Alternative autophagy dampens UVB-induced NLRP3 inflammasome activation in human keratinocytes.

Sunlight exposure results in an inflammatory reaction of the skin commonly known as sunburn, which increases skin cancer risk. In particular, the ultraviolet B (UVB) component of sunlight induces inflammasome activation in keratinocytes to instigate the cutaneous inflammatory responses. Here, we explore the intracellular machinery that maintains skin homeostasis by suppressing UVB-induced inflammasome activation in human keratinocytes. We found that pharmacological inhibition of autophagy promoted UVB-induced NLRP3 inflammasome activation. Unexpectedly, however, gene silencing of Atg5 or Atg7, which are critical for conventional autophagy, had no effect, whereas gene silencing of Beclin1, which is essential not only for conventional autophagy but also for Atg5/Atg7-independent alternative autophagy, promoted UVB-induced inflammasome activation, indicating an involvement of alternative autophagy. We found that damaged mitochondria were highly accumulated in UVB-irradiated keratinocytes when alternative autophagy was inhibited, and they appear to be recognized by NLRP3. Overall, our findings indicate that alternative autophagy, rather than conventional autophagy, suppresses UVB-induced NLRP3 inflammasome activation through the clearance of damaged mitochondria in human keratinocytes and illustrate a previously unknown involvement of alternative autophagy in inflammation. Alternative autophagy may be a new therapeutic target for sunburn and associated cutaneous disorders.

Increased resistance against tellurite is conferred by a mutation in the promoter region of uncommon tellurite resistance gene tehB in the ter-negative Shiga toxin-producing Escherichia coli O157:H7.

Resistance to potassium tellurite (PT) is an important indicator in isolating Shiga toxin-producing Escherichia coli (STEC) O157:H7 and other major STEC serogroups. Common resistance determinant genes are encoded in the ter gene cluster. We found an O157:H7 isolate that does not harbor ter but is resistant to PT. One nonsynonymous mutation was found in another PT resistance gene, tehA, through whole-genome sequence analyses. To elucidate the contribution of this mutation to PT resistance, complementation of tehA and the related gene tehB in isogenic strains and quantitative RT‒PCR were performed. The results indicated that the point mutation not only changed an amino acid of tehA, but also was positioned on a putative internal promoter of tehB and increased PT resistance by elevating tehB mRNA expression. Meanwhile, the amino acid change in tehA had negligible impact on the PT resistance. Comprehensive screening revealed that 2.3% of O157:H7 isolates in Japan did not harbor the ter gene cluster, but the same mutation in tehA was not found. These results suggested that PT resistance in E. coli can be enhanced through one mutational event even in ter-negative strains. IMPORTANCE: Selective agents are important for isolating Shiga toxin-producing Escherichia coli (STEC) because the undesirable growth of microflora should be inhibited. Potassium tellurite (PT) is a common selective agent for major STEC serotypes. In this study, we found a novel variant of PT resistance genes, tehAB, in STEC O157:H7. Molecular experiments clearly showed that one point mutation in a predicted internal promoter region of tehB upregulated the expression of the gene and consequently led to increased resistance to PT. Because tehAB genes are ubiquitous across E. coli, these results provide universal insight into PT resistance in this species.

Talk to us about your skin: The relationship between spoken language and haptic exploratory procedures.

OBJECTIVE: To enhance satisfaction, the cosmetics industry needs to clearly understand consumers' descriptions of their key tactile preferences. It is difficult for researchers to understand verbal descriptions from people whose native language is different from their own. Previous research has implied that some sensory words with the same lexical meanings have been observed in different haptic exploratory procedures (HEPs). Therefore, our study aims to investigate and understand the key tactile perceptions of people from five different countries based on their descriptions and their HEPs. METHODS: In Experiment 1, 1545 participants living in the US, Japan, China, Italy, and Thailand described their major tactile perceptions as efficacy in skincare, and we analysed the frequency of each word used in their answers. In Experiment 2, we confirmed the task to observe HEPs for Chinese, Italian, and Thai participants. A total of 24 participants in China, 33 participants in Italy, and 30 participants in Thailand freely explored their faces with their hands and answered which side more closely matched the major tactile adjectives. Experts classified the observed HEPs into six classifications within two categories and three contact area sizes and investigated the cultural differences. RESULTS: More than 2% of the Chinese, Italian, Thai, US, and Japanese participants described 33, 20, 29, 22, and 18 words, respectively, as efficacy in skincare. Verified words that described the major tactile perceptions in each native language had the same meanings as moistness, firmness, softness, smoothness, and so on. We could confirm the HEPs of these major feelings for the participants from each culture. Chinese and Thai participants' HEPs for moistness or softness were observed with a pressing movement. Conversely, Italian participants' HEPs for moistness or softness were observed with a rubbing movement. CONCLUSION: This study showed that words with the same lexical meanings evoked different HEPs. The results imply that different HEPs can provide different physical stimuli on the skin. Therefore, it is important to survey both objects and HEPs to better understand the tactile experience.

OBJECTIF: Pour améliorer la satisfaction, l'industrie cosmétique doit bien comprendre les descriptions que font les consommateurs de leurs principales préférences tactiles. Il est difficile pour les chercheurs de comprendre les descriptions verbales des personnes dont la langue maternelle est différente de la leur. Des recherches antérieures ont suggéré que certains mots sensoriels ayant les mêmes significations lexicales ont été observés dans différentes procédures exploratoires haptiques (PEH). Par conséquent, notre étude vise à étudier et à comprendre les perceptions tactiles clés des personnes de cinq pays différents en fonction de leurs descriptions et de leurs PEH. MÉTHODES: Dans l'expérience 1 545 participantes vivant aux États­Unis, au Japon, en Chine, en Italie et en Thaïlande ont décrit leurs principales perceptions tactiles comme l'efficacité dans les soins de la peau, et nous avons analysé la fréquence de chaque mot utilisé dans leurs réponses. Dans l'expérience 2, nous l'avons confirmé en observant les PEH pour les participantes chinoises, italiennes et thaïs. 24 participantes en Chine, 33 participantes en Italie et 30 participantes en Thaïlande ont librement exploré leur visage avec leurs mains et ont répondu à la question de savoir quel côté correspondait le mieux aux principaux adjectifs tactiles. Les experts ont classé les PEH observées en six classifications dans deux catégories et trois tailles de surface de contact, et ont étudié les différences culturelles. RÉSULTAT: Plus de deux pour cent des participantes chinoises, italiennes, thaïs, américaines et japonaises ont décrit 33, 20, 29, 22 et 18 mots, respectivement, comme une efficacité dans les soins de la peau. Les mots vérifiés qui décrivaient les principales perceptions tactiles dans chaque langue maternelle ayant les mêmes significations sont l'humidité, la fermeté, la douceur, la texture lisse, etc. Nous avons pu confirmer les PEH de ces sensations majeures pour les participants de chaque culture. Les PEH des participantes chinoises et thaïs pour l'humidité ou la douceur ont été observées avec un mouvement de pression. A l'inverse, les PEH pour l'humidité ou la douceur des participantes italiennes ont été observées avec un mouvement de frottement. CONCLUSION: Cette étude a montré que les mots ayant les mêmes significations lexicales évoquaient différentes PEH. Les résultats impliquent que différentes PEH peuvent fournir différents stimuli physiques sur la peau. Par conséquent, il est important d'étudier les objets et les PEH pour mieux comprendre l'expérience tactile.

Evaluation of a Capillary Microsampling Device for Analyzing Plasma Lenvatinib Concentration in Patients With Hepatocellular Carcinoma.

BACKGROUND: The anticancer drug, Lenvima (lenvatinib), has severe side effects. Therapeutic drug monitoring helps ensure its efficacy and safety. Regular and optimally timed blood sampling is tough, especially when lenvatinib is self-medicated. Microsampling using the easy to handle Microsampling Wing (MSW) may help circumvent this problem. However, current lenvatinib detection methods are not sensitive enough to detect its concentrations in microsamples (<50-250 µL). Thus, the aim of this study was 2-fold (1) develop an analytic method to estimate plasma lenvatinib concentrations in microsamples and (2) verify whether this method works on micro (5.6 µL) blood plasma samples obtained clinically through MSW from patients with unresectable hepatocellular carcinoma (HCC). METHODS: A simple, highly sensitive, and specific liquid chromatography-electrospray ionization tandem mass spectrometry method was developed. Using this novel protocol, the trough blood plasma concentration of lenvatinib was measured for both blood sampled conventionally and that using MSW. Thirty-five venous whole blood samples were obtained from 11 patients with HCC. Furthermore, the stability of lenvatinib in MSW samples during storage was evaluated. RESULTS: The mean plasma lenvatinib concentration estimates were not significantly different between the MSW and conventional venous blood samples. CV for interday and intraday assays was low. Up to day 5, the lenvatinib concentration in the MSW samples was 85%-115% of the initial day concentration (when stored at 25°C or 4°C). The interference of endogenous matrix components in the human plasma was low. CONCLUSIONS: These results indicate that the novel mass spectrometry protocol accurately measures lenvatinib in human plasma and is reproducible. Thus, MSW could be a useful microsampling device for lenvatinib therapeutic drug monitoring in patients with HCC when used in combination with this novel liquid chromatography-electrospray ionization tandem mass spectrometry detection method.

Development of a simple and cost-effective gel-based duplex PCR method to identify both encapsulated and unencapsulated Neisseria meningitidis applicable under resource-limited conditions.

Tens of thousands of cases of invasive meningococcal diseases (IMD) with thousands of deaths are reported annually worldwide; however, only approximately 40 cases occur each year in Japan. Therefore, the majority of medical technologists in Japan have never performed or prepared for analyses of the causative agent, Neisseria meningitidis. Since IMD outbreaks have been reported at mass gathering events, the risk of IMD will increase in Japan in 2021 because of the Olympics. In the present study, we developed a new simple gel-based duplex PCR method that may be employed by the majority Japanese clinical laboratories. It is simple to perform and time- and cost-effectively identifies encapsulated and unencapsulated N. meningitidis by detecting the encapsulated N. meningitidis-specific ctrB and N. meningitidis-specific ggt genes. We consider this simple and cost-effective identification method to compensate for the lack of experience and resource-poor conditions in most Japanese laboratories in which N. meningitidis has rarely been examined.

Quantification of autonomic nervous activity by heart rate variability and approximate entropy in high ultrafiltration rate during hemodialysis.

BACKGROUND: Few studies have focused on the imbalance of the autonomic nervous system in ultrafiltration rate (UFR) subjects without blood pressure variation during maintenance hemodialysis (HD), although the role of autonomic nervous system activation during HD has been proposed to be an important factor for the maintenance of blood pressure. METHODS: Variations over time in autonomic nervous activity due to differences in UFR were evaluated by measuring heart rate variability (HRV) and approximate entropy (ApEn) in 35 HD patients without blood pressure variations during HD session. The subjects were divided into 3 groups, those with UFR <10 ml/h/kg; ≥10 ml/h/kg but ≤15 ml/h/kg; and >15 ml/h/kg, and Holter ECG was recorded continuously during HD session using frequency analysis of RR intervals. High frequency (HF) and low frequency (LF) spectral components are found to be representative of the parasympathetic nervous system and sympathovagal balance, respectively, with the ratio of LF to HF of HRV providing a measure of sympathetic nervous system. RESULTS: In subjects with UFR >15 ml/h/kg, HF components were significantly lower, and LF/HF and ApEn values were significantly higher, in the latter half of an HD session than before starting HD. CONCLUSION: Removing water from these subjects would promote sustained sympathetic nervous overactivity. These findings indicate that the UFR during HD needs to be set at ≤15 ml/h/kg.

High concentrations of NaCl induce cell swelling leading to senescence in human cells.

Cell swelling and retardation in DNA replication are always observed in senescent cells. When DNA replication is slowed down with RNA and protein syntheses unchanged in proliferating cells, it causes a phenomenon known as unbalanced growth. The purpose of this study is to assess the role of cell swelling in unbalanced growth in terms of senescence and investigate the mechanism underlying this phenomenon. We tried to induce cell swelling with minimum damage to cells in this study. We perturbed the osmoregulatory functions to induce cell swelling under hypotonic and hypertonic conditions in normal human fibroblasts. Addition of excess NaCl was found to induce significant cell and nuclear swelling in dose- and time-dependent manners. Excess NaCl immediately retarded DNA replication, accumulated cells at G1 phase of the cell cycle, and eventually deprived division potential of the cells. Such cells showed typical senescent cell shape followed by expression of the typical senescence-associated genes. Excess NaCl also activated ERK1/2, p38, and JNK of the mitogen activated protein kinase family. Addition of U0126, an inhibitor of ERK1/2, prevented appearance of senescent features induced by excess NaCl. These results suggest that hypertonic conditions induce cell swelling due to unbalanced growth, thereby leading to cellular senescence.

Factors Predicting Adhesion between Renal Capsule and Perinephric Adipose Tissue in Partial Nephrectomy.

In minimally invasive partial nephrectomy (MIPN), it is important to preoperatively predict the degree of difficulty of tumor resection. When severe adhesions occur between the renal capsule and perinephric adipose tissue, detachment can be difficult. Preoperative prediction of adhesion is thought to be useful in the selection of surgical procedure. Subjects were 63 patients of a single surgeon who had received MIPN between April 2008 and August 2013 at Okayama University Hospital. Of these patients, this study followed 47 in whom the presence or absence of adhesions between the renal capsule and perinephric adipose tissue was confirmed using intraoperative videos. Data collected included: sex, BMI, CT finding (presence of fi broids in perinephric adipose tissue), comorbidities and lifestyle. Adhesion was observed in 7 patients (14.9%). The mean operative time was 291.6 min in the adhesion group, and 226.3 min in the group without. The increased time in the adhesions group was significant (p＜0.05). Predictive factors were a positive CT finding for fibroid structure and comorbidity of hypertension (p＜0.05). In MIPN, difficulty of surgery can be affected by the presence of adhesion of the perinephric adipose tissue. Predicting such adhesion from preoperative CT is thus important.

Hepatic inflammation facilitates transcription-associated mutagenesis via AID activity and enhances liver tumorigenesis.

Chronic inflammation triggers the aberrant expression of a DNA mutator enzyme, activation-induced cytidine deaminase (AID), and contributes to tumorigenesis through the accumulation of genetic aberrations. To gain further insight into the inflammation-mediated genotoxic events required for carcinogenesis, we examined the role of chronic inflammation in the emergence of genetic aberrations in the liver with constitutive AID expression. Treatment with thioacetamide (TAA) at low-dose concentrations caused minimal hepatic inflammation in both wild-type (WT) and AID transgenic (Tg) mice. None of the WT mice with low-dose TAA administration or AID Tg mice without hepatic inflammation developed cancers in their liver tissues over the 6 month study period. In contrast, all the AID Tg mice with TAA treatment developed multiple macroscopic hepatocellular carcinomas during the same observation period. Whole exome sequencing and additional deep-sequencing analyses revealed the enhanced accumulation of somatic mutations in various genes, including dual specificity phosphatase 6 (Dusp6), early growth response 1 (Egr1) and inhibitor of DNA binding 2 (Id2), which are putative tumor suppressors, in AID-expressing liver with TAA-mediated hepatic inflammation. Microarray and quantitative reverse transcription-polymerase chain reaction analyses showed the transcriptional upregulation of various genes including Dusp6, Egr1 and Id2 under hepatic inflammatory conditions. Together, these findings suggest that inflammation-mediated transcriptional upregulation of target genes, including putative tumor suppressor genes, enhances the opportunity for inflamed cells to acquire somatic mutations and contributes to the acceleration of tumorigenesis in the inflamed liver tissues.

Leptin receptor somatic mutations are frequent in HCV-infected cirrhotic liver and associated with hepatocellular carcinoma.

BACKGROUND & AIMS: Hepatocellular carcinoma develops in patients with chronic hepatitis or cirrhosis via a stepwise accumulation of various genetic alterations. To explore the genetic basis of development of hepatocellular carcinoma in hepatitis C virus (HCV)-associated chronic liver disease, we evaluated genetic variants that accumulate in nontumor cirrhotic liver. METHODS: We determined the whole exome sequences of 7 tumors and background cirrhotic liver tissues from 4 patients with HCV infection. We then performed additional sequencing of selected exomes of mutated genes, identified by whole exome sequencing, and of representative tumor-related genes on samples from 22 cirrhotic livers with HCV infection. We performed in vitro and in vivo functional studies for one of the mutated genes. RESULTS: Whole exome sequencing showed that somatic mutations accumulated in various genes in HCV-infected cirrhotic liver tissues. Among the identified genes, the leptin receptor gene (LEPR) was one of the most frequently mutated in tumor and nontumor cirrhotic liver tissue. Selected exome sequencing analyses detected LEPR mutations in 12 of 22 (54.5%) nontumorous cirrhotic livers. In vitro, 4 of 7 (57.1%) LEPR mutations found in cirrhotic livers reduced phosphorylation of STAT3 to inactivate LEPR-mediated signaling. Moreover, 40% of Lepr-deficient (C57BL/KsJ-db/db) mice developed liver tumors after administration of thioacetamide compared with none of the control mice. CONCLUSIONS: Based on analysis of liver tissue samples from patients, somatic mutations accumulate in LEPR in cirrhotic liver with chronic HCV infection. These mutations could disrupt LEPR signaling and increase susceptibility to hepatocarcinogenesis.

Accumulation of somatic mutations in TP53 in gastric epithelium with Helicobacter pylori infection.

BACKGROUND & AIMS: Helicobacter pylori infection is a risk factor for gastric cancer. To explore the genetic basis of gastric cancer that develops in inflamed gastric mucosa, we investigated genetic aberrations that latently accumulate in nontumorous gastric epithelium with H pylori infection. METHODS: We performed whole-exome sequencing of gastric tumors, noncancerous tissues with gastritis, and peripheral lymphocytes from 5 patients. We performed additional deep-sequencing analyses of selected tumor-related genes using 34 gastritis mucosal samples from patients with or without gastric cancer. We also performed deep sequencing analyses of gastric mucosal tissues from mice that express transgenic human TP53 and constitutively express activation-induced cytidine deaminase (AICDA or AID) (human TP53 knock-in/AID-transgenic mice). RESULTS: Whole-exome sequencing revealed that somatic mutations accumulated in various genes in inflamed gastric tissues. Additional deep-sequencing analyses of tissues from regions of gastritis confirmed nonsynonymous low-abundance mutations in TP53 in 15 cases (44.1%) and ARID1A in 5 cases (14.7%). The mutations that accumulated in gastric mucosal tissues with H pylori-induced gastritis, as well as gastric tumors, were predominantly C:G>T:A transitions in GpCpX motifs-a marker of cytidine deamination induced by AID. Constitutive expression of AID in the gastric mucosa of mice led to mutations in the human TP53, at amino acid coding positions identical to those detected in human gastric cancers. CONCLUSIONS: Studies of gastric tumors and tissues from humans and mice indicate that somatic mutations accumulate in various genes in gastric mucosal tissues with H pylori infection. Increased cytidine deaminase activity in these tissues appears to promote the accumulation of these mutations and might promote gastric carcinogenesis in patients with H pylori infection.

Emotion Regulation of Neuroticism: Emotional Information Processing Related to Psychosomatic State Evaluated by Electroencephalography and Exact Low-Resolution Brain Electromagnetic Tomography.

Emotion regulation is the process that adjusts the type or amount of emotion when we experience an emotional situation. The aim of this study was to reveal quantitative changes in brain activity during emotional information processing related to psychosomatic states and to determine electrophysiological features of neuroticism. Twenty-two healthy subjects (mean age 25 years, 14 males and 8 females) were registered. Electroencephalography (EEG) was measured during an emotional audiovisual memory task under three conditions (neutral, pleasant and unpleasant sessions). We divided the subjects into two groups using the Cornell Medical Index (CMI): (CMI-I: control group, n = 10: CMI-II, III or IV: neuroticism group, n = 12). We analyzed the digital EEG data using exact low-resolution brain electromagnetic tomography (eLORETA) current source density (CSD) and functional connectivity analysis in several frequency bands (δ, θ, α, ß, γ and whole band). In all subjects, bilateral frontal α CSD in the unpleasant session increased compared to the pleasant session, especially in the control group (p < 0.05). CSD of the neuroticism group was significantly higher than that of the control group in the full band at the amygdala and inferior temporal gyrus, and in the α band at the right temporal lobe (p < 0.05). Additionally, we found an increase in functional connectivity between the left insular cortex and right superior temporal gyrus in all subjects during the unpleasant session compared to the pleasant session (p < 0.05). In this study, using EEG analysis, we could find a novel cortical network related to brain mechanisms underlying emotion regulation. Overall findings indicate that it is possible to characterize neuroticism electrophysiologically, which may serve as a neurophysiological marker of this personality trait. © 2015 S. Karger AG, Basel.

Urinary phosphorus excretion per creatinine clearance as a prognostic marker for progression of chronic kidney disease: a retrospective cohort study.

BACKGROUND: Whether phosphate itself has nephrotoxicity in patients with chronic kidney disease (CKD) is controversial, although phosphate excretion into urine may cause tubular damage in rat models. To evaluate actual phosphate load on each nephron, we examined the association between 24-h urinary phosphorus excretion per creatinine clearance (24-h U-P/CCr), a newly proposed index that is a surrogate for nephron load, and CKD progression in patients with CKD. METHODS: We conducted a single-center, retrospective cohort study. To avoid potential confounders for protein intake, only patients on our educational program for CKD with a fixed diet regimen and aged 20 years or older were included. The observation period was 3 years. Primary outcomes were CKD progression defined as a composite of end-stage kidney disease (ESKD) or 50 % reduction of estimated glomerular filtration rate. Patients were stratified by quartiles of 24-h U-P/CCr levels as Quartiles 1-4. The association was examined in three models: unadjusted (Model 1), adjusted for risk factors for CKD progression (Model 2), and factors that affect renal phosphate handling (Model 3). RESULTS: A total of 191 patients met the eligibility criteria. Patients with higher 24-h U-P/CCr showed a higher risk for the composite outcomes. The hazard ratios [95 % confidence interval] for 24-h U-P/CCr levels in Quartile 2, 3, and 4, respectively, versus Quartile 1 were 2.56 (1.15-6.24), 7.53 (3.63-17.62), and 12.17 (5.82-28.64) in Model 1; 1.66 (0.63-4.97), 3.57 (1.25-11.71), and 5.34 (1.41-22.32) in Model 2; and 3.07 (0.97-11.85), 7.52 (2.13-32.69), and 7.89 (1.74-44.33) in Model 3. CONCLUSIONS: Our study showed that higher phosphorus excretion per creatinine clearance was associated with CKD progression.

In vitro apatite formation on nano-crystalline titania layer aligned parallel to Ti6Al4V alloy substrates with sub-millimeter gap.

Pure titanium substrates were chemically oxidized with H2O2 and subsequent thermally oxidized at 400 °C in air to form anatase-type titania layer on their surface. The chemically and thermally oxidized titanium substrate (CHT) was aligned parallel to the counter specimen such as commercially pure titanium (cpTi), titanium alloy (Ti6Al4V) popularly used as implant materials or Al substrate with 0.3-mm gap. Then, they were soaked in Kokubo's simulated body fluid (SBF, pH 7.4, 36.5 °C) for 7 days. XRD and SEM analysis showed that the in vitro apatite-forming ability of the contact surface of the CHT specimen decreased in the order: cpTi > Ti6Al4V > Al. EDX and XPS surface analysis showed that aluminum species were present on the contact surface of the CHT specimen aligned parallel to the counter specimen such as Ti6Al4V and Al. This result indicated that Ti6Al4V or Al specimens released the aluminum species into the SBF under the spatial gap. The released aluminum species might be positively or negatively charged in the SBF and thus can interact with calcium or phosphate species as well as titania layer, causing the suppression of the primary heterogeneous nucleation and growth of apatite on the contact surface of the CHT specimen under the spatial gap. The diffusion and adsorption of aluminum species derived from the half-sized counter specimen under the spatial gap resulted in two dimensionally area-selective deposition of apatite particles on the contact surfaces of the CHT specimen.

[Nasopharyngeal Hib Carriage Among Healthy Children Attending Daycare Centers in Yokohama After One Year of a Publicly Funded Vaccine Program].

Yokohama city started a regular, free vaccine program for Haemophilus influenzae type b (Hib) from February of 2011. This study was completed to verify the effectiveness of the vaccine on the nasopharyngeal Hib carriage among healthy children attending daycare centers in the Isogo area. The research was conducted during the late spring (Jun--Jul) and fall (Oct-Nov) of 2012. There was a significant decrease in the Hib carriage rate (spring 8.8%, fall 1.6%). During this period there was no increase in the Hib vaccine coverage. The Hib carriage rate of each daycare center was 0-18.4% in spring and 0-4.9% in fall. There was no significant relationship between the rate of non immunized children and that of Hib carriage. This improvement in nasopharyngeal Hib carriage shows the impact of community immunity.

A model of liver carcinogenesis originating from hepatic progenitor cells with accumulation of genetic alterations.

Activation-induced cytidine deaminase (AID) contributes to inflammation-associated carcinogenesis through its mutagenic activity. In our study, by taking advantage of the ability of AID to induce genetic aberrations, we investigated whether liver cancer originates from hepatic stem/progenitor cells that accumulate stepwise genetic alterations. For this purpose, hepatic progenitor cells enriched from the fetal liver of AID transgenic (Tg) mice were transplanted into recipient "toxin-receptor mediated conditional cell knockout" (TRECK) mice, which have enhanced liver regeneration activity under the condition of diphtheria toxin treatment. Whole exome sequencing was used to determine the landscape of the accumulated genetic alterations in the transplanted progenitor cells during tumorigenesis. Liver tumors developed in 7 of 11 (63.6%) recipient TRECK mice receiving enriched hepatic progenitor cells from AID Tg mice, while no tumorigenesis was observed in TRECK mice receiving hepatic progenitor cells of wild-type mice. Histologic examination revealed that the tumors showed characteristics of hepatocellular carcinoma and partial features of cholangiocarcinoma with expression of the AID transgene. Whole exome sequencing revealed that several dozen genes acquired single nucleotide variants in tumor tissues originating from the transplanted hepatic progenitor cells of AID Tg mice. Microarray analyses revealed that the majority of the mutations (>80%) were present in actively transcribed genes in the liver-lineage cells. These findings provided the evidence suggesting that accumulation of genetic alterations in fetal hepatic progenitor cells progressed to liver cancers, and the selection of mutagenesis depends on active transcription in the liver-lineage cells.

Characterization of blaTEM-52-carrying plasmids of extended-spectrum-ß-lactamase-producing Salmonella enterica isolates from chicken meat with a common supplier in Japan.

The acquisition of resistance to cephalosporins among Salmonella spp. is a major public health concern. This study identified clonal plasmids carrying bla(TEM-52) from 10 Salmonella enterica serovar Infantis and Manhattan isolates from retail chicken meats that originated from a common supplier in Japan. Whole-genome analyses of the representative plasmids, including pYM4, revealed that they are 38 kb in size and that pYM4 is identical to pDKX1 from beef in Denmark, suggesting a global dissemination of resistance mediated by the plasmids.

Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium.

Infection with Helicobacter pylori (H. pylori) is a risk factor for the development of gastric cancer. Here we show that infection of gastric epithelial cells with 'cag' pathogenicity island (cagPAI)-positive H. pylori induced aberrant expression of activation-induced cytidine deaminase (AID), a member of the cytidine-deaminase family that acts as a DNA- and RNA-editing enzyme, via the IkappaB kinase-dependent nuclear factor-kappaB activation pathway. H. pylori-mediated upregulation of AID resulted in the accumulation of nucleotide alterations in the TP53 tumor suppressor gene in gastric cells in vitro. Our findings provide evidence that aberrant AID expression caused by H. pylori infection might be a mechanism of mutation accumulation in the gastric mucosa during H. pylori-associated gastric carcinogenesis.

A Qualitative Study on the Development of Professionalism Among Japanese Dental Students.

BACKGROUND: Professionalism is believed to vary depending on factors such as era and culture. Therefore, clarifying the meaning of professionalism in each country, region, and workplace is essential. However, how professionalism is cultivated among dental students in Japanese schools has yet to be fully elucidated. Therefore, this study examined whether professionalism among Japanese dental students changes by year. This research will contribute to effective professional education. PARTICIPANTS AND METHODS: The participants included six fourth-year dental students and nine fifth-year dental students. Semi-structured interviews were conducted from November 2018 to January 2019, and verbatim transcripts were created from the recorded data. Based on these verbatim transcripts, thematic analysis was utilized to examine and identify professionalism components for each academic year. RESULTS: Three themes based on 14 constituent concepts were obtained for fourth-year students. Three themes based on 20 constituent concepts were obtained for fifth-year students. Fourth-year students primarily focused on technical aspects. In contrast, fifth-year students placed greater emphasis on attitude and communication skills. CONCLUSION: From fourth-year students, who primarily focus on classroom learning and practical training, to fifth-year students who gain clinical experience, the constituent elements of professionalism became more complex. However, this study did not examine other aspects of healthcare professionalism, such as interprofessional collaboration. A comprehensive education program tailored to the clinical setting is necessary for cultivating professionalism.

Trans men can achieve adequate muscular development through low-dose testosterone therapy: A long-term study on body composition changes.

BACKGROUND: Transgender individuals undergo the gender-affirming hormone therapy (GAHT) to achieve physical changes consistent with their gender identity. Few studies are available on the long-term safety and efficacy of GAHT. OBJECTIVES: To investigate the long-term physical effects and the safety of the testosterone therapy for trans men and to assess the impact of differential hormone dose. MATERIALS AND METHODS: Trans men who initiated GAHT between May 2000 and December 2021 were included in this retrospective analysis. Physical findings (body mass index, body fat percentage (BFP), lean body mass (LBM), and grip strength), blood testing results (hemoglobin, hematocrit, uric acid, creatinine, total cholesterol, triglycerides, and total testosterone), and menstrual cessation were recorded. We assessed the effects of testosterone on body composition changes and laboratory parameters, comparing a low-dose group (≤ 62.5 mg/wk) to a high-dose group (> 62.5 mg/wk). RESULTS: Of 291 participants, 188 patients (64.6%) were in the low-dose group and 103 (35.4%) in the high-dose group. Cumulative menstrual cessation rates up to 12 months were not significantly different between groups. Both groups showed a decrease in BFP and an increase in LBM during the first year of therapy, followed by a slight increase in both over the long term. The high-dose group exhibited greater LBM gains during the first year. Higher hormone doses and lower initial LBM values were associated with LBM increases at 3 and 6 months (3 mo, P = 0.006, P < 0.001; 6 mo, P = 0.015, P < 0.001). There were no long-term, dose-dependent side effects such as polycythemia or dyslipidemia. CONCLUSION: Long-term GAHT for trans men is safe and effective. Low-dose testosterone administration is sufficient to increase LBM in trans men. Higher testosterone doses can lead to an earlier increase in muscle mass.