Micro-CT imaging reveals<i> Mekk3 </i>heterozygosity prevents cerebral cavernous malformations in <i>Ccm2</i>-deficient mice

Mutations in CCM1 (aka KRIT1), CCM2, or CCM3 (aka PDCD10) gene cause cerebral cavernous malformation in humans. Mouse models of CCM disease have been established by deleting Ccm genes in postnatal animals. These mouse models provide invaluable tools to investigate molecular mechanism and therapeutic approaches for CCM disease. However, the full value of these animal models is limited by the lack of an accurate and quantitative method to assess lesion burden and progression. In the present study we have established a refined and detailed contrast enhanced X-ray micro-CT method to measure CCM lesion burden in mouse brains. As this study utilized a voxel dimension of 9.5μm (leading to a minimum feature size of approximately 25μm), it is therefore sufficient to measure CCM lesion volume and number globally and accurately, and provide high-resolution 3-D mapping of CCM lesions in mouse brains. Using this method, we found loss of Ccm1 or Ccm2 in neonatal endothelium confers CCM lesions in the mouse hindbrain with similar total volume and number. This quantitative approach also demonstrated a rescue of CCM lesions with simultaneous deletion of one allele of Mekk3. This method would enhance the value of the established mouse models to study the molecular basis and potential therapies for CCM and other cerebrovascular diseases

Functional interdependence of BRD4 and DOT1L in MLL leukemia.

Targeted therapies against disruptor of telomeric silencing 1-like (DOT1L) and bromodomain-containing protein 4 (BRD4) are currently being evaluated in clinical trials. However, the mechanisms by which BRD4 and DOT1L regulate leukemogenic transcription programs remain unclear. Using quantitative proteomics, chemoproteomics and biochemical fractionation, we found that native BRD4 and DOT1L exist in separate protein complexes. Genetic disruption or small-molecule inhibition of BRD4 and DOT1L showed marked synergistic activity against MLL leukemia cell lines, primary human leukemia cells and mouse leukemia models. Mechanistically, we found a previously unrecognized functional collaboration between DOT1L and BRD4 that is especially important at highly transcribed genes in proximity to superenhancers. DOT1L, via dimethylated histone H3 K79, facilitates histone H4 acetylation, which in turn regulates the binding of BRD4 to chromatin. These data provide new insights into the regulation of transcription and specify a molecular framework for therapeutic intervention in this disease with poor prognosis

Novel Vitamin and Gold-Loaded Nanofiber Facial Mask for Topical Delivery

l-ascorbic acid has been widely used in cosmetic and dermatological products because of its ability to scavenge free radicals and destroy oxidizing agents. However, it is chemically unstable and can easily be oxidized. The current cosmetic facial masks available in the market are pre-moistened, which means that the aqueous fluid content of the mask may oxidize some of the unstable active ingredients such as ascorbic acid. This work presents an anti-wrinkle nanofiber face mask containing ascorbic acid, retinoic acid, gold nanoparticles, and collagen. This novel face mask will only be wetted when applied to the skin, thus enhancing product stability. Once moistened, the content of the mask will gradually dissolve and release the active ingredients and ensure maximum skin penetration. The high surface area-to-volume ratio of the nanofiber mask will ensure maximum contact with the skin surface and help to enhance the skin permeation to restore its healthy appearance. Electrospun fiber mats may provide an attractive alternative to the commercial facial cotton masks

Development of a depth meter with automatic temperature compensation

85 p.A method to compensate the temperature effect on twin wire resistance probe depth metfiod was presented. Both analog and digital circuits were designed, fabricated, and tested. The error in measurement due to temperature effect could be greatiy reduced.RP-M-24-8

Lipid Vesicles for the Skin Delivery of Diclofenac: Cerosomes vs. Other Lipid Suspensions

Purpose: Lipid suspensions as drug carriers, including conventional liposomes, ethosomes, transferosomes, proniosomes, niosomes, PEG-PPG-PEG niosomes and stratum corneum liposomes (cerosomes), were formulated and compared. Methods: Lipid vesicles were formulated and assessed with regards to enhancement of skin permeation of diclofenac and stability profiles of the formulations. Formulation-induced changes of the biophysical structure of excised human skin were monitored using the Fourier transform infrared spectroscopy. Results: The stability profiles of these suspensions over 12 weeks did not show any significant drug leakage from the vesicles of interest (p > 0.05). FTIR observations indicated that the vesicles increased stratum corneum (SC) lipid fluidization and altered protein conformation. Skin permeability experiments showed that the free unencapsulated drug in the cerosomal formulations caused significant increase in drug permeation across the skin (p < 0.01). Low skin permeability of drug from the other lipid suspensions could be due to the entrapment of diclofenac within these vesicles which decreased the solubility of the hydrophilic drug in the skin lipids and the partition coefficient of the drug from these vesicles into the SC. Conclusion: Optimal drug entrapment in vesicles or alteration of the skin structure may not necessarily enhance the permeation of hydrophilic drugs across the human skin. These lipid vesicles may be further developed into carriers of both hydrophilic and hydrophobic drugs for topical and transdermal delivery, respectively

Effect of cetrimide and ascorbic acid on in vitro human skin permeation of haloperidol

10.1248/cpb.49.1395Chemical and Pharmaceutical Bulletin49111395-1400CPBT

Low regulatory T-cells: A distinct immunological subgroup in minimal change nephrotic syndrome with early relapse following rituximab therapy

10.1016/j.trsl.2021.03.019Translational research : the journal of laboratory and clinical medicine23548-6

T Lymphocyte Activation Markers as Predictors of Responsiveness to Rituximab among Patients with FSGS

10.2215/cjn.119411151181360-