Work, Self, and Society: A Socio-historical Study of Morita Therapy.

Morita therapy is known as a psychotherapy grounded in the culture of Japan, particularly its Buddhist culture. Its popularity in Japan and other East Asian countries is cited as an example of the relevance and importance of culture and religion in psychotherapy. To complement such interpretations, this study adopts a socio-historical approach to examine the role and significance of work in Morita's theory and practice within the broader work environment and culture of the 1920s and 1930s in Japan. Morita conceptualized shinkeishitsu as a personality disease and a social illness caused by an alienating work environment. He proposed a remedy that emphasized the subjective emotional experience of work. To his primarily middle-class clients and readers, Morita's reconciliation between the self and society and that between autonomy and compliance was persuasive and useful, providing a philosophy whereby they could integrate into the work environment without loss of self-worth. The socio-historical character of Morita therapy is vital to understanding its power and appeal during Morita's time. Moreover, it sheds light on the complex interrelationships between work, mental health, and society.

Imipenem/funobactam (formerly XNW4107) in vivo pharmacodynamics against serine carbapenemase-producing Gram-negative bacteria: a novel modelling approach for time-dependent killing.

BACKGROUND: Imipenem/funobactam (formerly XNW4107) is a novel ß-lactam/ß-lactamase inhibitor with activity against MDR Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacterales strains. Using a neutropenic murine thigh infection model, we aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) index, relative to funobactam exposure, that correlated most closely with the in vivo efficacy of imipenem/funobactam combination and the magnitude of index required for efficacy against serine carbapenemase-producing clinical strains. METHODS: Dose-fractionation was conducted against three strains. Imipenem human-simulated regimen (HSR, 500 mg q6h 1 h infusion) efficacy in combination with escalating funobactam exposures against seven A. baumannii, four P. aeruginosa and four Klebsiella pneumoniae (imipenem/funobactam MICs 0.25-16 mg/L) was assessed as 24 h change in log10cfu/thigh. RESULTS: Increased funobactam fractionation enhanced efficacy, indicating time-dependent killing. Changes in log10cfu/thigh versus %fT > MIC were poorly predictive of efficacy; bactericidal activity was observed at %fT > MIC = 0%. Across different threshold plasma funobactam concentrations (CTs), %fT > CT(1 mg/L) had the highest correlation with efficacy. Normalizing the %fT > CT = 1 mg/L index to the respective isolate imipenem/funobactam MIC ([%fT > CT]/MIC) allowed integration of the isolate's susceptibility, which further enhanced the correlation. Median (%fT > CT[1 mg/L])/MIC values associated with 1-log reductions were 9.82 and 9.90 for A. baumannii and P. aeruginosa, respectively. Median (%fT > CT[1 mg/L])/MIC associated with stasis was 55.73 for K. pneumoniae. Imipenem/funobactam 500/250 mg q6h 1 h infusion HSR produced >1-log kill against 6/7 A. baumannii, 4/4 P. aeruginosa and stasis against 4/4 K. pneumoniae. CONCLUSIONS: Imipenem/funobactam showed potent in vivo efficacy against serine carbapenemase-producers. The novel PK/PD index (%fT > CT)/MIC appeared to best describe in vivo activity.

Hypnosis, psychoanalysis, and Morita therapy: the evolution of Kokyo Nakamura's psychotherapeutic theories and practices.

Psychotherapy had developed into a dynamic and diverse field in pre-war Japan. Apart from thousands of spiritually oriented lay psychotherapists, there were a few quasi-professional practitioners who insisted on a rational approach and experimented with a variety of psychotherapeutic methods. Among them was Kokyo Nakamura, whose quest for a viable psychotherapeutic method is intriguing and illuminating. This paper examines the evolution of Nakamura's theories and practices by dividing it into three stages: hypnotic suggestion, psychoanalysis, and Morita therapy. His pragmatic and adaptive approach to psychotherapy provides not only an interesting example for studying the spread of psychotherapy across nations and cultures, but also valuable clues to understanding its nature as a body of knowledge and therapeutic method.

Seeking double personality: Nakamura Kokyo's work in abnormal psychology in early 20th-century Japan.

This paper examines Nakamura Kokyo's study of a woman with a split personality who lived in his home as a maid from 1917 until her death in 1940. She was his indispensable muse and assistant in his efforts to promote abnormal psychology and psychotherapy. This paper first explores the central position of multiple personality in Nakamura's theory of the subconscious, which was largely based on the model of dissociation. It then examines how it became a central issue in Nakamura's disputes with religions including the element of spirit possession, which invoked Western psychical research to modernize their doctrines. While both were concerned with the subconscious and alterations in personality, Nakamura's psychological view was distinguished from those spiritual understandings by his emphasis on individual memories, particularly those that were traumatic, and hysteria. The remaining sections of the paper will examine Nakamura's views on memory and hysteria, which conflicted with both the academic mainstream and the established cultural beliefs. This conflict may partly explain the limited success of Nakamura's academic and social campaigns.

The moral power of suggestion: A history of suggestion in Japan, 1900-1930.

In Japan, as in the west, suggestion theory was the predominant theory of hypnosis, and suggestive therapy was one of the most important, if not the most important, form of psychotherapy in the early 20th century. While the use of suggestion was met with objections on both scientific and moral grounds in the west, it was seen in a more positive light and has had a significant influence on the development of psychotherapy in Japan. With regard to the contexts of suggestion, suggestive power, suggestibility, and the effects of suggestion, this study will examine the distinctive conceptions and practices of suggestion developed by analogy with existing ideas about interpersonal influence, particularly with the concept of kanka (assimilative transformation) in Japan. They provide an interesting comparison to the western ideas of suggestion, helping us understand the historical and cultural particularity of western dynamic psychiatry and psychotherapy, particularly their presumptions about interpersonal influence.

In-silico guided discovery of novel CCR9 antagonists.

Antagonism of CCR9 is a promising mechanism for treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease. There is limited experimental data on CCR9 and its ligands, complicating efforts to identify new small molecule antagonists. We present here results of a successful virtual screening and rational hit-to-lead campaign that led to the discovery and initial optimization of novel CCR9 antagonists. This work uses a novel data fusion strategy to integrate the output of multiple computational tools, such as 2D similarity search, shape similarity, pharmacophore searching, and molecular docking, as well as the identification and incorporation of privileged chemokine fragments. The application of various ranking strategies, which combined consensus and parallel selection methods to achieve a balance of enrichment and novelty, resulted in 198 virtual screening hits in total, with an overall hit rate of 18%. Several hits were developed into early leads through targeted synthesis and purchase of analogs.

Straighten the Back to Sit: Belly-Cultivation Techniques as "Modern Health Methods" in Japan, 1900-1945.

In Japan, the first half of the twentieth century saw a remarkable revival of concern with the cultivation of the belly, with a variety of belly-cultivation techniques, particularly breathing exercise and meditative sitting, widely practiced for improving health and treating diseases. This article carefully examines some practitioners' experiences of belly-cultivation practice in attempting to understand its healing effects for them within their life histories and contemporary intellectual, social and cultural contexts. It shows that belly-cultivation practice served as a medium for some practitioners to reflect on and retell their life stories, and that the personal charisma of certain masters and the communities developing around them provided practitioners with a valuable sense of belonging in an increasingly industrialized and urbanized society. Moreover, these belly-cultivation techniques provided an embodied way for some to explore and affirm their sense of self and develop individual identity. While they were increasingly promoted as cultural traditions capable of cultivating national character, they also served as healing practices by inspiring practitioners with a sense of collective identity and purpose. With these analyses, this article sheds light on the complicated meanings of belly-cultivation for practitioners, and provides illustrative examples of the multitude of meanings of the body, bodily cultivation and healing.

A Disorder of Qi: Breathing Exercise as a Cure for Neurasthenia in Japan, 1900-1945.

Neurasthenia became a common disease and caused widespread concern in Japan at the turn of the twentieth century, whereas only a couple of decades earlier the term "nerve" had been unfamiliar, if not unknown, to many Japanese. By exploring the theories and practices of breathing exercise-one of the most popular treatments for neurasthenia at the time-this paper attempts to understand how people who practiced breathing exercises for their nervous ills perceived, conceived, and accordingly cared for their nerves. It argues that they understood "nerve" based on their existing conceptions of qi Neurasthenia was for them a disorder of qi, although the qi had assumed modern appearances as blood and nervous current. The paper hopes to contribute to the understanding of how the concept of nerves has been accepted and assimilated in East Asia. It also points out the need to understand the varied cultures of nerves not only at the level of concept and metaphor, but also at the level of perception and experience.

Overview of strategies to improve the antibacterial property of dental implants.

The increasing number of peri-implant diseases and the unsatisfactory results of conventional treatment are causing great concern to patients and medical staff. The effective removal of plaque which is one of the key causes of peri-implant disease from the surface of implants has become one of the main problems to be solved urgently in the field of peri-implant disease prevention and treatment. In recent years, with the advancement of materials science and pharmacology, a lot of research has been conducted to enhance the implant antimicrobial properties, including the addition of antimicrobial coatings on the implant surface, the adjustment of implant surface topography, and the development of new implant materials, and significant progress has been made in various aspects. Antimicrobial materials have shown promising applications in the prevention of peri-implant diseases, but meanwhile, there are some shortcomings, which leads to the lack of clinical widespread use of antimicrobial materials. This paper summarizes the research on antimicrobial materials applied to implants in recent years and presents an outlook on the future development.

Novel targets for immunotherapy associated with exhausted CD8 + T cells in cancer.

In response to prolonged stimulation by tumour antigens, T cells gradually become exhausted. There is growing evidence that exhausted T cells not only lose their potent effector functions but also express multiple inhibitory receptors. Checkpoint blockade (CPB) therapy can improve cancer by reactivating exhausted effector cell function, leading to durable clinical responses, but further improvements are needed given the limited number of patients who benefit from treatment, even with autoimmune complications. Here, we suggest, based on recent advances that tumour antigens are the primary culprits of exhaustion, followed by some immune cells and cytokines that also play an accomplice role in the exhaustion process, and we also propose that chronic stress-induced hypoxia and hormones also play an important role in promoting T-cell exhaustion. Understanding the classification of exhausted CD8+ T-cell subpopulations and their functions is important for the effectiveness of immune checkpoint blockade therapies. We mapped the differentiation of T-cell exhausted subpopulations by changes in transcription factors, indicating that T-cell exhaustion is a dynamic developmental process. Finally, we summarized the novel immune checkpoints associated with depletion in recent years and combined them with bioinformatics to construct a web of exhaustion-related immune checkpoints with the aim of finding novel therapeutic targets associated with T-cell exhaustion in malignant tumours, aiming to revive the killing ability of exhausted T cells and restore anti-tumour immunity through combined targeted immunotherapy.

Discovery of potent and selective matrix metalloprotease 12 inhibitors for the potential treatment of chronic obstructive pulmonary disease (COPD).

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease associated with irreversible progressive airflow limitation. Matrix metalloproteinase-12 (MMP-12) has been characterized to be one of the major proteolytic enzymes to induce airway remodeling, destruction of elastin and the aberrant remodeling of damaged alveoli in COPD and asthma. The goal of this project is to develop and identify an orally potent and selective small molecule inhibitor of MMP-12 for treatment of COPD and asthma. Syntheses and structure-activity relationship (SAR) studies of a series of dibenzofuran (DBF) sulfonamides as MMP-12 inhibitors are described. Potent inhibitors of MMP-12 with excellent selectivity against other MMPs were identified. Compound 26 (MMP118), which exhibits excellent oral efficacy in the MMP-12 induced ear-swelling inflammation and lung inflammation mouse models, had been successfully advanced into Development Track status.

A novel fully human recombinant antibody neutralizing α-hemolysin of Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to almost all ß-lactam antibiotics. Hence, new ways to control MRSA infection, such as antibacterial antibodies, need to be explored. α-hemolysin is the most important virulence factor widely expressed in S. aureus. This study aimed to develop a new fully human antibody against α-hemolysin of S. aureus and research its neutralizing effect. The single-chain antibody fragments (scFvs) against S. aureus were screened from a fully human scFv library using phage display technology. The selected scFvs had good binding affinities to α-hemolysin and S. aureus. The IgG-like scFv-Fc inserted into the pcDNA3.1 or pMH3 vector was expressed in HEK293F suspension cells to extend the half-life and restore Fc function. The size of purified scFv-Fc was about 55 kDa. The functions of expressed scFv-Fcs against α-hemolysin were validated. The cytotoxicity assays showed that scFv555-Fc had better protective effects on A549 cells than other scFv-Fcs. The results of anti-rabbit erythrocyte lysis and A549 cell apoptosis assay confirmed that scFv555-Fc had a significant neutralizing effect on α-hemolysin. The scFv555-Fc was used to construct the docking model of antigen-antibody complexes using Discovery Studio software. It predicted that the key binding sites of α-hemolysin were TYR28, LYS37, PHE39, ARG56, and LYS58, which might be the key toxic sites of α-hemolysin. A novel fully human scFv-Fc antibody neutralizing the α-hemolysin toxin of S. aureus was successfully developed. The findings might provide a new theoretical basis and treatment method for preventing MRSA infection.

EphA2 recognizes Dermatophagoidespteronyssinus to mediate airway inflammation in asthma.

Most of the asthma with low Th2 is severe steroid-resistant asthma, the exact pathogenesis of which has not yet been fully elucidated. We found that IL-6 and IL-8 were highly expressed in the sputum supernatant of severe asthma and ephrin type-A receptor 2 (EphA2) was highly expressed on bronchial epithelial cells. So, is there a connection between these two phenomena? To clarify this issue, we stimulated bronchial epithelial cells 16HBE with Dermatophagoides pteronyssinus and its compontents LPS, respectively, and detected the activation of EphA2, activation of downstream pathways and secretion of inflammatory cytokines. A mouse asthma model was established, and the therapeutic effects of inhibiting or blocking EphA2 on mouse asthma were investigated. The results showed that D. pteronyssinus and its component LPS phosphorylated EphA2 on 16HBE, activated downstream signaling pathways STAT3 and p38 MAPK, and promoted the secretion of IL-6 and IL-8. After knockout of EphA2 on 16HBE, the activation of inflammatory pathways was attenuated and the secretion of IL-6 and IL-8 was significantly reduced. Inhibition or blockade of EphA2 on mouse airways resulted in a significant reduction in airway hyperresponsiveness and airway inflammation, and a significant decrease in the expression levels of IL-6, IL-17F, IL-1α, IL-1ß and TNF in bronchoalveolar lavage fluid and lung tissue. Our study uncovers a novel role for EphA2 expressed on airway epithelial cells in the pathogenesis of asthma; EphA2 recognizes D. pteronyssinus or its component LPS and promotes the secretion of IL-6 and IL-8 by airway epithelial cell, thereby mediating airway inflammation. Thus, it is possible to provide a new molecular therapy for severe asthma.

In vitro and in vivo activities of a novel ß-lactamase inhibitor combination imipenem/XNW4107 against recent clinical Gram-negative bacilli from China.

OBJECTIVES: XNW4107 is a novel ß-lactamase inhibitor that possesses broad activity against serine-ß-lactamases. XNW4107 in combination with imipenem exhibited potent in vitro activity against carbapenem-resistant bacteria and particularly against carbapenem-resistant Acinetobacter baumannii. This study aimed to evaluate the in vitro and in vivo antibacterial activities of imipenem/XNW4107. METHODS: The minimum inhibitory concentrations, minimum bactericidal concentrations, time-kill curves, post-antibiotic effects, and spontaneous frequency of resistance were used to investigate the imipenem/XNW4107 in vitro activity. A mouse systemic infection model was used to evaluate the imipenem/XNW4107 in vivo efficacy. RESULTS: MIC90 of imipenem/XNW4107 against imipenem-nonsusceptible A. baumannii (n = 106) was 8 mg/L, which was 16-fold lower than the MIC90 of imipenem; the resistance rate decreased from 90% to 20% applying the CLSI imipenem breakpoint. MIC90 of imipenem/XNW4107 against imipenem-resistant Klebsiella pneumoniae (n = 54) was 2 mg/L, which was 128-fold lower than the MIC90 of imipenem; 80% imipenem-nonsusceptible Pseudomonas aeruginosa (n = 101) exhibited MICs of imipenem/XNW4107 from 2 to 8 mg/L, which were 4- to 8-fold lower than the MICs of imipenem. Imipenem/XNW4107 was bactericidal against A. baumannii, K. pneumoniae, and Escherichia coli. The time-kill curves showed that increasing concentrations did not result in progressively increased killing at concentrations >4 × MIC. Imipenem/XNW4107 has a low potential for resistance development in tested strains except for K. pneumoniae. Imipenem/XNW4107 provided good protection against imipenem-resistant A. baumannii and K. pneumoniae in vivo. CONCLUSIONS: The broad-spectrum profile and potent in vitro and in vivo antibacterial activities support imipenem/XNW4107 as a promising investigational candidate.

[Preparation and functional identification of human single chain recombinant antibody targeting α-hemolysin of Staphylococcus aureus].

Objective To prepare a new fully human antibody against α-hemolysin of Staphylococcus aureus (S. aureus) and to investiagete its neutralizing effect. Methods The IgG-like scFv-Fc inserted into the pcDNA3.1 vector by homologous recombination was expressed in HEK293F suspension cells and purified. ELISA was used to detect the purified scFv538-Fc's binding activity and specificity to S. aureus. The cell proliferation & toxicity assay and rabbit erythrocyte hemolysis assay were used to identify the scFv538-Fc against α-hemolysin of S. aureus. Results A new fully human recombinant antibody scFv-Fc against S. aureus. α-hemolysin was successfully prepared. The mass of the purified scFv-Fc was about 55 kDa. The purified antibody had binding activity to scFv538-Fc, and the antibody bound to Staphylococcus aureus specifically. The results of A549 cytotoxicity assays showed that scFv538-Fc had protective effects on A549 cells. The result of anti-rabbit erythrocyte hemolysis assay confirmed that scFv538-Fc had a significant neutralizing effect on toxins. Conclusion A novel fully human scFv-Fc antibody neutralizing the α-hemolysin toxin of S. aureus is successfully prepared.

Mechanistic pathways in CF3COOH-mediated deacetalization reactions.

It has been widely accepted that both the protection of carbonyls and the deprotection of acetals and ketals involve the participation of a water molecule: formation of acetals and ketals is a dehydration process, whereas the deprotection is often referred to as hydrolysis, which, as implied by its name, always requires the presence of water. Herein, we report experimental evidence and mechanistic investigations that provide an alternative view to this process. We have demonstrated that water is not required to convert acetals and ketals to the corresponding carbonyls. The (1)H NMR experimental results revealed that the TFA-mediated transformation of acetal to aldehyde occurs via a hemiacetal TFA ester intermediate, which differentiates itself from the classic acid-catalyzed hydrolysis, where the hemiacetal is the putative intermediate responsible for the formation of the aldehyde. More interestingly, alcohols are not the final byproducts as they are in the classical hydrolysis, rather, the two alcohol molecules are converted to two TFA esters under the reaction conditions. On the basis of the NMR evidence, we have proposed that the two TFA esters are formed in two separate steps via a different mechanism along the reaction pathway. Formation of the TFA esters renders the reaction irreversible. To the best of our knowledge, the cascade reaction pathway presented by the TFA-mediated conversion of acetals and ketals to carbonyls has never been previously postulated.

Affinity improvement of the fully human anti­TSLP recombinant antibody.

Thymic stromal lymphopoietin (TSLP) is a potentially important target for the treatment of asthma and malignancies. However, a fully human antibody reactive with TSLP is currently unavailable for clinical use. In a previous study, a human anti­TSLP­single­chain antibody variable fragment (anti­TSLP­scFv) 84 was selected by phage display from a constructed human scFv library. In the present study, a computer simulation method was developed using Discovery Studio 4.5 software, to increase the affinity of anti­TSLP­scFv­84. Specific primers were designed and mutated DNA sequences of anti­TSLP­scFvs were obtained by overlap extension PCR. The mutant scFvs were expressed in pLZ16 and affinity­enhanced anti­TSLP­scFv­M4 was screened using ELISA. However, in general the scFvs have low stability and short half­lives in vivo. Therefore, scFv­84 and scFv­M4 were inserted into eukaryotic expression vectors (pcDNA3.1­sp­Fc and PMH3EN­sp­Fc) and then transfected into 293F cells to express anti­TSLP­scFv­Fc. ELISA and western blotting results indicated the size of the anti­TSLP­scFv­Fc to be ~50 kDa. Binding of anti­TSLP­scFv­Fc­M4 to TSLP was enhanced compared with the pre­mutated scFv­Fc­84. The affinity of the mutated recombinant antibody was determined using the BIAcore technique and found to be ~10­fold greater than the pre­mutated antibody.

Techniques for nothingness: Debate over the comparability of hypnosis and Zen in early-twentieth-century Japan.

This paper explores a debate that took place in Japan in the early twentieth century over the comparability of hypnosis and Zen. The debate was among the first exchanges between psychology and Buddhism in Japan, and it cast doubt on previous assumptions that a clear boundary existed between the two fields. In the debate, we find that contemporaries readily incorporated ideas from psychology and Buddhism to reconstruct the experiences and concepts of hypnosis and Buddhist nothingness. The resulting new theories and techniques of nothingness were fruits of a fairly fluid boundary between the two fields. The debate, moreover, reveals that psychology tried to address the challenges and possibilities posed by religious introspective meditation and intuitive experiences in a positive way. In the end, however, psychology no longer regarded them as viable experimental or psychotherapeutic tools but merely as particular subjective experiences to be investigated and explained.

[PD-1 overexpression in HEK293T cells transfected with pMH3-PD1].

Objective To optimize the transfection conditions of HEK293T cells and compare the expression levels of human programmed death 1 (hPD-1) in different eukaryotic vectors to obtain the target protein efficiently. Methods L9(33) orthogonal test was designed to optimize the conditions of cell transfection.The DNA sequence of hPD-1 extracellular domain gene was amplified by PCR and then cloned into different vectors:pcDNA3.1, pCMV3 and pMH3, PD-1 recombinant protein was expressed in HEK293T cells transiently and the expression levels was evaluated by ELISA and Western blot analysis. Results The gene of hPD-1 extracellular domain was successfully cloned into pcDNA3.1 and pMH3 eukaryotic expression vectors, and the target protein was successfully expressed. Under the optimal transfection conditions, the expression level of hPD-1 recombinant protein in pMH3 vector was the highest, followed by that of pCMV3 and pcDNA3.1 vectors. Conclusion The extracellular domain of hPD-1 is successfully expressed and the expression level of pMH3-PD1 was the highest among the three vectors tested.

[The efficiently expression of soluble CD20 in HEK293T cells].

Objective To construct the eukaryotic expression vector of CD20 and overexpress soluble CD20 proteins in HEK293T cells. Methods The total RNA from human peripheral blood mononuclear cells (PBMCs) was used to amplify the coding sequence of CD20 by reverse transcription PCR, and then the CD20 gene was cloned into the expression vector pCMV3-C-His. After PCR and sequencing validation, the recombinant CD20 protein was transiently expressed in HEK293T cells and detected by ELISA and Western blot analysis. Moreover, the expression conditions were optimized to improve the expression level of CD20. Results The coding sequence of CD20 was successfully cloned into eukaryotic expression vector pCMV3-C-His. After 72 hours of transfection, the expression of CD20 was detected both in intracellular and supernatant by Western blot analysis. The passage number of HEK293T cells was related to the expression level of CD20 in supernatant. Conclusion The coding sequence of CD20 was successfully cloned into the eukaryotic expression vector, and CD20 was over expressed in HEK293T cells.