dog's sore from scratching?
There are many things that can be put on a dog's sore from scratching. Some people recommend using a cream or ointment, while others recommend using a bandage. It really depends on the severity of the scratch and what the person believes will work best.
What is the best anti itch medicine for dogs?
There are many different types of anti itch medicines for dogs, but some of the most popular include Benadryl and Zyrtec. It is important to choose the right medicine for your dog, as each one has different side effects and requirements.
Can you use human hydrocortisone cream on dogs?
There is no definitive answer to this question as it depends on the specific dog and cream. However, many veterinarians believe that using human hydrocortisone cream on dogs can be effective in relieving some of the symptoms of corticosteroid withdrawal, such as diarrhea, vomiting, and lethargy. It is always best to speak with a veterinarian before using any type of medication or cream on a pet.
What can I give my dog orally for itchy skin?
There are a few things that can be given orally to a dog with itchy skin. Some of these include antihistamines, topical flea and tick products, and probiotics.
What causes excessive licking in dogs?
There are a few potential causes of excessive licking in dogs. One possibility is that the dog is trying to soothe itself after feeling anxious or scared. Another possibility is that the dog is trying to clean itself excessively. Finally, some dogs may lick excessively due to boredom or because they are responding to something they smell, such as food or another dog.
Can you give a dog Benadryl to stop itching?
There are a few things you can do to try and stop your dog from itching. First, you can try giving them a bath. This will help to remove any oils or sweat that may be contributing to the itching. You can also give them a topical treatment such as Benadryl ointment. Finally, you can try using a canine antihistamine like Benadryl on a daily basis.
How do I know if my dog has a yeast infection on his paws?
Yeast infections are common in dogs, but can also be seen in cats. The most common sign is a yellow discharge from the dog's paws. If you see this, your veterinarian will likely prescribe medication to clear up the infection.
Can dogs lick themselves raw?
There is no evidence to suggest that dogs can lick themselves raw. In fact, licking oneself can cause skin irritation and even infection. Dogs are typically very careful when licking their fur, and would likely avoid doing so if it were harmful.


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Coronavirus Case Update: Oct. 12, 2020
YOUNGSTOWN, Ohio – The Ohio Department of Health reports 4,077 new cases of COVID-19 since Friday to bring the cumulative number of cases in the state to 170,179, as well as 5,005 total deaths – up 11 since Friday. The Pennsylvania Department of Health reports 173,304 total cases – up 3,996 from Friday – and 8,368 deaths, up 60.
In Mahoning County, the ODH reports 3,388 cases – up 47 from Friday – with 527 hospitalizations and 282 deaths. Mahoning County Public Health reports 3,332 cases.
The ODH reports 2,093 cases in Trumbull County – up 30 from Friday – with 355 hospitalizations and 133 deaths. In Columbiana County, the ODH reports 2,024 positive cases – 18 new cases from Friday – along with 226 hospitalizations and 86 deaths.
Mahoning and Trumbull counties both were upgraded on Thursday to Red in the state's color-coded Public Health Advisory System, indicating very high exposure and spread. Columbiana County has an Orange rating, indicating increased exposure and spread.
Of the total cases reported by ODH, 160,321 are confirmed. ODH reported 9,858 probable cases based on the CDC's expanded case definition. There have been 16,442 hospitalizations and 3,434 intensive care admissions, as well as 5,005 total deaths, which breaks down to 4,697 confirmed deaths and another 308 probable deaths under the CDC expanded diagnosis definition. The 21-day reported case average is 1,191.
The state reports a presumed 143,826 Ohioans have recovered after testing positive. Presumed recovered is defined as cases with a symptom onset date of greater than 21 days prior who are not deceased, according to the ODH website.
Thus far, Ohio has conducted 3,652,066 tests. CLICK HERE for a map of testing locations in the state.
The Pennsylvania Department of Health reports 173,304 total cases, with 725 people hospitalized with 81 on ventilators. The commonwealth reports 8,368 COVID-related deaths thus far. Of the cases reported, 167,068 are confirmed.
Of all tests conducted in Pennsylvania, 2,044,706 were reported negative. With positive cases, 81% have recovered (If a case has not been reported as a death and it is more than 30 days past the date of their first positive test or onset of symptoms, then the person is considered recovered, according to the health department's website).
Mercer County has 831 total cases – up 29 from Friday – and 25 deaths with 12,798 negative tests, while Lawrence County has 628 total cases – 26 new cases from Friday – and 23 deaths, as well as 8,300 negative tests.
The figures are updated daily by the Ohio Department of Health at 2 p.m. and Pennsylvania Department of Health at noon.
For more stories on the coronavirus and its impact on businesses, both locally and nationally, go to our coronavirus news page here.
Copyright 2024 The Business Journal, Youngstown, Ohio.


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Amber Round
The legacy of the rally "Amber Volga" began in 1964, when the first automobile speed competition organized by the physical training body of Riga Taxi Park was held. The competition was held on the asphalt loops of Riga Culture and Leisure Park "Mezaparks", instead of Bikernieku racetrack, which had not yet been built.
Since 1968, the competition was transferred to the new Bikernieku motor sport racetrack. It became the most prestigious race in the former Soviet Union, and it included participants not only from the Baltic States, Leningrad, Moscow and Minsk, but also from distant Krasnodar and Tashkent. Traditionally, this competition was held in autumn, when, despite frequent raining, it was widely attended.
The "Amber Volga" was organized for the last time in 1991. Afterwards, the competition was renamed "Amber Round" for another couple of years. Not long after this the event was discontinued entirely. Fortunately, this historical and legendary race was renewed in 2010.
In 2015, the race was organized in six stages, where the participants competed for places in five test classes – VAZ 1300, VAZ 1600, "Volga", "Formula Easter" and "Formula Mondial". The most widely represented class was "Volga". Competition stages took places in Latvia, Estonia and Russia.
In cooperation with organizers of the competition, we deliver "Falken" tires to the participants of the "Amber Round".


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Blanket Shipping Ban
We have had 55 millimetres of rain since Saturday afternoon and it is still raining intermittently now. Fortunately, unlike other parts of Greece which have experienced flash floods and mud slides, the rain on Symi has been steady and the island is soaking it up well. There is a blanket shipping ban in effect today so the only maritime movement is the coastguard patrol and the water ship. There is a south westerly Force 8 blowing up into the Aegean and it is rough off shore. Nimos and the rocks are fringed with white. There is a big 3 masted gulet in the harbour at the moment and it has warps out in all directions. Mean little squalls are whipping across the harbour, hurling rain and spray at our windows and rattling the shutters.
The last visitors resident on the island are mooching about, waiting for shipping updates and worrying if they will be able to catch their flights from Rhodes. This is a problem with late season traveling – some years October passes without any serious weather problems and other years ferries are cancelled and flights missed. In the fifteen years I have lived on the island I have never been able to quite make up my mind which conditions could be regarded as 'normal' for Symi in October – aside from the obviously unpredictable!
Have a good week.


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1. Introduction to Criminal Law
2. Theories of Punishment
4. Inchoate Crimes
5. Homicide and Murder
6. Theft Crimes
View Index
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Murder Part II; Intent to Kill
In this video, you should consider the following:
- Immediate Intent to kill that results in death is murder.
- Premeditated intent to kill that results in death is also murder.
Delivered by:Professor Melissa A. Hale


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Arrested Development: Season 2
In 20th Century Fox Home Entertainment's release of the second season of the comedy series "Arrested Development," the studio has once again added a hidden extra, tucked away from immediate view.
Insert the third disc of the DVD set in your player and from the Main Menu go to the Episodes selection. There, highlight the entry" The Immaculate Election" and then press the "Left" arrow key on your remote control to get th complete election videos of 'George-Michael, Steve Holt and the Indian kid.