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The physiological functions of progesterone (P4) in female reproductive organs including the mammary glands are mediated via the progesterone receptor (PR), but not all P4 functions can be explained by PR-mediated signaling. Progesterone receptor membrane component 1 (PGRMC1), a potential mediator of P4 actions, plays an important role in the ovary and uterus in maintaining female fertility and pregnancy, but its function in mammary glands has not been elucidated. This study investigated the role of PGRMC1 in mouse mammary gland development. Unlike in the uterus, exogenous estrogen (E2) and/or P4 did not alter PGRMC1 expression in the mammary gland, and Pgrmc1-knockout (KO) mice displayed reduced ductal elongation and side branching in response to hormone treatment. During pregnancy, PGRMC1 was expressed within both the luminal and basal epithelium and gradually increased with gestation and decreased rapidly after parturition. Moreover, although lactogenic capacity was normal after parturition, Pgrmc1 KO resulted in defective mammary gland development from puberty until midpregnancy, while the expression of PR and its target genes was not significantly different between wild-type and Pgrmc1-KO mammary gland. These data suggest that PGRMC1 is essential for mammary gland development during puberty and pregnancy in a PR-independent manner.

X-linked adrenoleukodystrophy (ALD), an inherited neurometabolic disorder caused by mutations in ABCD1, which encodes the peroxisomal ABC transporter, mainly affects the brain, spinal cord, adrenal glands, and testes. In ALD patients, very-long-chain fatty acids (VLCFAs) fail to enter the peroxisome and undergo subsequent β-oxidation, resulting in their accumulation in the body. It has not been tested whether in vivobase editing or prime editing can be harnessed to ameliorate ALD. We developed a humanized mouse model of ALD by inserting a human cDNA containing the pathogenic variant into the mouse Abcd1locus. The humanized ALD model showed increased levels of VLCFAs. To correct the mutation, we tested both base editing and prime editing and found that base editing using ABE8e(V106W) could correct the mutation in patient-derived fibroblasts at an efficiency of 7.4%. Adeno-associated virus (AAV)-mediated systemic delivery of NG-ABE8e(V106W) enabled robust correction of the pathogenic variant in the mouse brain (correction efficiency: ∼5.5%), spinal cord (∼5.1%), and adrenal gland (∼2%), leading to a significant reduction in the plasma levels of C26:0/C22:0. This established humanized mouse model and the successful correction of the pathogenic variant using a base editor serve as a significant step toward treating human ALD disease.

Asb2, ankyrin repeat, and SOCS box protein 2 form an E3 ubiquitin ligase complex. Asb2 ubiquitin ligase activity drives the degradation of filamins, which have essential functions in humans.

Radiation-induced lung injury (RILI) due to nuclear or radiological exposure remains difficult to treat because of insufficient clinical data. The goal of this study was to establish an appropriate and efficient minipig model and introduce a thoracic computed tomography (CT)-based method to measure the progression of RILI. Go&x0308;ttingen minipigs were allocated to control and irradiation groups. The most obvious changes in the CT images after irradiation were peribronchial opacification, interlobular septal thickening, and lung volume loss. Hounsfield units (HU) in the irradiation group reached a maximum level at 6 weeks and decreased thereafter, but remained higher than those of the control group. Both lung area and cardiac right lateral shift showed significant changes at 22 weeks post irradiation. The white blood cell (WBC) count, a marker of pneumonitis, increased and reached a maximum at 6 weeks in both peripheral blood and bronchial alveolar lavage fluid. Microscopic findings at 22 weeks post irradiation were characterized by widening of the interlobular septum, with dense fibrosis and an increase in the radiation dose–dependent fibrotic score. Our results also showed that WBC counts and microscopic findings were positively correlated with the three CT parameters. In conclusion, the minipig model can provide useful clinical data regarding RILI caused by the adverse effects of high-dose radiotherapy. Peribronchial opacification, interlobular septal thickening, and lung volume loss are three quantifiable CT parameters that can be used as a simple method for monitoring the progression of RILI.

Nanoscale grating patterns with indium--zinc-oxide (IZO) layer have been successfully fabricated by ultraviolet (UV) nanoimprinting technique and sputter deposition process. Nanoscale groove prepared here can play important roles as alignment layers as well as conducting electrodes. Performance for LC alignment was tested by evaluating order parameter. A preliminary version of twist nematic (TN) LC cell with the nanopattern coated IZO was also fabricated and evaluated.