Distribution and metabolism of 14C-sulfoquinovosylacylpropanediol (14C-SQAP) after a single intravenous administration in tumor-bearing mice.

Sulfoquinovosylacylpropanediol (SQAP) is a novel potent radiosensitizer that inhibits angiogenesis in vivo and results in increased oxigenation and reduced tumor volume. We investigated the distribution, metabolism, and excretion of SQAP in male KSN-nude mice transplanted with a human pulmonary carcinoma, Lu65. For the metabolism analysis, a 2 mg (2.98 MBq)/kg of [glucose-U-14C]-SQAP (CP-3839) was intravenously injected. The injected SQAP was decomposed into a stearic acid and a sulfoquinovosylpropanediol (SQP) in the body. The degradation was relatively slow in the carcinoma tissue.1,3-propanediol[1-14C]-SQAP (CP-3635) was administered through intravenous injection of a 1 mg (3.48 MBq)/kg dose followed by whole body autoradiography of the mice. The autoradiography analysis demonstrated that SQAP rapidly distributed throughout the whole body and then quickly decreased within 4 hours except the tumor and excretion organs such as liver, kidney. Retention of SQAP was longer in tumor parts than in other tissues, as indicated by higher levels of radioactivity at 4 hours. The radioactivity around the tumor had also completely disappeared within 72 hours.

Promotion of crystalline cellulose degradation by expansins from Oryza sativa.

MAIN CONCLUSION: Enzymatic activities of Oryza sativa expansins, which were heterologously overexpressed in Escherichia coli , were analyzed. Results suggested that expansins promote degradation of cellulose by cellulase in a synergistic manner. Sustainable production of future biofuels is dependent on efficient saccharification of lignocelluloses. Expansins have received a lot of attention as proteins promoting biological degradation of cellulose using cellulase. The expansins are a class of plant cell wall proteins that induce cell wall loosening without hydrolysis. In this study, the expansins from Oryza sativa were classified using phylogenetic analysis and five proteins were selected for functional evaluation. At low cellulose loading, the cellulase in expansin mixtures was up to 2.4 times more active than in mixtures containing only cellulase, but at high cellulose loading the activity of cellulase in expansin mixtures and cellulase only mixtures did not differ. Furthermore, expansin activity was greater in cellulase mixtures compared with cellulase-deficient mixtures. Therefore, the expansins showed significant synergistic activity with cellulase. Expansin may play an important role in efficient saccharification of cellulose.

[The psychological effects of taking in "Shikohin": A cross-sectional exploratory study].

This study explores the psychological effects that Japanese people experience when consuming their "Shikohin", such as alcohol, tea, coffee, and tobacco. We'conducted a cross-sectional study among 542 people, from 20-to 69-year-old; who regularly consumed any one of "Shikohin" in Tokyo, Kanagawa, Saitama, and Chiba. The participants responded to an anonymous questionnaire concerning the consumption patterns of their "Shikohin" and the psychological effects that they experienced in taking in their "Shikohin". Results obtained using the K-J methods showed three common psychological effects in each "Shikohin". These effects included an increase in relaxation response, the promotion of social relationships, and an increase in positive mood. Our findings suggest that Japanese people may get some common effects through consumption of different "Shikohin".

Preliminary assessment of the behavioral activation model in Japanese undergraduate students.

Many studies have reported that behavioral activation is an effective intervention for depression. The behavioral activation model is based on several formulations. For example, depressive mood leads to avoidant behaviors, avoidance negatively affects social contacts, decreased socialization lessens opportunities for positive reinforcement, and a decrease in positive reinforcement results in more depressive mood. The purpose of this study was to examine relationships among avoidant behavior, social contact, frequency of positive reinforcement, and depressive mood by using structural equation modeling to assess support for aspects of this behavioral activation model. Participants were 630 Japanese undergraduate students and vocational school students. Results provided preliminary support for the model. Treating both avoidance and activating behavior might contribute to decreased impairment.

Japanese Society of Anxiety and Related Disorders/Japanese Society of Neuropsychopharmacology: Clinical practice guideline for social anxiety disorder (2021).

The development of clinical practice guidelines for social anxiety disorder began in March 2018 when the Joint Clinical Practice Guideline Development Committee for Anxiety and Obsessive-Compulsive Disorders was formed by the Japanese Society of Anxiety and Related Disorders and Japanese Society of Neuropsychopharmacology to jointly develop guidelines for anxiety and obsessive-compulsive disorders. Based on the universal concept of evidence-based medicine, three clinical questions (CQs) about pharmacotherapy and psychotherapy were developed for clinical guidelines for social anxiety disorder, panic disorders, and obsessive-compulsive disorder in accordance with the Minds "Manual for Guidelines Development 2017 by the Japan Council for Quality Health Care: CQ1-"What is the recommended pharmacotherapy for social anxiety disorder in adults?"; CQ2-"What is the recommended psychotherapy (psychological intervention) for social anxiety disorder in adults?"; and CQ3-"What are the recommendations regarding monotherapy and combination therapy for social anxiety disorder in adults in terms of pharmacotherapy and psychotherapy (psychological interventions)?" Summarized recommendations for social anxiety disorder in adults are selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitor for CQ1, cognitive behavioral therapy for CQ2, and there are no recommendations regarding monotherapy and combination therapy for CQ3. These were answered by considering the balance between benefits and harms based on systematic reviews of each. The aim of this brief guideline for the standard-of-care (i.e., medical treatment) for social anxiety disorder in adults (18 years and older) was to help "shared decision making," in which medical professionals, including physicians, and patients share scientific evidence to decide on a course of treatment.

Preliminary Evaluation of Translated and Culturally Adapted Internet-Delivered Cognitive Therapy for Social Anxiety Disorder: Multicenter, Single-Arm Trial in Japan.

BACKGROUND: Internet-delivered cognitive therapy for social anxiety disorder (iCT-SAD), which is a therapist-guided modular web-based treatment, has shown strong efficacy and acceptability in English-language randomized controlled trials in the United Kingdom and Hong Kong. However, it is not yet known whether iCT-SAD can retain its efficacy following linguistic translation and cultural adaptation of treatment contents and implementation in other countries such as Japan. OBJECTIVE: This study aimed to examine the preliminary efficacy and acceptability of the translated and culturally adapted iCT-SAD in Japanese clinical settings. METHODS: This multicenter, single-arm trial recruited 15 participants with social anxiety disorder. At the time of recruitment, participants were receiving usual psychiatric care but had not shown improvement in their social anxiety and required additional treatment. iCT-SAD was provided in combination with usual psychiatric care for 14 weeks (treatment phase) and for a subsequent 3-month follow-up phase that included up to 3 booster sessions. The primary outcome measure was the self-report version of the Liebowitz Social Anxiety Scale. The secondary outcome measures examined social anxiety-related psychological processes, taijin kyofusho (the fear of offending others), depression, generalized anxiety, and general functioning. The assessment points for the outcome measures were baseline (week 0), midtreatment (week 8), posttreatment (week 15; primary assessment point), and follow-up (week 26). Acceptability was measured using the dropout rate from the treatment, the level of engagement with the program (the rate of module completion), and participants' feedback about their experience with the iCT-SAD. RESULTS: Evaluation of the outcome measures data showed that iCT-SAD led to significant improvements in social anxiety symptoms during the treatment phase (P<.001; Cohen d=3.66), and these improvements were maintained during the follow-up phase. Similar results were observed for the secondary outcome measures. At the end of the treatment phase, 80% (12/15) of participants demonstrated reliable improvement, and 60% (9/15) of participants demonstrated remission from social anxiety. Moreover, 7% (1/15) of participants dropped out during treatment, and 7% (1/15) of participants declined to undergo the follow-up phase after completing the treatment. No serious adverse events occurred. On average, participants completed 94% of the modules released to them. Participant feedback was positive and highlighted areas of strength in treatment, and it included further suggestions to improve suitability for Japanese settings. CONCLUSIONS: Translated and culturally adapted iCT-SAD demonstrated promising initial efficacy and acceptability for Japanese clients with social anxiety disorder. A randomized controlled trial is required to examine this more robustly.

Antidepressants for social anxiety disorder: A systematic review and meta-analysis.

AIM: This systematic review is aimed to update and reintegrate the pharmacotherapy of social anxiety disorder (SAD), including the Japanese medical database. METHODS: We conducted a systematic review and meta-analysis of pharmacotherapy of SAD according to the Medical Information Distribution Service. We used data from a most recent systematic review, and updated search were conducted using MEDLINE, PubMed, CENTRAL, ICTRP, and ICHUSHI from August 1st, 2017 to January 31st, 2022. The outcome were response rates assessed by Clinical Global Impressions Improvement, efficacy assessed by the Liebowitz Social Anxiety Scale (LSAS), and dropout rates. We performed a random effect of meta-analysis to obtain the differences in each outcome between active medication and placebo. We used RevMan version 5.3 for analyses. RESULTS: We identified 5 studies through update search and performed meta-analysis for 33 studies on selective serotonin reuptake inhibitor (SSRI) and 6 studies on serotonin noradrenalin reuptake inhibitor (SNRI). The response rate (RR = 1.62) and the LSAS score reduction (mean difference = -9.65) of SSRI, and the response rate (RR = 1.57) and the LSAS score reduction (mean difference = -11.72) of SNRI were significantly different from placebo. The dropout rates of SSRI or SNRI were not significant. The response rates of SSRIs in both Japanese studies (RR = 1.44) and countries other than Japan (RR = 1.67) were significant. Most findings were based on low quality of evidence. CONCLUSION: SSRIs are valid option for pharmacotherapy of SAD including Japanese patients. SNRIs are another effective option. However, the results should be interpreted cautiously due to several risk of bias.

Camptothecin (CPT) directly binds to human heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) and inhibits the hnRNP A1/topoisomerase I interaction.

Camptothecin (CPT) is an anti-tumor natural product that forms a ternary complex with topoisomerase I (top I) and DNA (CPT-top I-DNA). In this study, we identified the direct interaction between CPT and human heterogeneous nuclear ribonucleoprotein A1 (hnRNP A1) using the T7 phage display technology. On an avidin-agarose bead pull down assay, hnRNP A1 protein was selectively pulled down in the presence of C20-biotinylated CPT derivative (CPT-20-B) both in vitro and in vivo. The interaction was also confirmed by an analysis on a quartz-crystal microbalance (QCM) device, yielding a K(D) value of 82.7 nM. A surface plasmon resonance (SPR) analysis revealed that CPT inhibits the binding of hnRNP A1 to top I (K(D): 260 nM) in a non-competitive manner. Moreover, an in vivo drug evaluation assay using Drosophila melanogaster showed that the knockout of the hnRNP A1 homolog Hrb87F gene showed high susceptibility against 5-50 µM of CPT as compared to a wild-type strain. Such susceptibility was specific for CPT and not observed after treatment with other cytotoxic drugs. Collectively, our data suggests that CPT directly binds to hnRNP A1 and non-competitively inhibits the hnRNP A1/top I interaction in vivo. The knockout strain loses the hnRNP A1 homolog as a both CPT-binding partner and naïve brakes of top I, which enhances the formation of the CPT-top I-DNA ternary complexes and subsequently sensitizes the growth inhibitory effect of CPT in D. melanogaster.

The effects of video and nonnegative social feedback on distorted appraisals of bodily sensations and social anxiety.

The effects of video feedback and nonnegative feedback from other people were examined as possibly ameliorating distorted appraisals of bodily sensations, as well as subjective and physiological anxiety in socially anxious individuals. Nonnegative feedback from a confederate emphasized the absence of negative outcomes (e.g., did not seem to tremble) rather than the presence of positive outcomes (e.g., looked calm). Socially anxious students were randomly assigned to either the experimental group, which received video and social feedback (n=12), or the control group (n 13). Participants were asked to give a videotaped speech twice. After the first speech, the experimental group watched the videotape of their speech and received feedback from a confederate, whereas the control group watched the video of another person's speech. The intervention improved distorted appraisal of bodily sensations and anticipatory anxiety for the experimental group. However, there were no differential effects on anxiety between the groups during speeches.

Implicit and explicit associations in the fear structure of social anxiety.

Summary.-Implicit associations in the fear structure of social anxiety were investigated and their relations with explicit associations were examined in the present study. The Implicit Association Test was used to assess implicit associations. Individuals scoring High (n = 26) and Low (n = 18) on Social Anxiety completed two forms of the Implicit Association Test and rated the probability and cost of negative social outcomes. Analyses showed an implicit association between anxiety responses and negative evaluations was more strongly formed in the High Social Anxiety group than in the Low Social Anxiety group. Furthermore, relations between implicit associations and explicit measures were minimal. These findings suggested that the Implicit Association Test is suitable for the assessment of implicit associations in the fear structure of social anxiety, and that implicit associations of social anxiety are relatively independent of explicit associations.

[Distorted cognition of bodily sensations in subtypes of social anxiety].

The purpose of this study was to investigate the relationship between subtypes of social anxiety and distorted cognition of bodily sensations. The package of questionnaires including the Social Phobia Scale (SPS) and the Social Interaction Anxiety Scale (SIAS) was administered to 582 undergraduate students. To identify subtypes of social anxiety, cluster analysis was conducted using scores of the SPS and SIAS. Five clusters were identified and labeled as follows: Generalized type characterized by intense anxiety in most social situations, Non-anxious type characterized by low anxiety levels in social situations, Averaged type whose anxiety levels are averaged, Interaction anxiety type who feels anxiety mainly in social interaction situations, and Performance anxiety type who feels anxiety mainly in performance situations. Results of an ANOVA indicated that individuals with interaction type fear the negative evaluation from others regarding their bodily sensations whereas individuals with performance type overestimate the visibility of their bodily sensations to others. Differences in salient aspects of cognitive distortion among social anxiety subtypes may show necessity to select intervention techniques in consideration of subtypes.

Effects of safety behaviour on the maintenance of anxiety and negative belief social anxiety disorder.

BACKGROUND: Safety behaviour plays an important role in the maintenance of social anxiety disorder (SAD). SAD patients engage in various safety behaviours in social situations in order to decrease the risk of negative evaluations from others. AIMS: The present study examined the effect of safety behaviour on the maintenance of anxiety and negative belief in SAD by using Structural Equation Modelling (SEM). METHODS: Participants were a healthy group (442) and a SAD group (46) who met the SAD criteria for DSM-IV and who had high scores of SAD symptoms. In the assumed maintenance model, independence variables were safety and avoidance behaviour and dependence variables were anxiety and negative belief. RESULTS: This result showed that the SAD group significantly has more high scores than the healthy group in all scales of anxiety, negative belief and avoidance behaviour, expect for safety behaviour. The result of the multiple-group procedure indicated that safety behaviour contributes more strongly to anxiety and negative belief in the SAD group than in the healthy group. CONCLUSIONS: It is speculated that the SAD group have a stronger link between safety behaviour and negative belief than the healthy group, whereas frequency of the use of safety behaviour is equivalent between two groups. These results support the findings of previous studies.

DmGEN shows a flap endonuclease activity, cleaving the blocked-flap structure and model replication fork.

Drosophila melanogaster XPG-like endonuclease (DmGEN) is a new category of nuclease belonging to the RAD2/XPG family. The DmGEN protein has two nuclease domains (N and I domains) similar to XPG/class I nucleases; however, unlike class I nucleases, in DmGEN these two nuclease domains are positioned close to each other as in FEN-1/class II and EXO-1/class III nucleases. To confirm the properties of DmGEN, we characterized the active-site mutant protein (E143A E145A) and found that DmGEN had flap endonuclease activity. DmGEN possessed weak nick-dependent 5'-3' exonuclease activity. Unlike XPG, DmGEN could not incise the bubble structure. Interestingly, based on characterization of flap endonuclease activity, DmGEN preferred the blocked-flap structure as a substrate. This feature is distinctly different from FEN-1. Furthermore, DmGEN cleaved the lagging strand of the model replication fork. Immunostaining revealed that DmGEN was present in the nucleus of actively proliferating Drosophila embryos. Thus, our studies revealed that DmGEN belongs to a new class (class IV) of the RAD2/XPG nuclease family. The biochemical properties of DmGEN and its possible role are also discussed.

Selective Inactivation of Bacteriophage in the Presence of Bacteria by Use of Ground Rh-Doped SrTiO3 Photocatalyst and Visible Light.

Bacteriophage (denoted as phage) infection in the bacterial fermentation industry is a major problem, leading to the loss of fermented products such as alcohol and lactic acid. Currently, the prevention of phage infection is limited to biological approaches, which are difficult to apply in an industrial setting. Herein, we report an alternative chemical approach using ground Rh-doped SrTiO3 (denoted as g-STO:Rh) as a visible-light-driven photocatalyst. The g-STO:Rh showed selective inactivation of phage without bactericidal activity when irradiated with visible light (λ > 440 nm). After inactivation, the color of g-STO:Rh changed from gray to purple, suggesting that the Rh valence state partially changed from 3+ to 4+ induced by photocatalysis, as confirmed by diffuse reflectance spectroscopy. To study the effect of the Rh4+ ion on phage inactivation under visible-light irradiation, the survival rate of phage for g-STO:Rh was compared to that for ground Rh,Sb-codoped SrTiO3 (denoted as g-STO:Rh,Sb), where the change of Rh valence state from 3+ to 4+ is almost suppressed under visible-light irradiation due to charge compensation by the Sb5+ ion. Only g-STO:Rh effectively inactivated phage, which indicated that Rh4+ ion induced by photocatalysis particularly contributed to phage inactivation under visible-light irradiation. These results suggested that g-STO:Rh has potential as an antiphage material in bacterial fermentation.

Characterization of a second proliferating cell nuclear antigen (PCNA2) from Drosophila melanogaster.

The eukaryotic DNA polymerase processivity factor, proliferating cell nuclear antigen, is an essential component in the DNA replication and repair machinery. In Drosophila melanogaster, we cloned a second PCNA cDNA that differs from that encoded by the gene mus209 (for convenience called DmPCNA1 in this article). The second PCNA cDNA (DmPCNA2) encoded a 255 amino acid protein with 51.7% identity to DmPCNA1, and was ubiquitously expressed during Drosophila development. DmPCNA2 was localized in nuclei as a homotrimeric complex and associated with Drosophila DNA polymerase delta and epsilonin vivo. Treatment of cells with methyl methanesulfonate or hydrogen peroxide increased the amount of both DmPCNA2 and DmPCNA1 associating with chromatin, whereas exposure to UV light increased the level of association of only DmPCNA1. Our observations suggest that DmPCNA2 may function as an independent sliding clamp of DmPCNA1 when DNA repair occurs.

Drosophila damaged DNA binding protein 1 contributes to genome stability in somatic cells.

The damaged DNA-binding protein (DDB) complex consists of a heterodimer of p127 (DDB1) and p48 (DDB2) subunits and is believed to have a role in nucleotide excision repair (NER). We used the GAL4-UAS targeted expression system to knock down DDB1 in wing imaginal discs of Drosophila. The knock-down was achieved in transgenic flies using over-expression of inverted repeat RNA of the D-DDB1 gene [UAS-D-DDB1(650)-dsRNA]. As a consequence of RNA interference (RNAi), the fly had a shrunken wing phenotype. The wing spot test showed induced genome instability in transgenic flies with RNAi knock-down of D-DDB1 in wing imaginal discs. When Drosophila larvae with RNAi knock-down of D-DDB1 in wing imaginal discs were treated with the chemical mutagen methyl methanesulfonate (MMS), the frequency of flies with a severely shrunken wing phenotype increased compared to non-treated transgenic flies. These results suggested that DDB1 plays a role in the response to DNA damaged with MMS and in genome stability in Drosophila somatic cells.

DmGEN, a novel RAD2 family endo-exonuclease from Drosophila melanogaster.

A novel endo-exonuclease, DmGEN (Drosophila Melanogaster XPG-like endonuclease), was identified in D.melanogaster. DmGEN is composed of five exons and four introns, and the open reading frame encodes a predicted product of 726 amino acid residues with a molecular weight of 82.5 kDa and a pI of 5.36. The gene locus on Drosophila polytene chromosomes was detected at 64C9 on the left arm of chromosome 3 as a single site. The encoded protein showed a relatively high degree of sequence homology with the RAD2 nucleases, especially XPG. Although the XPG-N- and XPG-I-domains are highly conserved in sequence, locations of the domains are similar to those of FEN-1 and EXO-1, and the molecular weight of the protein is close to that of EXO-1. In vitro, DmGEN showed endonuclease and 3'-5' exonuclease activities with both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA), but the endonuclease action with dsDNA was quite specific: 5'-3' exonuclease activity was found to occur with nicked DNA, while dsDNA was endonucleolytically cut at 3-4 bp from the 5' end. Homologs are widely found in mammals and higher plants. The data suggest that DmGEN belongs to a new class of RAD2 nuclease.

Sporicidal performance induced by photocatalytic production of organic peroxide under visible light irradiation.

Bacteria that cause serious food poisoning are known to sporulate under conditions of nutrient and water shortage. The resulting spores have much greater resistance to common sterilization methods, such as heating at 100 °C and exposure to various chemical agents. Because such bacteria cannot be inactivated with typical alcohol disinfectants, peroxyacetic acid (PAA) often is used, but PAA is a harmful agent that can seriously damage human health. Furthermore, concentrated hydrogen peroxide, which is also dangerous, must be used to prepare PAA. Thus, the development of a facile and safe sporicidal disinfectant is strongly required. In this study, we have developed an innovative sporicidal disinfection method that employs the combination of an aqueous ethanol solution, visible light irradiation, and a photocatalyst. We successfully produced a sporicidal disinfectant one hundred times as effective as commercially available PAA, while also resolving the hazards and odor problems associated with PAA. The method presented here can potentially be used as a replacement for the general disinfectants employed in the food and health industries.

Purification of Drosophila DNA polymerase zeta by REV1 protein-affinity chromatography.

Studies on the biochemical properties of very-large-size eukaryotic DNA polymerases have been limited by the difficulty in obtaining sufficient purified forms of each enzyme. Our aim was to determine and elucidate the biochemical properties of one such polymerase, pol zeta (DNA polymerase zeta) from Drosophila melanogaster (Dmpol zeta). Using an REV1 (UV-revertible gene 1) protein-affinity column, we have isolated the enzyme directly from Drosophila embryos. Completely purified Dmpol zeta was found to have a molecular mass of approx. 240 kDa, and to be sensitive to aphidicolin and resistant to ddTTP (2',3'-dideoxythymidine-5-triphosphate) and N-ethylmaleimide. The enzyme has a preference for poly(dA)/oligo(dT)(10:1) as a template primer and has high processivity for DNA synthesis. Moreover, Dmpol zeta showed significantly higher fidelity compared with Rattus norvegicus DNA polymerase, an error-prone DNA polymerase, in an M13 forward mutation assay. The activities of bypassing pyrimidine dimers and (6-4) photoproducts and extending from mismatched primer-template termini in (6-4) photoproduct by Dmpol zeta were not detected. Drosophila REV7 interacted with Dmpol zeta in vitro, but did not influence the DNA synthesis activity of Dmpol zeta. The present study is the first report about characterization of purified pol zeta from multicellular organisms, and the second concerning the characterization of yeast pol zeta.

Enhancement of Cellulose Degradation by Cattle Saliva.

Saccharification of cellulose is a promising technique for producing alternative source of energy. However, the efficiency of conversion of cellulose into soluble sugar using any currently available methodology is too low for industrial application. Many additives, such as surfactants, have been shown to enhance the efficiency of cellulose-to-sugar conversion. In this study, we have examined first whether cattle saliva, as an additive, would enhance the cellulase-catalyzed hydrolysis of cellulose, and subsequently elucidated the mechanism by which cattle saliva enhanced this conversion. Although cattle saliva, by itself, did not degrade cellulose, it enhanced the cellulase-catalyzed degradation of cellulose. Thus, the amount of reducing sugar produced increased approximately 2.9-fold by the addition of cattle saliva. We also found that non-enzymatic proteins, which were present in cattle saliva, were responsible for causing the enhancement effect. Third, the mechanism of cattle saliva mediated enhancement of cellulase activity was probably similar to that of the canonical surfactants. Cattle saliva is available in large amounts easily and cheaply, and it can be used without further purification. Thus, cattle saliva could be a promising additive for efficient saccharification of cellulose on an industrial scale.