Mutation of the Thap4 gene causes dwarfism and testicular anomalies in rats and mice.

The petit (pet) locus is associated with dwarfism, testicular anomalies, severe thymic hypoplasia, and high postnatal lethality, which are inherited in autosomal recessive mode of inheritance in rats with a Wistar strain genetic background. Linkage analysis localized the pet locus between 98.7 Mb and 101.2 Mb on rat chromosome 9. Nucleotide sequence analysis identified 2 bp deletion in exon 2 of the Thap4 gene as the causative mutation for pet. This deletion causes a frameshift and premature termination codon, resulting in a truncated THAP4 protein lacking approximately two-thirds of the C-terminal side. Thap4 is expressed in various organs, including the testis and thymus in rats. To elucidate the biological function of THAP4 in other species, we generated Thap4 knockout mice lacking exon 2 of the Thap4 gene through genome editing. Thap4 knockout mice also exhibited dwarfism and small testis but did not show high postnatal lethality. Thymus weights of adult Thap4 knockout male mice were significantly higher compared to wild-type male mice. Although Thap4 knockout male mice were fertile, their testis contained seminiferous tubules with spermatogenesis and degenerative seminiferous tubules lacking germ cells. Additionally, we observed vacuoles in seminiferous tubules, and clusters of cells in the lumen in seminiferous tubules in Thap4 knockout male mice. These results demonstrate that spontaneous mutation of Thap4 gene in rats and knockout of Thap4 gene in mice both cause dwarfism and testicular anomalies. Thap4 gene in rats and mice is essential for normal testicular development, maintaining spermatogenesis throughout the entire region of seminiferous tubules.

Nursing Students' Use of Recovery Stories of People with Mental Illness in Their Experiences: A Qualitative Study.

This study clarified nursing students' experiences of an educational program where they listened to the recovery stories of individuals with mental illness in a classroom setting. In this qualitative study, the program was delivered to third year nursing students in December 2019 (n = 62), after which they completed an anonymous free-response questionnaire. The responses were classified into seven clusters: understanding how patients perceive and appraise nursing care practices; interpreting experiences of disease realistically; deciphering patients' histories based on their recovery stories; exploring ways to engage with patients based on knowledge of determinants of nursing care quality; finding ways to engage with patients grounded in respect; recognizing the importance of creating a therapeutic environment; gaining a sensitive understanding based on real-world stories. These clusters were grouped into "understanding the quality of nursing practices" and "gaining knowledge for application to nursing practices."

Subjective recovery accounts of Japanese female patients suffering from alcohol use disorder. A phenomenological study.

PURPOSE: This study aimed to examine the subjective recovery accounts of Japanese female patients with alcohol use disorder (AUD) and the factors that affect their recovery. DESIGN AND METHODS: This qualitative study used a phenomenological design. A focus group with 10 Japanese participants was conducted. FINDINGS: Five theme clusters emerged: drinking to forget unpleasant feelings, fighting compulsive cravings with craving, unhealed wounds from past traumatic experiences, encounters with role models in self-help groups, and changing one's mindset to a proactive pursuit of happiness. PRACTICE IMPLICATIONS: To support the recovery of women with AUD, psychiatric nurses should help them improve their family relationships, find recovery models, and proactively provide them with trauma-informed care.

Association between Regular Exercise and Self-Rated Health and Sleep Quality among Adults in Japan during the COVID-19 Pandemic.

Regular exercise may be associated with better self-rated health and sleep status. However, this correlation among various age groups, such as young, middle-aged, and older people, as well as during the COVID-19 pandemic, has not been examined. This study examined the correlation between regular exercise and self-rated health and sleep quality among adults in Japan during the COVID-19 pandemic. Data were collected using an online survey conducted between February 26 and 27, 2021. A total of 1410 adults in Japan (age range, 20-86 years) completed the online survey. Regular exercise was divided into: (1) more than 30 min of moderate exercise a day, (2) more than 2 days per week, and (3) continuous for 1 year or longer. Self-rated health and sleep quality were assessed using the Likert scale. After adjusting for multiple confounders, regular exercise was correlated with decreased poor self-rated health and poor sleep quality in middle-aged adults; however, no significant correlation was observed among young and older adults. The promotion of regular exercise among middle-aged people during the COVID-19 pandemic may contribute to better self-rated health and sleep quality status.

Resilience and related factors as predictors of relapse risk in patients with substance use disorder: a cross-sectional study.

BACKGROUND: Resilience, referring to the inherent ability to naturally recover in the face of adverse conditions, is an essential concept in discussions of substance use disorder (SUD) recovery. This study's objective was to shed light on resilience and related factors that affect relapse risk in patients with SUDs. METHOD: Fifty-two patients with SUDs were given a self-administrated questionnaire from February to April 2015 consisting of question items for sociodemographic characteristics, relapse risk (Stimulant Relapse Risk Scale), and resilience (Bidimensional Resilience Scale). Scale scores were tested for associations with subject attributes, after which resilience's effects on relapse risk were analyzed using correlation and multiple regression (forced-entry) analyses. RESULTS: Stimulants were the most common substance related to SUD (n = 26, 21.7%; multiple answers). Bivariate correlation showed that higher acquired resilience was significantly associated with a lower relapse risk (r = - 0.314, P < 0.01). Reduced relapse risk was significantly associated with current employment (Std. ß = - 0.446, P < 0.05). CONCLUSION: Our findings demonstrate the necessity of recovery support to enhance acquired resistance in patients with SUDs to prevent relapses. Reinforcing employment support services and encouraging patients to continue treatment were suggested as potentially effective measures to enhance resilience in individuals with SUDs on their road to recovery.

A Japanese version of the stressors in nursing students (SINS) scale.

OBJECTIVES: To translate and study the factor structure of a Japanese version of the Stressors in Nursing Students scale. METHODS: The Stressors in Nursing Students scale was translated into Japanese and administered to a large cohort (N = 1298) of female Japanese nursing students across five universities and across all four years of the nursing programme. The data were analysed using exploratory factor analysis. RESULTS: Exploratory factor analysis revealed four factors: 'Clinical'; 'Conflict and confidence'; 'Education'; and 'Free time'. The relationship between the total score on the Stressors in Nursing Students scale and the demographic aspects of the sample was weak but there was a significant increase in the perception of stressors between first and second year students. CONCLUSIONS: There were similarities and differences between the perception of stressors by nursing students in Japan compared with, for example, the United Kingdom and China mainland. While a four-factor structure was found here, the distribution of items in the Stressors in Nursing Students scale differed from previous studies in the United Kingdom and China with the 'Free time' factor being unique to this study. Stress is an issue for nursing students and is related to the specific stressors they encounter in the process of their work and study. Findings can inform the development of strategies to reduce such stressors among nursing students in multiple, global contexts.

Synthetic Study toward Total Synthesis of (±)-Germine: Synthesis of (±)-4-Methylenegermine.

The total synthesis of 4-methylenegermine is described.

Resilience Associated with Self-Disclosure and Relapse Risks in Patients with Alcohol Use Disorders.

BACKGROUND: The aim of this study was to clarify the self-disclosure and risks of relapse associated with promoting resilience of patients with alcohol use disorders (AUD) and participating in self-help groups. METHODS: An anonymous, self-administered questionnaire survey was administered to 48 patients with AUD and participating in self-help groups; this questionnaire consisted of basic attributes, a bidimensional resilience scale to assess both innate and acquired resilience factors, a scale to assess depth of self-disclosure, and a scale assessing relapse risks. We conducted an evaluation by dividing the respondents into a high group and low group based on their median values for both innate and acquired resilience. RESULTS: Innate/acquired resilience had a mutually reinforcing relationship, and, compared with the low resilience group, the high resilience group had significantly reduced risks for relapses and resulted in deeper self-disclosure. CONCLUSION: Patients with high resilience had lower risk of alcohol relapse and deeper self-disclosure. The results suggest that one way of supporting patients with AUD in recovery is assisting them in building personal relationships with others and in deepening self-disclosure in a setting where they can relax, thus promoting their natural ability to recover.

Regiospecific and stereoselective syntheses of (+/-) morphine, codeine, and thebaine via a highly stereocontrolled intramolecular 4 + 2 cycloaddition leading to a phenanthrofuran system.

Total syntheses of the morphine alkaloids are described that use a direct stereoselective formation of the phenanthrofuran system via an intramolecular 4 + 2 cycloaddition of a diene tethered to the 4-position of a 7-methoxybenzofuran-3-carboxylic acid ester.

Pyranonaphthoquinone lactones: a new class of AKT selective kinase inhibitors alkylate a regulatory loop cysteine.

The naturally occurring pyranonaphthoquinone (PNQ) antibiotic lactoquinomycin and related aglycones were found to be selective inhibitors of the serine-threonine kinase AKT. A set of synthetic PNQs were prepared and a minimum active feature set and preliminary SAR were determined. PNQ lactones inhibit the proliferation of human tumor cell lines containing constitutively activated AKT and show expected effects on cellular biomarkers. Biochemical data are presented supporting a proposed bioreductive alkylation mechanism of action.

Successful pregnancy and delivery after transfer of a single blastocyst derived from a vitrified mature human oocyte.

OBJECTIVE: To describe the first case of delivery after the transfer of a single blastocyst derived from a vitrified mature human oocyte. DESIGN: Case report. SETTING: Private assisted reproduction clinic. PATIENT(S): A normal 31-year-old woman. INTERVENTION(S): An unsuccessful attempt was made to extract sperm from the patient's nonobstructive azoospermic husband by testicular sperm extraction. MAIN OUTCOME MEASURE(S): Transfer of single blastocyst derived from vitrified human oocyte and donor sperm. RESULT(S): A healthy male neonate weighing 3000 g was born. CONCLUSION(S): Vitrification is a useful method of preserving mature human oocytes and has the advantage of time-effectiveness, simplicity, cost reduction, and no need for devices such as programmable freezers.

Synthesis and activity of novel analogs of hemiasterlin as inhibitors of tubulin polymerization: modification of the A segment.

Analogs of hemiasterlin (1) and HTI-286 (2), which contain various aromatic rings in the A segment, were synthesized as potential inhibitors of tubulin polymerization. The structure-activity relationships related to stereo- and regio-chemical effects of substituents on the aromatic ring in the A segment were studied. Analogs, which carry a meta-substituted phenyl ring in the A segment show comparable activity for inhibition of tubulin polymerization to 2, as well as in the cell proliferation assay using KB cells containing P-glycoprotein, compared to those of 1 and 2.

Synthesis and biological activity of analogues of the antimicrotubule agent N,beta,beta-trimethyl-L-phenylalanyl-N(1)-[(1S,2E)-3-carboxy-1-isopropylbut-2-enyl]- N(1),3-dimethyl-L-valinamide (HTI-286).

Hemiasterlin, a tripeptide isolated from marine sponges, induces microtubule depolymerization and mitotic arrest in cells. HTI-286, an analogue from an initial study of the hemiasterlins, is presently in clinical trials. In addition to its potent antitumor effects, 2 has the advantage of circumventing the P-glycoprotein-mediated resistance that hampers the efficacy of other antimicrotubule agents such as paclitaxel and vincristine in animal models. This paper describes an in-depth study of the structure--activity relationships of analogues of 2, their effects on microtubule polymerization, and their in vitro and in vivo anticancer activity. Regions of the molecule necessary for potent activity are identified. Groups tolerant of modification, leading to novel analogues, are reported. Potent analogues identified through in vivo studies in tumor xenograft models include one superior analogue, HTI-042.

D-piece modifications of the hemiasterlin analog HTI-286 produce potent tubulin inhibitors.

Modifications of the D-piece carboxylic acid group of the hemiasterlin analog HTI-286 gave tubulin inhibitors which were potent cytotoxic agents in taxol resistant cell lines expressing P-glycoprotein. Amides derived from proline had potency comparable to HTI-286. Reduction of the carboxylic acid to ketones and alcohols or its conversion to acidic heterocycles also gave potent analogs. Synthetic modifications of the carboxylic acid could be carried out selectively using a wide range of synthetic reagents. Proline analog 3 was found to be effective in a human xenograft model in athymic mice.

Purification and characterization of an aldehyde oxidase from Pseudomonas sp. KY 4690.

An aldehyde oxidase, which oxidizes various aliphatic and aromatic aldehydes using O(2) as an electron acceptor, was purified from the cell-free extracts of Pseudomonas sp. KY 4690, a soil isolate, to an electrophoretically homogeneous state. The purified enzyme had a molecular mass of 132 kDa and consisted of three non-identical subunits with molecular masses of 88, 39, and 18 kDa. The absorption spectrum of the purified enzyme showed characteristics of an enzyme belonging to the xanthine oxidase family. The enzyme contained 0.89 mol of flavin adenine dinucleotide, 1.0 mol of molybdenum, 3.6 mol of acid-labile sulfur, and 0.90 mol of 5'-CMP per mol of enzyme protein, on the basis of its molecular mass of 145 kDa. Molecular oxygen served as the sole electron acceptor. These results suggest that aldehyde oxidase from Pseudomonas sp. KY 4690 is a new member of the xanthine oxidase family and might contain 1 mol of molybdenum-molybdpterin-cytosine dinucleotide, 1 mol of flavin adenine dinucleotide, and 2 mol of [2Fe-2S] clusters per mol of enzyme protein. The enzyme showed high reaction rates toward various aliphatic and aromatic aldehydes and high thermostability.

Muraymycins, novel peptidoglycan biosynthesis inhibitors: synthesis and SAR of their analogues.

A series of Muraymycin analogues was synthesized. These analogues showed excellent antimicrobial activity against gram-positive organisms. These analogues also showed excellent inhibitory activity against the target peptidoglycan biosynthesis enzyme MraY, the cell membrane associated transglycosylase responsible for the formation of Lipid II.

Use of bis-(chiral alpha-methylbenzyl)glycine esters for synthesis of enantiopure beta-hydroxyamino esters.

[reaction: see text] Aldol reactions using bis-(chiral alpha-methylbenzyl)glycine esters with aldehydes gave excellent diastereoselectivity. Thus, an enantiopure ribosylglycine was prepared for the synthesis of analogues of the natural antibiotics muraymycin. This method was extended for formation of beta-hydroxyamino esters.

Effects of epinephrine on underperfusion-reperfusion injuries in diabetic and non-diabetic rat hearts.

The sympathetic nervous systems may bear relevance to the increased incidence of heart failure in diabetes (DM). In our isolated rat hearts perfused at constant low flow rate, norepinephrine dose-dependently enhanced diabetic myocardial damage, particularly during underperfusion. The purpose of this investigation is to examine the effects of epinephrine on the ischemic injury and on the reperfusion injury in DM and non-DM rat hearts, and to clarify whether the cardiac states during underperfusion at constant low pressure are similar to those at constant low flow rate. Isolated streptozotocin-induced 6-week DM and non-DM rat hearts with a balloon in the left ventricle (LV) were paced and normal perfused at 75 cm H2O with normoxic Krebs-Henseleit solution. Then the hearts were underperfused at 35 cm H2O, a constant low pressure with below one-third of the pre-ischemic coronary perfusion flow (CPF) level. Four min after the start of underperfusion, the perfusate was changed to that containing epinephrine 10(-6) M. After 45 min underperfusion with or without epinephrine, all of the hearts were reperfused without epinephrine at 75 cm H2O for 45 min. To detect changes in LV stiffness, the isometric tension along the longitudinal direction of the whole heart and the LV isovolumic pressure were monitored simultaneously. In DM hearts, the underperfusion alone caused a slight increase in LV stiffness, and all the changes recovered to the pre-ischemic levels during reperfusion. Epinephrine during underperfusion accelerated the start of increase in LV stiffness and the decrease in CPF. During reperfusion the changes recovered partly to the control levels. In non-DM hearts, epinephrine during underperfusion caused only a slight increase in LV stiffness though a similar low CPF to DM hearts. However, the reperfusion caused a marked increase in LV stiffness and a lower recovery of CPF. Epinephrine at constant low pressure, as well as norepinephrine at constant low flow rate, enhanced the ischemic injury, particularly in DM hearts, while aggravated the reperfusion injury in non-DM hearts.

Inhibition of Src kinase activity by 4-anilino-7-thienyl-3-quinolinecarbonitriles.

Based on a screening lead from a yeast-based assay to identify Src family kinase inhibitors, a series of 4-anilino-7-thienyl-3-quinolinecarbonitriles was prepared. When the thiophene ring was substituted with a water-solubilizing group in a 2,5-, 3,5- or 2,4-pattern, potent inhibition of Src kinase activity was observed.