[A Case of Hepatic Undifferentiated Embryonal Sarcoma in an Adult].

A 20-year-old woman was admitted with abdominal pain and a cystic liver tumor. A hemorrhagic cyst was suspected. Contrast-enhanced computed tomography(CT)and magnetic resonance imaging(MRI)revealed a space-occupying solid mass in the right lobule. Positron emission tomography(PET)-CT revealed 18F-fluorodeoxyglucose uptake in the tumor. We performed a right hepatic lobectomy. Histopathological evaluation of the resected tumor revealed an undifferentiated embryonal sarcoma of the liver(UESL). The patient refused adjuvant chemotherapy but showed no recurrence 30 months postoperatively. UESL is a rare malignant mesenchymal tumor that occurs in infants and children. It is extremely rare and is associated with poor prognosis in adults. In this report, we described a case of adult UESL.

[A Case of Laparoscopic Resection Following Preoperative Chemoradiotherapy of a Locally Recurrent Rectal Cancer after a Prior Endoscopic Curative Resection].

A man in his seventies underwent endoscopic mucosal resection(EMR)of a rectal cancer 3 years ago. Histopathological examination showed that the specimen had been resected curatively. However, a routine follow-up colonoscopy revealed a submucosal mass on the EMR scar. Computed tomography imaging revealed a mass in the posterior wall of the rectum, with suspected invasion of the sacrum. We performed a biopsy during endoscopic ultrasonography and diagnosed a local recurrence of the rectal cancer. After preoperative chemoradiotherapy(CRT), laparoscopic low anterior resection with ileostomy was performed. Histopathological examination revealed invasion of the rectal wall from the muscularis propria to the adventitia and tissue fibrosis at the radial margin, which was devoid of cancerous cells. Subsequently, the patient received adjuvant chemotherapy with uracil/tegafur and leucovorin for 6 months. No recurrence has been reported over a postoperative follow- up period of 4 years. Preoperative CRT may be an effective treatment for locally recurrent rectal cancer after endoscopic resection.

Survey of psychiatric symptoms among inpatients with COVID-19 using the Diagnosis Procedure Combination data and medical records in Japan.

Physical symptoms such as fatigue and muscle weakness, and psychiatric symptoms like depression and anxiety are considered as complications and sequelae of COVID-19. This epidemiological study investigated the actual status of psychiatric symptoms and disorders caused by COVID-19, from four major university hospitals and five general hospitals in Fukuoka Prefecture, Japan, having a population of 5 million. We conducted a survey of psychiatric disorders associated with COVID-19 using Diagnosis Procedure Combination (DPC) data and the psychiatric records of the hospitals. In the study period from January 2019 to September 2021, 2743 COVID-19 admissions were determined from DPC data across the nine sites. These subjects had significantly more anxiety, depression, and insomnia, and were receiving higher rates of various psychotropic medications than controls influenza and respiratory infections. A review of psychiatric records revealed that the frequency of organic mental illness with insomnia and confusion was proportional to the severity of COVID-19 infection and that anxiety symptoms appeared independent of infection severity. These results indicate that COVID-19 is more likely to produce psychiatric symptoms such as anxiety and insomnia than conventional infections.

Accuracy of Therapeutic Drug Monitoring of Teicoplanin at the Onset of Febrile Neutropenia.

Background and Objectives: Teicoplanin (TEIC) is an effective drug for patients with febrile neutropenia (FN); however, it has been reported that these patients may have increased TEIC clearance compared with patients who do not have FN. The purpose of this study was to study therapeutic drug monitoring in patients with FN when the TEIC dosing design was based on the population mean method. Materials and Methods: Thirty-nine FN patients with hematological malignancy were included in the study. To calculate the predicted blood concentration of TEIC, we used the two population pharmacokinetic (population PK) parameters (parameters 1 and 2) reported by Nakayama et al. and parameter 3, which is a modification of the population PK of Nakayama et al. We calculated the mean prediction error (ME), an indicator of prediction bias, and the mean absolute prediction error (MAE), an indicator of accuracy. Furthermore, the percentage of predicted TEIC blood concentration within 25% and 50% of the measured TEIC blood concentration was calculated. Results: The ME values were -0.54, -0.25, and -0.30 and the MAE values were 2.29, 2.19, and 2.22 for parameters 1, 2, and 3, respectively. For all of the three parameters, the ME values were calculated as minus values, and the predicted concentrations tended to be biased toward smaller values relative to the measured concentrations. Patients with serum creatinine (Scr) < 0.6 mg/dL and neutrophil counts < 100/µL had greater ME and MAE values and a smaller percentage of predicted TEIC blood concentration within 25% of measured TEIC blood concentrations compared with other patients. Conclusions: In patients with FN, the accuracy of predicting TEIC blood concentrations was good, with no significant differences between each parameter. However, patients with a Scr < 0.6 mg/dL and a neutrophil count < 100/µL showed slightly inferior prediction accuracy.

[A Case Report of Rectal MiNEN Laparoscopic Resection].

A 74-year-old woman underwent colonoscopy for positive fecal occult blood test. A colonoscopy revealed a Type 1 tumor in the rectosigmoid region. The tumor was diagnosed as well-differentiated adenocarcinoma(tub1)by biopsy. Laparoscopic high anterior resection was performed. The final diagnosis was MiNEN(adenocarcinoma:NEC=6:4), RS, pT4a(SE), INF c, Ly1c, V1b, Pn1b, BD2, pN2a(5/28), cM0, pStage Ⅲc. All lymph node metastases were of NEC origin. This case was considered to be at high risk of recurrence and require adjuvant chemotherapy focused on NEC. She was referred to an advanced medical institution for carboplatin and etoposide therapy. MiNEN is a rare disease, and has a poor prognosis. In order to establish a therapeutic strategy of MiNEN, it is important to accumulate further cases and evidence.

Immune response and protective efficacy of the SARS-CoV-2 recombinant spike protein vaccine S-268019-b in mice.

Vaccines that efficiently target severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent for coronavirus disease (COVID-19), are the best means for controlling viral spread. This study evaluated the efficacy of the COVID-19 vaccine S-268019-b, which comprises the recombinant full-length SARS-CoV-2 spike protein S-910823 (antigen) and A-910823 (adjuvant). In addition to eliciting both Th1-type and Th2-type cellular immune responses, two doses of S-910823 plus A-910823 induced anti-spike protein IgG antibodies and neutralizing antibodies against SARS-CoV-2. In a SARS-CoV-2 challenge test, S-910823 plus A-910823 mitigated SARS-CoV-2 infection-induced weight loss and death and inhibited viral replication in mouse lungs. S-910823 plus A-910823 promoted cytokine and chemokine at the injection site and immune cell accumulation in the draining lymph nodes. This led to the formation of germinal centers and the induction of memory B cells, antibody-secreting cells, and memory T cells. These findings provide fundamental property of S-268019-b, especially importance of A-910823 to elicit humoral and cellular immune responses.

Development of dual-functional catalysis for hydrazine oxidation by an organic p-n bilayer through in situ formation of a silver co-catalyst.

Dual-functional catalysis indicates that an organic p-n bilayer induces the catalytic oxidation involved in downhill reactions, not only under illumination but also in the dark. When the organo-bilayer is composed of a perylene derivative (3,4,9,10-perylenetetracarboxylic-bis-benzimidazole (PTCBI), n-type) and cobalt phthalocyanine (CoPc, p-type), only the photocatalytic oxidation of hydrazine (N2H4) occurs. However, the loading of Ag co-catalyst onto the CoPc surface in the PTCBI/CoPc bilayer successfully led to dual catalysis in terms of the oxidation of N2H4 to N2. To develop the present dual catalysis Ag loading was essential to achieve the catalysis performance particularly without irradiation.

Early Elevation of Cell-Free DNA After Acute Mesenteric Ischemia in Rats.

BACKGROUND: Acute mesenteric ischemia (AMI) is challenging to diagnose in the early phase. We tested the hypothesis that blood levels of cell-free DNA would increase early after AMI. In addition, proteome analysis was conducted as an exploratory analysis to identify other potential diagnostic biomarkers. METHODS: Mesenteric ischemia, abdominal sepsis, and sham model were compared in Sprague-Dawley rats. The abdominal sepsis model was induced by cecum puncture and mesenteric ischemia model by ligation of the superior mesenteric artery. Blood levels of cell-free DNA were measured 2 h and 6 h after wound closure. Shotgun proteome analysis was performed using plasma samples obtained at the 2 h timepoint; quantitative analysis was conducted for proteins detected exclusively in the AMI models. RESULTS: Blood cell-free DNA levels at 2 h after wound closure were significantly higher in the AMI model than in the sham and the abdominal sepsis models (P < 0.05). Cell-free DNA was positively correlated with the pathologic ischemia severity score (correlation coefficient 0.793-0.834, P < 0.001). Derivative proteome analysis in blood at 2-h time point revealed higher intensity of paraoxonase-1 in the AMI models than in the abdominal sepsis models; the significantly high blood paraoxonase-1 levels in the AMI models were confirmed in a separate quantitative analysis (P = 0.015). CONCLUSIONS: Cell-free DNA was demonstrated to be a promising biomarker for the early diagnosis of mesenteric ischemia in a rat model of AMI. Paraoxonase-1 may also play a role in the differential diagnosis of mesenteric ischemia from abdominal sepsis. The current results warrant further investigation in human studies.

The Changes in Concentration of Cerebral Oxygenated Hemoglobin During Single Event-Related Japanese Shiritori Task in Patients With Major Depression Disorder: Comparison With Healthy Subjects.

Patients with major depressive disorder (MDD) have been reported to show cognitive impairments in attention, cognition control, and motivation. The purpose of this study is to compare and examine the characteristics of frontal and temporal cortical activity in outpatients with MDD during the word production task (Shiritori) using a single event-related Near-Infrared Spectroscopy (NIRS) measurement method that was originally devised. The subjects were 29 MDD patients and 29 age matched healthy controls. In this task, one session consisted of two contrasting conditions (word production task, control condition), and all subjects alternated between these conditions. Each word was visually presented by a monitor for 0.3 s as an activation task and a fixed circle was presented for 12 s. In the activation task, subjects had to immediately generate a noun that starts with the last syllable of the presented word and they were required to say only creatures. From the data obtained at each measurement point during the 20 trials, and averaged waveform during activation task (20 trials) was calculated for each channel. During the word production task, the MDD patients showed significantly smaller activation than the controls in the prefrontal cortex area and inferior parietal area, especially in the left area. In addition, there was a significant negative correlation between Δoxy-Hb at the bilateral temporal lobe area and HAM-D total score in the MDD patients. These findings suggest that a single event-related NIRS measurement during Japanese shiritori tasks may be useful tool for evaluating psychophysiological indices in MDD patients, that relationship between activation and symptom may be of help in predicting functional outcome in patients.

C9orf72-derived arginine-rich poly-dipeptides impede phase modifiers.

Nuclear import receptors (NIRs) not only transport RNA-binding proteins (RBPs) but also modify phase transitions of RBPs by recognizing nuclear localization signals (NLSs). Toxic arginine-rich poly-dipeptides from C9orf72 interact with NIRs and cause nucleocytoplasmic transport deficit. However, the molecular basis for the toxicity of arginine-rich poly-dipeptides toward NIRs function as phase modifiers of RBPs remains unidentified. Here we show that arginine-rich poly-dipeptides impede the ability of NIRs to modify phase transitions of RBPs. Isothermal titration calorimetry and size-exclusion chromatography revealed that proline:arginine (PR) poly-dipeptides tightly bind karyopherin-ß2 (Kapß2) at 1:1 ratio. The nuclear magnetic resonances of Kapß2 perturbed by PR poly-dipeptides partially overlapped with those perturbed by the designed NLS peptide, suggesting that PR poly-dipeptides target the NLS binding site of Kapß2. The findings offer mechanistic insights into how phase transitions of RBPs are disabled in C9orf72-related neurodegeneration.

[A Case of Squamous Cell Carcinoma of the Lung from Gastrointestinal Perforation Due to Small Intestinal Metastasis].

An 80s male, with a medical history of hypertension, hyperuricemia, and atrial fibrillation, visited our emergency outpatient department with vomiting and diarrhea as the chief complaint in August 2017. The blood examination revealed a high level of inflammatory reaction. The plain abdominal CT revealed fluid retention contacting the small intestine and intraabdominal free gas. We diagnosed the case as a small intestinal perforation, following which we performed emergency surgery. The small intestine was perforated, and an abscess cavity was formed between the transverse mesocolon and mesentery proper. Thus, the abscess was removed, and about 30 cm of the small intestine, including the perforated site, was resected, followed by the reconstruction. The resected specimens revealed squamous cell carcinoma at the small intestinal perforated site. Lung squamous cell carcinoma was diagnosed by subsequent chest CT and immunostaining. We administered 3 courses of chemotherapy combined with carboplatin and albumin-bound paclitaxel. Although the effect was partially observed, interstitial pneumonia occurred, which was inferred to be drug-induced. The patient died in 195 days following the surgery. Herein, we reported a case of lung cancer, which was diagnosed on the detection of gastrointestinal perforation caused by a small intestinal metastasis.

Structural and dynamics analysis of intrinsically disordered proteins by high-speed atomic force microscopy.

Intrinsically disordered proteins (IDPs) are ubiquitous proteins that are disordered entirely or partly and play important roles in diverse biological phenomena. Their structure dynamically samples a multitude of conformational states, thus rendering their structural analysis very difficult. Here we explore the potential of high-speed atomic force microscopy (HS-AFM) for characterizing the structure and dynamics of IDPs. Successive HS-AFM images of an IDP molecule can not only identify constantly folded and constantly disordered regions in the molecule, but can also document disorder-to-order transitions. Moreover, the number of amino acids contained in these disordered regions can be roughly estimated, enabling a semiquantitative, realistic description of the dynamic structure of IDPs.

Dynamics of proteins with different molecular structures under solution condition.

Incoherent quasielastic neutron scattering (iQENS) is a fascinating technique for investigating the internal dynamics of protein. However, low flux of neutron beam, low signal to noise ratio of QENS spectrometers and unavailability of well-established analyzing method have been obstacles for studying internal dynamics under physiological condition (in solution). The recent progress of neutron source and spectrometer provide the fine iQENS profile with high statistics and as well the progress of computational technique enable us to quantitatively reveal the internal dynamic from the obtained iQENS profile. The internal dynamics of two proteins, globular domain protein (GDP) and intrinsically disordered protein (IDP) in solution, were measured with the state-of-the art QENS spectrometer and then revealed with the newly developed analyzing method. It was clarified that the average relaxation rate of IDP was larger than that of GDP and the fraction of mobile H atoms of IDP was also much higher than that of GDP. Combined with the structural analysis and the calculation of solvent accessible surface area of amino acid residue, it was concluded that the internal dynamics were related to the highly solvent exposed amino acid residues depending upon protein's structure.

Postharvest Properties of Ultra-Late Maturing Peach Cultivars and Their Attributions to Melting Flesh (M) Locus: Re-evaluation of M Locus in Association With Flesh Texture.

The postharvest properties of two ultra-late maturing peach cultivars, "Tobihaku" (TH) and "Daijumitsuto" (DJ), were investigated. Fruit were harvested at commercial maturity and held at 25°C. TH exhibited the characteristics of normal melting flesh (MF) peach, including rapid fruit softening associated with appropriate level of endogenous ethylene production In contrast, DJ did not soften at all during 3 weeks experimental period even though considerable ethylene production was observed. Fruit of TH and DJ were treated with 5,000 ppm of propylene, an ethylene analog, continuously for 7 days. TH softened rapidly whereas DJ maintained high flesh firmness in spite of an increase in endogenous ethylene production, suggesting that DJ but not TH lacked the ability to be softened in response to endogenous and exogenous ethylene/propylene. DNA-seq analysis showed that tandem endo-polygalacturonase (endoPG) genes located at melting flesh (M) locus, Pp-endoPGM (PGM), and Pp-endoPGF (PGF), were deleted in DJ. The endoPG genes at M locus are known to control flesh texture of peach fruit, and it was suggested that the non-softening property of DJ is due to the lack of endoPG genes. On the other hand, TH possessed an unidentified M haplotype that is involved in determination of MF phenotype. Structural identification of the unknown M haplotype, designated as M 0, through comparison with previously reported M haplotypes revealed distinct differences between PGM on M 0 haplotype (PGM-M0 ) and PGM on other haplotypes (PGM-M1 ). Peach M haplotypes were classified into four main haplotypes: M 0 with PGM-M0 ; M 1 with both PGM-M1 and PGF; M 2 with PGM-M1 ; and M 3 lacking both PGM and PGF. Re-evaluation of M locus in association with MF/non-melting flesh (NMF) phenotypes in more than 400 accessions by using whole genome shotgun sequencing data on database and/or by PCR genotyping demonstrated that M 0 haplotype was the common haplotype in MF accessions, and M 0 and M 1 haplotypes were dominant over M 2 and M 3 haplotypes and co-dominantly determined the MF trait. It was also assumed on the basis of structural comparison of M haplotypes among Prunus species that the ancestral haplotype of M 0 diverged from those of the other haplotypes before the speciation of Prunus persica.

Structure of the HLTF HIRAN domain and its functional implications in regression of a stalled replication fork.

HLTF (helicase-like transcription factor) is a yeast RAD5 homolog that is found in mammals. HLTF has E3 ubiquitin ligase and DNA helicase activities, and is a pivotal protein in template-switched DNA synthesis that allows DNA replication to continue even in the presence of DNA damage by utilizing a newly synthesized undamaged strand as a template. In addition, HLTF has a DNA-binding domain termed HIRAN (HIP116 and RAD5 N-terminal). HIRAN has been hypothesized to play a role in DNA binding; however, the structural basis of its role in DNA binding has remained unclear. In the past five years, several crystal structures of HIRAN have been reported. These structures revealed new insights into the molecular mechanism underlying DNA binding by HIRAN. Here, the structural information on HIRAN is summarized and the function of HIRAN in recognizing the 3'-terminus of the daughter strand at a stalled replication fork and the implications for its involvement in fork regression are discussed.

Continuous nitrogen fertilization retards the vertical migration of Fukushima nuclear accident-derived cesium-137 in apple orchard soil.

We monitored the levels of cesium-137 (137Cs) in the soils of five orchards for six years following the Fukushima Daiichi Nuclear Power Plant accident on 11 March 2011 and found that the vertical distribution of accident-derived 137Cs varied significantly among the orchards with varying land-use and fertilizer management. Based on these results, this study evaluated how nitrogen (N) fertilizer management may have affected the vertical migration of 137Cs in the orchard soils. We selected an experimental orchard producing 'Jonathan' apples, where a long-term N-fertilizer trial has continued since 1973, with an N-fertilized plot (N plot; N added at 20 g m-2 y-1) and a non-fertilized plot (0 N plot). Five years after the accident, the vertical migration of accident-derived 137Cs was significantly lower in the N plot (2.3 cm) than in the 0 N plot (4.3 cm), suggesting greater 137Cs retention in the surface of the N plot. Application of a cesium bromide (133CsBr) tracer suggested that the retarded vertical migration of 137Cs in the N plot may be related to significantly lower amounts of exchangeable 133Cs and significantly higher proportions of non-exchangeable 133Cs in the upper 2 cm. We did not find any evidence of the aboveground plants contributing to more 133Cs retention in the N plot. However, greater 137Cs retention in the surface (0-2 cm) of the N plot may be due to more dissolved organic carbon (DOC), and high DOC may have contributed to deeper 137Cs migration in both the plots. Our results suggest that continuous N fertilizer application significantly retarded the migration of 137Cs by approximately one-half and resulted in less 137Cs reaching the mobile exchangeable form in the deeper root-zone layers.

[Two Cases of Laparoscopic Partial Resection of Stomach Using a Trans-Gastric Wall Approach for Submucosal Tumors].

We performed laparoscopic partial resection of the stomach with a trans-gastric wall approach for submucosal tumors. Case 1: A 67-year-old woman was referred to our hospital because of tarry stool. Upper gastrointestinal endoscopy revealed a well demarcated, round, 45mm intraluminal-type submucosal tumor with delle on the anterior wall of the gastric upper body. Case 2: An 86-year-old woman was referred to our hospital because of anemia. Upper gastrointestinal endoscopy revealed a well demarcated, round, 25mm intraluminal-type submucosal tumor on the posterior wall of the gastric upper body. Laparoscopic partial resection of the stomach with a trans-gastric wall approach was performed. The operation times were 58 minutes and 73 minutes, respectively, and blood loss was low in both cases. This operative procedure is safe and easy and allows for resection resected with a direct view for surgeons without endoscopists.

Structure of HIRAN domain of human HLTF bound to duplex DNA provides structural basis for DNA unwinding to initiate replication fork regression.

Replication fork regression is a mechanism to rescue a stalled fork by various replication stresses, such as DNA lesions. Helicase-like transcription factor, a SNF2 translocase, plays a central role in the fork regression and its N-terminal domain, HIRAN (HIP116 and Rad5 N-terminal), binds the 3'-hydroxy group of single-stranded DNA. Furthermore, HIRAN is supposed to bind double-stranded DNA (dsDNA) and involved in strand separation in the fork regression, whereas structural basis for mechanisms underlying dsDNA binding and strand separation by HIRAN are still unclear. Here, we report the crystal structure of HIRAN bound to duplex DNA. The structure reveals that HIRAN binds the 3'-hydroxy group of DNA and unexpectedly unwinds three nucleobases of the duplex. Phe-142 is involved in the dsDNA binding and the strand separation. In addition, the structure unravels the mechanism underlying sequence-independent recognition for purine bases by HIRAN, where the N-glycosidic bond adopts syn conformation. Our findings indicate direct involvement of HIRAN in the fork regression by separating of the daughter strand from the parental template.

Calcium sensing via EF-hand 4 enables thioredoxin activity in the sensor-responder protein calredoxin in the green alga Chlamydomonas reinhardtii.

Calcium (Ca2+) and redox signaling enable cells to quickly adapt to changing environments. The signaling protein calredoxin (CRX) from the green alga Chlamydomonas reinhardtii is a chloroplast-resident thioredoxin having Ca2+-dependent activity and harboring a unique combination of an EF-hand domain connected to a typical thioredoxin-fold. Using small-angle X-ray scattering (SAXS), FRET, and NMR techniques, we found that Ca2+-binding not only induces a conformational change in the EF-hand domain, but also in the thioredoxin domain, translating into the onset of thioredoxin redox activity. Functional analyses of CRX with genetically altered EF-hands revealed that EF-hand 4 is important for mediating the communication between the two domains. Moreover, we crystallized a variant (C174S) of the CRX target protein peroxiredoxin 1 (PRX1) at 2.4 Å resolution, modeled the interaction complex of the two proteins, and analyzed it by cross-linking and MS analyses, revealing that the interaction interface is located close to the active sites of both proteins. Our findings shed light on the Ca2+ binding-induced changes in CRX structure in solution at the level of the overall protein and individual domains and residues.