Lateral olfactory tract usher substance (LOTUS), an endogenous Nogo receptor antagonist, ameliorates disease progression in amyotrophic lateral sclerosis model mice.

Nogo-Nogo receptor 1 (NgR1) signaling is significantly implicated in neurodegeneration in amyotrophic lateral sclerosis (ALS). We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of NgR1 that prevents all myelin-associated inhibitors (MAIs), including Nogo, from binding to NgR1. Here we investigated the role of LOTUS in ALS pathogenesis by analyzing G93A-mutated human superoxide dismutase 1 (SOD1) transgenic (Tg) mice, as an ALS model, as well as newly generated LOTUS-overexpressing SOD1 Tg mice. We examined expression profiles of LOTUS and MAIs and compared motor functions and survival periods in these mice. We also investigated motor neuron survival, glial proliferation in the lumbar spinal cord, and neuromuscular junction (NMJ) morphology. We analyzed downstream molecules of NgR1 signaling such as ROCK2, LIMK1, cofilin, and ataxin-2, and also neurotrophins. In addition, we investigated LOTUS protein levels in the ventral horn of ALS patients. We found significantly decreased LOTUS expression in both SOD1 Tg mice and ALS patients. LOTUS overexpression in SOD1 Tg mice increased lifespan and improved motor function, in association with prevention of motor neuron loss, reduced gliosis, increased NMJ innervation, maintenance of cofilin phosphorylation dynamics, decreased levels of ataxin-2, and increased levels of brain-derived neurotrophic factor (BDNF). Reduced LOTUS expression may enhance neurodegeneration in SOD1 Tg mice and ALS patients by activating NgR1 signaling, and in this study LOTUS overexpression significantly ameliorated ALS pathogenesis. LOTUS might serve as a promising therapeutic target for ALS.

Dual functions of discoidinolysin, a cholesterol-dependent cytolysin with N-terminal discoidin domain produced from Streptococcus mitis strain Nm-76.

Background: Some strains of Streptococcus mitis exhibit ß-hemolysis due to the ß-hemolytic activity of cholesterol-dependent cytolysin (CDC). Recently, a gene encoding an atypical lectinolysin-related CDC was found in S. mitis strain Nm-76. However, the product of this gene remains uncharacterized. We aimed to characterize this atypical CDC and its molecular functions and contribution to the pathogenicity of S. mitis strain Nm-76. Methods: Phylogenetic analysis of the CDC gene was conducted based on the web-deposited information. The molecular characteristics of CDC were investigated using a gene-deletion mutant strain and recombinant proteins expressed in Escherichia coli. Results: The gene encoding CDC found in Nm-76 and its homolog are distributed among many S. mitis strains. This CDC is phylogenetically different from other previously characterized CDCs, such as S. mitis-derived human platelet aggregation factor (Sm-hPAF)/lectinolysin and mitilysin. Because this CDC possesses an additional N-terminal domain, including a discoidin motif, it was termed discoidinolysin (DLY). In addition to the preferential lysis of human cells, DLY displayed N-terminal domain-dependent facilitation of human erythrocyte aggregation and intercellular associations between human cells. Conclusion: DLY functions as a hemolysin/cytolysin and erythrocyte aggregation/intercellular association molecule. This dual-function DLY could be an additional virulence factor in S. mitis.

Pulmonary actinomycosis mimicking lung cancer on 18F-fluorodeoxyglucose positron emission tomography: a case report.

BACKGROUND: Pulmonary actinomycosis is a chronic disease characterized by abscess formation, draining sinuses, fistulae, and tissue fibrosis. It can mimic other conditions, particularly malignant and granulomatous diseases, and is perhaps extremely challenging to diagnose. CASE PRESENTATION: A 64-year-old Japanese man presented with 6-week history of a painful solid lump in the chest wall. Chest computed tomography scan revealed a mass-like consolidation in the left upper lobe, with rib erosion and direct extension into the anterior chest wall. 18F-fluorodeoxyglucose positron emission tomography scan showed increased metabolic activity in the mass, which is indicative of primary lung cancer. The bronchoscopy and computed tomography scan-guided transthoracic biopsy results were considered nondiagnostic. Finally, the patient was diagnosed with pulmonary actinomycosis via surgical resection. He completed an 8-week course of antibiotic therapy and experienced no recurrence. CONCLUSIONS: There is no difference in positron emission tomography/computed tomography scan findings between actinomycosis and malignancy. Therefore, pulmonary actinomycosis should be considered in the differential diagnosis of cases involving intensive activity on 18F-fluorodeoxyglucose positron emission tomography scan.

Efficacy of specimen pasting after cold snare polypectomy for pathological evaluation of horizontal margins.

Background and study aims Several studies have reported that pathological horizontal margin evaluation cannot be diagnosed in cold snare polypectomy (CSP) specimens. We conducted a prospective randomized controlled trial to determine the efficacy of pasting CSP specimens on paper for pathological horizontal margins. Patients and methods This was a single-center, prospective study conducted at Osaka Saiseikai Nakatsu Hospital. In this study, the indications for CSP were adenomas ≤ 10 mm. Colorectal polyps resected by CSP were randomized to the pasting and non-pasting groups after exclusion of fragmented specimens, and the extended CSP specimens pasted on paper were formalin-fixed in the pasting group. The primary endpoint was rate of unclear horizontal margins after CSP. Results A total of 216 CSP specimens were analyzed. The rate of unclear horizontal margins was significantly lower in the pasting group than in the non-pasting group (15.1 % vs 33.6 %, P  = 0.002). CSP specimen pasting significantly reduced the rate of unclear horizontal margins. On multivariate analysis, non-pasting group (odds ratio [OR], 2.69; 95 % confidence interval [CI], 1.38-5.41; P  = 0.003) and right colon (OR, 1.98; 95 %CI, 1.01-4.01; P  = 0.047) were independent risk factors for unclear horizontal margins in CSP specimens. Conclusions Pasting the extended specimen is important for accurate pathological examination after CSP.

Inhibition of Crmp1 Phosphorylation at Ser522 Ameliorates Motor Function and Neuronal Pathology in Amyotrophic Lateral Sclerosis Model Mice.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal neurodegenerative disorder that affects upper and lower motor neurons; however, its pathomechanism has not been fully elucidated. Using a comprehensive phosphoproteomic approach, we have identified elevated phosphorylation of Collapsin response mediator protein 1 (Crmp1) at serine 522 in the lumbar spinal cord of ALS model mice overexpressing a human superoxide dismutase mutant (SOD1G93A). We investigated the effects of Crmp1 phosphorylation and depletion in SOD1G93A mice using Crmp1S522A (Ser522→Ala) knock-in (Crmp1ki/ki ) mice in which the S522 phosphorylation site was abolished and Crmp1 knock-out (Crmp1-/-) mice, respectively. Crmp1ki/ki /SOD1G93A mice showed longer latency to fall in a rotarod test while Crmp1-/-/SOD1G93A mice showed shorter latency compared with SOD1G93A mice. Survival was prolonged in Crmp1ki/ki /SOD1G93A mice but not in Crmp1-/-/SOD1G93A mice. In agreement with these phenotypic findings, residual motor neurons and innervated neuromuscular junctions (NMJs) were comparatively well-preserved in Crmp1ki/ki /SOD1G93A mice without affecting microglial and astroglial pathology. Pathway analysis of proteome alterations showed that the sirtuin signaling pathway had opposite effects in Crmp1ki/ki /SOD1G93A and Crmp1-/-/SOD1G93A mice. Our study indicates that modifying CRMP1 phosphorylation is a potential therapeutic strategy for ALS.

Anchored Palladium Complex-Generated Clusters on Zirconia: Efficiency in Reductive N-Alkylation of Amines with Carbonyl Compounds under Hydrogen Atmosphere.

Carbon-nitrogen bond formation is an important method on both laboratory and industrial scales because it realizes the production of valuable pharmaceuticals, agrochemicals, and fine chemicals. Direct reductive N-alkylation of amines with carbonyl compounds via intermediary imine compounds, especially under catalytic hydrogenation conditions, is one of the most convenient, economical, and environmentally friendly methods for this process. Here we report a novel palladium species on zirconia having specific activity towards hydrogenation of imines but other carbonyl groups remaining intact. The present catalytic property offers a practical synthetic method of functionalized secondary amines by reductive N-alkylation under mild conditions with high atom-efficiency. Mechanistic studies revealed that the catalytically active species is the palladium cluster, which is generated in situ from molecular palladium complexes on the support by exposure to atmospheric hydrogen. These fundamental findings are expected to progress in developing novel cluster catalysts for chemical processes directed towards a sustainable society.

Proton transfer pathway from the oxygen-evolving complex in photosystem II substantiated by extensive mutagenesis.

We report a structure-based biological approach to identify the proton-transfer pathway in photosystem II. First, molecular dynamics (MD) simulations were conducted to analyze the H-bond network that may serve as a Grotthuss-like proton conduit. MD simulations show that D1-Asp61, the H-bond acceptor of H2O at the Mn4CaO5 cluster (W1), forms an H-bond via one water molecule with D1-Glu65 but not with D2-Glu312. Then, D1-Asp61, D1-Glu65, D2-Glu312, and the adjacent residues, D1-Arg334, D2-Glu302, and D2-Glu323, were thoroughly mutated to the other 19 residues, i.e., 114 Chlamydomonas chloroplast mutant cells were generated. Mutation of D1-Asp61 was most crucial. Only the D61E and D61C cells grew photoautotrophically and exhibit O2-evolving activity. Mutations of D2-Glu312 were less crucial to photosynthetic growth than mutations of D1-Glu65. Quantum mechanical/molecular mechanical calculations indicated that in the PSII crystal structure, the proton is predominantly localized at D1-Glu65 along the H-bond with D2-Glu312, i.e., pKa(D1-Glu65) > pKa(D2-Glu312). The potential-energy profile shows that the release of the proton from D1-Glu65 leads to the formation of the two short H-bonds between D1-Asp61 and D1-Glu65, which facilitates downhill proton transfer along the Grotthuss-like proton conduit in the S2 to S3 transition. It seems possible that D1-Glu65 is involved in the dominant pathway that proceeds from W1 via D1-Asp61 toward the thylakoid lumen, whereas D2-Glu312 and D1-Arg334 may be involved in alternative pathways in some mutants.

Tonsillectomy Improved Therapeutic Response in Anti-SRP Myopathy With Chronic Tonsillitis.

Chronic tonsillitis has been attracted attention as a source of abnormal immune responses and a possible trigger of autoimmune diseases such as IgA nephritis, IgA vasculitis, palmoplantar pustulosis, psoriasis, rheumatoid arthritis, Behçet's disease, and myositis. Here we present the first report of anti-signal recognition particle antibody-associated necrotizing myopathy (anti-SRP myopathy) with IgA nephropathy and chronic tonsillitis in which the therapeutic response to intravenous immunoglobulin (IVIG) treatment was dramatically improved after tonsillectomy and accompanied by a rapid increase in ΔIgG, defined as the change in serum IgG levels 2 weeks after the start of IVIG treatment relative to pre-treatment levels. Moreover, serum anti-SRP antibody titers became undetectable after tonsillectomy even though the resected tonsils did not produce anti-SRP antibodies. Tonsillectomy should be considered when chronic tonsillitis is observed in patients with autoimmune diseases showing poor response to treatment, including anti-SRP myopathy.

Neurogenic pulmonary edema secondary to epileptic seizure.

Neurogenic pulmonary edema (NPE) is a non-cardiogenic pulmonary edema that is caused by an acute central nervous system injury and usually develops rapidly after an injury. Although several episodes of NPE resolve spontaneously, the condition may cause unexpected death among patients with epilepsy.

An EGFR T790M-mutated lung adenocarcinoma undergoing large-cell neuroendocrine carcinoma transformation after osimertinib therapy: a case report.

BACKGROUND: Osimertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, is selective for both epidermal growth factor receptor tyrosine kinase inhibitor-sensitizing and T790M resistance mutations. Almost all patients who initially respond to an epidermal growth factor receptor tyrosine kinase inhibitor subsequently report disease progression. Epidermal growth factor receptor-dependent resistance mechanisms, bypass pathway activation, and histological transformation have been reported with osimertinib therapy. CASE PRESENTATION: We report a case of a 64-year-old Asian man with epidermal growth factor receptor T790M-positive adenocarcinoma that transformed to epidermal growth factor receptor T790M-negative large-cell neuroendocrine carcinoma after osimertinib therapy. A prompt rebiopsy revealed a rare mechanism of resistance to epidermal growth factor receptor tyrosine kinase inhibitor, and subsequently treatment with carboplatin and etoposide was effective. CONCLUSIONS: Despite the promising emergence of circulating tumoral DNA testing, this case report emphasizes the importance of rebiopsy of a progressive epidermal growth factor receptor-mutant tumor.

Coinfection with SARS-CoV-2 and influenza A virus.

Since December 2019, coronavirus disease 2019 (COVID-19) has been an international public health emergency. The possibility of COVID-19 should be considered primarily in patients with new-onset fever or respiratory tract symptoms. However, these symptoms can occur with other viral respiratory illnesses. We reported a case of severe acute respiratory syndrome coronavirus 2 and influenza A virus coinfection. During the epidemic, the possibility of COVID-19 should be considered regardless of positive findings for other pathogens.

Long-read sequencing identifies the pathogenic nucleotide repeat expansion in RFC1 in a Japanese case of CANVAS.

Recently, a recessively inherited intronic repeat expansion in replication factor C1 (RFC1) was identified in cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Here, we describe a Japanese case of genetically confirmed CANVAS with autonomic failure and auditory hallucination. The case showed impaired uptake of iodine-123-metaiodobenzylguanidine and 123I-ioflupane in the cardiac sympathetic nerve and dopaminergic neurons, respectively, by single-photon emission computed tomography. Long-read sequencing identified biallelic pathogenic (AAGGG)n nucleotide repeat expansion in RFC1 and heterozygous benign (TAAAA)n and (TAGAA)n expansions in brain expressed, associated with NEDD4 (BEAN1). Enrichment of the repeat regions in RFC1 and BEAN1 using a Cas9-mediated system clearly distinguished between pathogenic and benign repeat expansions. The haplotype around RFC1 indicated that the (AAGGG)n expansion in our case was on the same ancestral allele as that of European cases. Thus, long-read sequencing facilitates precise genetic diagnosis of diseases with complex repeat structures and various expansions.

Pulmonary mucosa-associated lymphoid tissue lymphoma mimicking lung cancer.

Pulmonary mucosa-associated lymphoid tissue (MALT) lymphoma is the most frequent subset of primary pulmonary lymphoma. MALT lymphoma may manifest as a solid mass, mimicking lung cancer.

Direct phase-locking of a Ti:Sapphire optical frequency comb to a remote optical frequency standard.

We report on an ultralow noise optical frequency transfer from a remotely located Sr optical lattice clock laser to a Ti:Sapphire optical frequency comb through telecom-wavelength optical fiber networks. The inherent narrow linewidth of the Ti:Sapphire optical frequency comb eliminates the need for a local reference high-finesse cavity. The relative fractional frequency instability of the optical frequency comb with respect to the remote optical reference was 6.7(1) × 10-18 at 1 s and 1.05(3) × 10-19 at 1,000 s including a 2.9 km-long fiber network. This ensured the optical frequency comb had the same precision as the optical standard. Our result paves the way for ultrahigh-precision spectroscopy and conversion of the highly precise optical frequency to radio frequencies in a simpler setup.

Transudative chylothorax associated with alcoholic cirrhosis.

We present the case of a 53-year-old man with decompensated alcoholic cirrhosis who was referred for right pleural effusion. After investigation, the patient was ultimately diagnosed with cirrhotic chylothorax. Chylothorax is a rare manifestation of cirrhosis, which results from the trans-diaphragmatic passage of chylous ascites. While chylothorax generally results in an exudative pleural effusion, cirrhotic chylothorax is always a transudative effusion. Biochemical characteristics are useful for diagnosis, avoiding potentially harmful diagnostic and therapeutic procedures.

Birt-Hogg-Dubé syndrome in the elderly.

We present the case of a 73-year-old woman who developed pneumothorax for the first time that was a clinical clue to the diagnosis of Birt-Hogg-Dubé (BHD) syndrome. Although younger onset of pneumothorax is more common in BHD syndrome, the characteristic chest CT findings may contribute to the diagnosis of this disorder in spontaneous pneumothorax of the elderly.

IgA nephropathy with diffuse alveolar haemorrhage.

Immunoglobulin (Ig)A nephropathy is the most common cause of primary glomerulonephritis worldwide. While IgA nephropathy has been associated with a variety of other diseases, pulmonary complications are extremely rare. A 58-year-old man presented with a 2-week history of fever and exertional dyspnoea. A chest imaging revealed bilateral consolidation predominantly in upper lungs. Laboratory findings showed elevated serum creatinine with proteinuria and haematuria. Flexible bronchoscopy revealed diffuse alveolar haemorrhage, and IgA nephropathy was confirmed on a renal biopsy. He received prednisone with good effect. This case highlights the need to consider IgA nephropathy in the differential diagnosis of pulmonary renal syndrome.

Airway foreign body manifested as a coin lesion.

Foreign body aspiration is a potentially life-threatening event. The nature of the inhaled objects is highly variable, ranging from organic to inorganic material. Although most pills are radiolucent, lanthanum carbonate is radiopaque and may be identified on chest X-rays.