Establishment of the Embryonic Shoot Meristem Involves Activation of Two Classes of Genes with Opposing Functions for Meristem Activities.

The shoot meristem, a stem-cell-containing tissue initiated during plant embryogenesis, is responsible for continuous shoot organ production in postembryonic development. Although key regulatory factors including KNOX genes are responsible for stem cell maintenance in the shoot meristem, how the onset of such factors is regulated during embryogenesis is elusive. Here, we present evidence that the two KNOX genes STM and KNAT6 together with the two other regulatory genes BLR and LAS are functionally important downstream genes of CUC1 and CUC2, which are a redundant pair of genes that specify the embryonic shoot organ boundary. Combined expression of STM with any of KNAT6, BLR, and LAS can efficiently rescue the defects of shoot meristem formation and/or separation of cotyledons in cuc1cuc2 double mutants. In addition, CUC1 and CUC2 are also required for the activation of KLU, a cytochrome P450-encoding gene known to restrict organ production, and KLU counteracts STM in the promotion of meristem activity, providing a possible balancing mechanism for shoot meristem maintenance. Together, these results establish the roles for CUC1 and CUC2 in coordinating the activation of two classes of genes with opposite effects on shoot meristem activity.

Autosomal dominant optic atrophy with OPA1 gene mutations accompanied by auditory neuropathy and other systemic complications in a Japanese cohort.

Purpose: This study aimed to describe the genetic and clinical characteristics of four Japanese patients with autosomal dominant optic atrophy (DOA) accompanied by auditory neuropathy and other systemic complications (i.e., DOA-plus disease). Methods: Four patients from four independent families underwent comprehensive ophthalmic and auditory examinations and were diagnosed with DOA-plus disease. The disease-causing gene variants in the OPA1 gene were identified by direct sequencing. The genetic and clinical data of 48 DOA patients without systemic complications-that is, with simple DOA-were compared to those of DOA-plus patients. Results: DOA-plus patients noticed a decrease in vision before the age of 14 and hearing impairment 3 to 13 years after the development of visual symptoms. Two patients had progressive external ophthalmoplegia, and one patient had vestibular dysfunction and ataxia. The DOA-plus phenotypes accounted for 13.3% (4/30) of the families with the OPA1 gene mutations. Each DOA-plus patient harbored one of the monoallelic mutations in the OPA1 gene: c.1334G>A, p.R445H, c.1618A>C, p.T540P, and c.892A>C, p.S298R. Missense mutations accounted for 100% (4/4) of the DOA-plus families and only 11.5% (3/26) of the families with simple DOA. Conclusions: All the patients with the DOA-plus phenotype carried one of the missense mutations in the OPA1 gene. They all had typical ocular symptoms and signs of DOA in their first or second decade, and other systemic complications-such as auditory neuropathy, vestibular dysfunction, and ataxia-followed the ocular symptoms. We should consider the occurrence of extraocular complications in cases with DOA, especially when they carry the missense mutations in the OPA1 gene.

[BRAF Inhibitor-Induced Erythema Nodosum-Like Lesions].

BRAF inhibitors have been licensed for the treatment of unresectable or metastatic BRAF-mutated melanomas. In Japan, the BRAF inhibitor vemurafenib has been available since December 2014. Several adverse events induced by BRAF inhibitors have been reported, such as Stevens-Johnson syndrome, toxic epidermal necrosis, squamous cell carcinoma, secondary melanoma, and hand-foot syndrome. Recently, inflammatory skin lesions clinically resembling erythema nodosum have been reported as side effects that may lead to treatment discontinuation. In this report, we described the first Japanese case of erythema nodosum-like lesions induced by vemurafenib and discussed the countermeasures to this adverse reaction. Dose reduction or interruption of BRAF inhibitors should be considered on a case-by-case basis because the condition may resolve spontaneously or under symptomatic treatment. We postulate that erythema nodosum-like lesions can be controlled by careful follow-up and supportive care.

O2-dependent large electron flow functioned as an electron sink, replacing the steady-state electron flux in photosynthesis in the cyanobacterium Synechocystis sp. PCC 6803, but not in the cyanobacterium Synechococcus sp. PCC 7942.

To determine whether alternative electron flow (AEF) can replace the photosynthetic electron flow in cyanobacteria, we used an open O2-electrode system to monitor O2-exchange over a long period. In air-grown Synechocystis sp. PCC 6803 (S. 6803(WT)), the quantum yield of PSII, Y(II), held even after photosynthesis was suppressed by CO2 shortage. The S. 6803 mutant, deficient in flavodiiron (FLV) proteins 1 and 3, showed the same phenotype as S. 6803(WT). In contrast, Y(II) decreased in Synechococcus sp. PCC 7942 (S. 7942). These results suggest that AEF functioned as the Y(II) in S. 6803 and replaced the photosynthetic electron flux. In contrast, the activity of AEF in S. 7942 was lower. The affinity of AEF for O2 in S. 6803 did not correspond to those of FLVs in bacteria or terminal oxidases in respiration. AEF might be driven by photorespiration.

Cutaneous manifestations of Helicobacter cinaedi infection.

Helicobacter cinaedi causes gastroenteritis and bacter-aemia, particularly in immunocompromised individuals. Although cellulitis is sometimes reported to accompany infection by this pathogen, the cutaneous manifestations are poorly understood. To clarify the characteristic cutaneous features, 47 cases of H. cinaedi bacteraemia experienced at Sapporo City General Hospital as nosocomial infection were retrospectively evaluated. Thirty-four percent (16 cases) of the patients showed cutaneous lesions. They all had sudden onset of erythemas accompanied by high temperature. The most common cutaneous manifestations were found to be superficial cellulitis, which results in painful erythemas or infiltrated erythematous plaques on the extremities. These skin lesions can be an early clinical indicator of H. cinaedi bacteraemia in the setting of nosocomial infection.

Secukinumab-induced oral lichen planus in a psoriatic arthritis patient ameliorated after a switch to risankizumab.

Lichen planus is a chronic T-cell-mediated disorder in which lymphocytes, including Th17 cells, react toward the dermo-epidermal junction, which shows interface changes. Recently, IL-17-mediated changes in the oral mycobiome, including the proliferation of Candida and Aspergillus fungi, have been proposed as a possible pathomechanism of oral lichen planus (OLP). We treated a 54-year-old male who had been suffering from psoriatic arthritis. Secukinumab rapidly improved the skin and joint symptoms, but a painful erosion on the lip and thrush on the buccal mucosa appeared within 4 weeks. The erosion was histopathologically diagnosed as OLP. Although the candidiasis was successfully treated with topical miconazole nitrate, the labial OLP worsened during the secukinumab administration, despite the application of various topical agents. We finally switched from secukinumab to risankizumab, an anti-IL-23p19 agent, which dramatically improved the patient's OLP lesion in 4 weeks without candidiasis recurrence. Anti-IL-23p19 agents do not affect the oral mycobiome, and they are a potential therapeutic option for refractory OLP, including OLP induced by biologics.

Pediatric allergies in Japan: Coronavirus disease pandemic-related risk factors.

Background: The coronavirus disease 2019 (COVID-19) pandemic impacted various parts of society, including Japanese children with allergies. Objective: This study investigated risk factors for pediatric allergic diseases associated with the state of emergency owing to the COVID-19 pandemic in Japan, including during school closures. Methods: Parents of pediatric patients (0-15 years) with allergies were enrolled and queried regarding the impact of school closure on pediatric allergies compared to that before the COVID-19 pandemic. Results: A valid response was obtained from 2302 parents; 1740 of them had children with food allergies. Approximately 4% (62/1740) of the parents reported accidental food allergen ingestion was increased compared to that before the COVID-19 pandemic. Accidental ingestion during school closures was associated with increased contact with meals containing allergens meant for siblings or other members of the family at home. The exacerbation rate during the pandemic was highest for atopic dermatitis at 13% (127/976), followed by allergic rhinitis at 8% (58/697), and bronchial asthma at 4% (27/757). The main risk factors for worsening atopic dermatitis, allergic rhinitis, and bronchial asthma were contact dermatitis of the mask area (34/120 total comments); home allergens, such as mites, dogs, and cats (15/51 total comments); and seasonal changes (6/25 total comments), respectively. Conclusion: The main factors affecting allergic diseases were likely related to increased time at home, preventive measures against COVID-19, and refraining from doctor visits. Children with allergies were affected by changes in social conditions; however, some factors, such as preventing accidental ingestion and the management of allergens at home, were similar to those before the COVID-19 pandemic. Patients who had received instructions on allergen avoidance at home before the pandemic were able to manage their disease better even when their social conditions changed.

CUP-SHAPED COTYLEDON1 transcription factor activates the expression of LSH4 and LSH3, two members of the ALOG gene family, in shoot organ boundary cells.

The establishment of organ boundaries is a fundamental process for proper morphogenesis in multicellular organisms. In plants, the shoot meristem repetitively forms organ primordia from its periphery, and boundary cells are generated between them to separate their cellular fates. The genes CUP-SHAPED COTYLEDON1 (CUC1) and CUC2, which encode plant-specific NAC transcription factors, play central roles in establishment of the shoot organ boundaries in Arabidopsis thaliana. Here we show that CUC1 protein activates expression of LIGHT-DEPENDENT SHORT HYPOCOTYLS 4 (LSH4) and its homolog LSH3 in shoot organ boundary cells. Both genes encode nuclear proteins of the Arabidopsis LSH1 and Oryza G1 (ALOG) family, the members of which are widely conserved in land plants. Expression of LSH4 and LSH3 is detected in the boundary cells of various shoot organs, such as cotyledons, leaves and floral organs, and requires the activity of CUC1 and CUC2. Experiments using the glucocorticoid receptor system indicate that transcription of LSH4 and LSH3 is directly up-regulated by CUC1. Constitutive expression of LSH4 in the shoot apex causes inhibition of leaf growth in the vegetative phase, and formation of extra shoots or shoot organs within a flower in the reproductive phase. Together, our results indicate that CUC1 directly activates transcription of the nuclear factor genes LSH4 and LSH3, which may suppress organ differentiation in the boundary region.

Loss of epidermal Langerhans cells in psoriasiform lesions of de novo induced or worsened pre-existing psoriasis following uses of immune checkpoint inhibitors.

Immune checkpoint inhibitors (ICI), including monoclonal antibodies to programmed death 1, programmed death ligand 1, and cytotoxic T lymphocyte-associated antigen 4, have provided great therapeutic benefits for cancer patients at advanced stages. However, the introduction of ICI frequently results in the development of immune-related adverse events (irAE) through activation of autoreactive T cells. Here, we present three cases of cancer patients with cutaneous irAE, including development of de novo psoriasis and exacerbation of pre-existing psoriasis. Interestingly, these patients shared an altered histological feature characterized by loss of epidermal CD1a+ cells, namely Langerhans cells (LC), in the psoriasiform lesions in contrast to "conventional psoriasis" exhibiting unchanged or activated LC. A possible underlying mechanism was that ICI-mediated hyperactivation of effector T cells contributed to aggravation or establishment of psoriasis phenotype, which might be associated with direct cytotoxicity or expulsion of LC from the epidermis.

Sensitivity of malignant rhabdoid tumor cell lines to PD 0332991 is inversely correlated with p16 expression.

Malignant rhabdoid tumor (MRT) is a rare and highly aggressive neoplasm of young children. MRT is characterized by inactivation of integrase interactor 1 (INI1). Cyclin-dependent kinase 4 (CDK4), which acts downstream of INI1, is required for the proliferation of MRT cells. Here we investigated the effects of PD 0332991 (PD), a potent inhibitor of CDK4, against five human MRT cell lines (MP-MRT-AN, KP-MRT-RY, G401, KP-MRT-NS, KP-MRT-YM). In all of the cell lines except KP-MRT-YM, PD inhibited cell proliferation >50%, (IC(50) values 0.01 to 0.6 µM) by WST-8 assay, and induced G1-phase cell cycle arrest, as shown by flow cytometry and BrdU incorporation assay. The sensitivity of the MRT cell lines to PD was inversely correlated with p16 expression (r=0.951). KP-MRT-YM cells overexpress p16 and were resistant to the growth inhibitory effect of PD. Small interfering RNA against p16 significantly increased the sensitivity of KP-MRT-YM cells to PD (p<0.05). These results suggest that p16 expression in MRT could be used to predict its sensitivity to PD. PD may be an attractive agent for patients with MRT whose tumors express low levels of p16.

A Case of Guillain-Barré Syndrome and Stevens-Johnson Syndrome/Toxic Epidermal Necrosis Overlap After Pembrolizumab Treatment.

A 76-year-old man was admitted to our hospital with Guillain-Barré syndrome (GBS), presenting with facial palsy, dysarthria, and dysphagia as Grade 3 immune-related adverse events (irAEs) due to pembrolizumab administration for Stage IV lung adenocarcinoma. Although prednisolone (1 mg/kg) was started for GBS due to the irAE, dark erythema and skin eruptions appeared on the patient's torso. Then erosion was observed on 18% of the body surface area and skin biopsy was performed. Finally, the patient was diagnosed with Stevens-Johnson syndrome/toxic epidermal necrosis overlap. Intravenous immunoglobulin therapy was started, and the skin symptoms improved, with the erosion becoming epithelial. He died of aspiration pneumonia related to GBS, although his neurological symptoms had improved after steroid and intravenous immunoglobulin therapy. This is the first reported case of pembrolizumab-induced GBS and Stevens-Johnson syndrome/toxic epidermal necrosis overlap. It is necessary to be careful that the possibility of other severe irAEs may occur simultaneously.