NADH improves AIF dimerization and inhibits apoptosis in iPSCs-derived neurons from patients with auditory neuropathy spectrum disorder.

Auditory neuropathy spectrum disorder (ANSD) is a hearing impairment involving disruptions to inner hair cells (IHCs), ribbon synapses, spiral ganglion neurons (SGNs), and/or the auditory nerve itself. The outcomes of cochlear implants (CI) for ANSD are variable and dependent on the location of lesion sites. Discovering a potential therapeutic agent for ANSD remains an urgent requirement. Here, 293T stable transfection cell lines and patient induced pluripotent stem cells (iPSCs)-derived auditory neurons carrying the apoptosis inducing factor (AIF) p.R422Q variant were used to pursue a therapeutic regent for ANSD. Nicotinamide adenine dinucleotide (NADH) is a main electron donor in the electron transport chain (ETC). In 293T stable transfection cells with the p.R422Q variant, NADH treatment improved AIF dimerization, rescued mitochondrial dysfunctions, and decreased cell apoptosis. The effects of NADH were further confirmed in patient iPSCs-derived neurons. The relative level of AIF dimers was increased to 150.7 % (P = 0.026) from 59.2 % in patient-neurons upon NADH treatment. Such increased AIF dimerization promoted the mitochondrial import of coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4), which further restored mitochondrial functions. Similarly, the content of mitochondrial calcium (mCa2+) was downregulated from 136.7 % to 102.3 % (P = 0.0024) in patient-neurons upon NADH treatment. Such decreased mCa2+ levels inhibited calpain activity, ultimately reducing the percentage of apoptotic cells from 30.5 % to 21.1 % (P = 0.021). We also compared the therapeutic effects of gene correction and NADH treatment on hereditary ANSD. NADH treatment had comparable restorative effects on functions of ANSD patient-specific cells to that of gene correction. Our findings offer evidence of the molecular mechanisms of ANSD and introduce NADH as a potential therapeutic agent for ANSD therapy.

Nature nurtures authenticity: Mechanisms and consequences.

Contact with nature may benefit, not only the bodily organism, but also the psychological self. We proposed that, assuming humans' innate affinity for nature (the biophilia hypothesis), nature would be conducive to a sense of environment-self fit, which would be experienced as authenticity (being aligned with one's true self). We formulated several hypotheses: (a) nature fosters authenticity, and it does so through at least four plausible mechanisms: self-esteem, basic needs satisfaction (autonomy, competence, relatedness), mindfulness, and positive affect; (b) self-esteem is the strongest mechanism overall, and autonomy is the strongest mechanism of the three basic needs; (c) self-esteem and authenticity mediate sequentially the positive impact of nature on current psychological well-being (higher life satisfaction and meaning in life); and (d) authenticity mediates the positive influence of nature on longer term psychological well-being (higher life satisfaction and meaning in life, lower depression, anxiety, and stress). We obtained support for these hypotheses across 12 studies (N = 5,512). These were diverse in terms of setting (field, laboratory), design (cross-sectional, experimental, longitudinal), methodology (varying manipulations of nature and assessment of mediators and/or dependent measures), and sampling (university/community, East Asian/Western). The findings establish nature as a correlate and determinant of authenticity, chiefly via the mechanism of self-esteem, and further establish authenticity (preceded by self-esteem) as a mediator of the positive influence of nature on psychological well-being. The findings are also generative and have policy implications. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Trajectory of Nostalgia in Emerging Adulthood.

We examined the change and stability of nostalgia in emerging adulthood. We followed 327 students through their 4 university years with six assessments. Nostalgia demonstrated moderate rank stability (r = .25-.79). A Trait-State-Occasion model analysis indicated that the stable trait component, slowing-change trait component, and state component explained 37% to 43%, 10% to 27%, and 29% to 49% of variation in nostalgia on specific occasions, respectively. Longitudinal multilevel analysis revealed that the mean nostalgia level declined across university years. Greater intensity of negative life events at the start of university was associated with higher initial nostalgia and slower decline of it, while the emotion intensified when experiencing more negative life events. Nostalgia in emerging adulthood displays moderate stability, with negative life events contributing to the shape of its trajectory.

Impaired AIF-CHCHD4 interaction and mitochondrial calcium overload contribute to auditory neuropathy spectrum disorder in patient-iPSC-derived neurons with AIFM1 variant.

Auditory neuropathy spectrum disorder (ANSD) is a hearing impairment caused by dysfunction of inner hair cells, ribbon synapses, spiral ganglion neurons and/or the auditory nerve itself. Approximately 1/7000 newborns have abnormal auditory nerve function, accounting for 10%-14% of cases of permanent hearing loss in children. Although we previously identified the AIFM1 c.1265 G > A variant to be associated with ANSD, the mechanism by which ANSD is associated with AIFM1 is poorly understood. We generated induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells (PBMCs) via nucleofection with episomal plasmids. The patient-specific iPSCs were edited via CRISPR/Cas9 technology to generate gene-corrected isogenic iPSCs. These iPSCs were further differentiated into neurons via neural stem cells (NSCs). The pathogenic mechanism was explored in these neurons. In patient cells (PBMCs, iPSCs, and neurons), the AIFM1 c.1265 G > A variant caused a novel splicing variant (c.1267-1305del), resulting in AIF p.R422Q and p.423-435del proteins, which impaired AIF dimerization. Such impaired AIF dimerization then weakened the interaction between AIF and coiled-coil-helix-coiled-coil-helix domain-containing protein 4 (CHCHD4). On the one hand, the mitochondrial import of ETC complex subunits was inhibited, subsequently leading to an increased ADP/ATP ratio and elevated ROS levels. On the other hand, MICU1-MICU2 heterodimerization was impaired, leading to mCa2+ overload. Calpain was activated by mCa2+ and subsequently cleaved AIF for its translocation into the nucleus, ultimately resulting in caspase-independent apoptosis. Interestingly, correction of the AIFM1 variant significantly restored the structure and function of AIF, further improving the physiological state of patient-specific iPSC-derived neurons. This study demonstrates that the AIFM1 variant is one of the molecular bases of ANSD. Mitochondrial dysfunction, especially mCa2+ overload, plays a prominent role in ANSD associated with AIFM1. Our findings help elucidate the mechanism of ANSD and may lead to the provision of novel therapies.

1-Deoxynojirimycin promotes cardiac function and rescues mitochondrial cristae in mitochondrial hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is the most prominent cause of sudden cardiac death in young people. Due to heterogeneity in clinical manifestations, conventional HCM drugs have limitations for mitochondrial hypertrophic cardiomyopathy. Discovering more effective compounds would be of substantial benefit for further elucidating the pathogenic mechanisms of HCM and treating patients with this condition. We previously reported the MT-RNR2 variant associated with HCM that results in mitochondrial dysfunction. Here, we screened a mitochondria-associated compound library by quantifying the mitochondrial membrane potential of HCM cybrids and the survival rate of HCM-induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) in galactose media. 1-Deoxynojirimycin (DNJ) was identified to rescue mitochondrial function by targeting optic atrophy protein 1 (OPA1) to promote its oligomerization, leading to reconstruction of the mitochondrial cristae. DNJ treatment further recovered the physiological properties of HCM iPSC-CMs by improving Ca2+ homeostasis and electrophysiological properties. An angiotensin II-induced cardiac hypertrophy mouse model further verified the efficacy of DNJ in promoting cardiac mitochondrial function and alleviating cardiac hypertrophy in vivo. These results demonstrated that DNJ could be a potential mitochondrial rescue agent for mitochondrial hypertrophic cardiomyopathy. Our findings will help elucidate the mechanism of HCM and provide a potential therapeutic strategy.

Distress prospectively predicts higher nostalgia, and nostalgia prospectively predicts lower distress.

OBJECTIVE: We were concerned with the relation between distress and nostalgia. At the state level, extensive research has established that momentary nostalgia is evoked by (experimentally manipulated) distress. However, at the trait level, the directionality of this relation is unclear. We conducted a longitudinal study to clarify the directional relation between these two constructs. METHOD: We surveyed first-year university students (N = 3167) twice across six months. We assessed nostalgia, psychological distress (depression), and physical distress (somatization) at both timepoints. We also assessed Big Five personality at the first timepoint. RESULTS: Initial distress prospectively predicted increased nostalgia, and initial nostalgia prospectively predicted reduced distress, six months later and independently of the Big Five. CONCLUSIONS: Habitual nostalgia follows rather than precedes naturalistically occurring distress and serves to relieve it.

KLF14 regulates the growth of hepatocellular carcinoma cells via its modulation of iron homeostasis through the repression of iron-responsive element-binding protein 2.

BACKGROUND: Hepatocellular carcinoma (HCC) is a multifactor-driven malignant tumor with rapid progression, which causes the difficulty to substantially improve the prognosis of HCC. Limited understanding of the mechanisms in HCC impedes the development of efficacious therapies. Despite Krüpple-Like factors (KLFs) were reported to be participated in HCC pathogenesis, the function of KLF14 in HCC remains largely unexplored. METHODS: We generated KLF14 overexpressed and silenced liver cancer cells, and nude mouse xenograft models for the in vitro and in vivo study. Luciferase reporter assay, ChIP-qPCR, Co-IP, immunofluorescence were performed for mechanism research. The expression of KLF14 in HCC samples was analyzed by quantitative RT-PCR, Western blotting, and immunohistochemistry (IHC) analysis. RESULTS: KLF14 was significantly downregulated in human HCC tissues, which was highly correlated with poor prognosis. Inhibition of KLF14 promoted liver cancer cells proliferation and overexpression of KLF14 suppressed cells growth. KLF14 exerts its anti-tumor function by inhibiting Iron-responsive element-binding protein 2 (IRP2), which then causes transferrin receptor-1(TfR1) downregulation and ferritin upregulation on the basis of IRP-IREs system. This then leading to cellular iron deficiency and HCC cells growth suppression in vitro and in vivo. Interestingly, KLF14 suppressed the transcription of IRP2 via recruiting SIRT1 to reduce the histone acetylation of the IRP2 promoter, resulting in iron depletion and cell growth suppression. More important, we found fluphenazine is an activator of KLF14, inhibiting HCC cells growth through inducing iron deficiency. CONCLUSION: KLF14 acts as a tumor suppressor which inhibits the proliferation of HCC cells by modulating cellular iron metabolism via the repression of IRP2. We identified Fluphenazine, as an activator of KLF14, could be a potential compound for HCC therapy. Our findings therefore provide an innovative insight into the pathogenesis of HCC and a promising therapeutic target.

Nostalgia in the brain.

Nostalgia, a complex emotion that arises from one's yearnful memories, involves multiple psychological processes. Cognitive neuroscience research has shed light on the neural mechanism of nostalgia as well as its adaptive functions. Nostalgia involves brain regions implicated in self-reflection, autobiographical memory, emotion regulation and reward processing. Also, nostalgia buffers various psychological and physical threats by modulating activities in brain regions implicated in emotion regulatory processing (i.e., both top-down emotion regulation and bottom-up sensory and attention processing) and reward processing. These findings deepen understanding of nostalgia and have implications for its application in clinical situations.

Discerning cultural shifts in China? Commentary on Hamamura et al. (2021).

By examining the changes in the conceptual associations between individualism-collectivism and 10 other concepts based on the Google Ngram Chinese Corpus from the 1950s to the 1990s, Hamamura et al. (2021) inferred (a) no rise in individualism; (b) continuing collectivism; and (c) no effect of modernization on individualism in contemporary China. We question the validity of these conclusions given the following issues in their research: (a) misinterpretation of statistical results; (b) improper calculation of cultural associations; and (c) inappropriate generalization of specific findings. Contrary to their original findings, our reanalysis of their data suggests that individualism has been increasingly accepted and associated with some positive (vs. negative) aspects of life (e.g., income vs. loss, richness vs. poverty) over recent decades in China. Future research should use more rigorous methods and diverse corpora to clarify and explain changes in individualism and collectivism in China. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The analgesic effect of nostalgia elicited by idiographic and nomothetic approaches on thermal stimulus.

Nostalgia is shown to relieve an individual's perception of pain evoked by cold water, pressure, and thermal stimuli. However, there is no direct evidence to show the analgesic effects of different nostalgia-inducing methods on various stimulus intensities. We conducted two studies to examine the analgesic effect, at different pain intensities, after inducing nostalgia either idiographically or nomothetically. Study 1 (N = 118) induced nostalgia through an idiographic approach (i.e., event reflection task) and found that nostalgia relieved both high and low thermal pain. Study 2 (N = 66) induced nostalgia through a nomothetic approach (i.e., viewing nostalgic pictures) and found that nostalgia relieved low but not high thermal pain. The findings verify the analgesic effect of nostalgia on thermal pain and suggest the potential moderating role of the nostalgia induction approach and pain intensity. Practically, these findings have implications for using nostalgia as a nonpharmacological treatment for pain.

Patterns of brain activity associated with nostalgia: a social-cognitive neuroscience perspective.

Nostalgia arises from tender and yearnful reflection on meaningful life events or important persons from one's past. In the last two decades, the literature has documented a variety of ways in which nostalgia benefits psychological well-being. Only a handful of studies, however, have addressed the neural basis of the emotion. In this prospective review, we postulate a neural model of nostalgia. Self-reflection, autobiographical memory, regulatory capacity and reward are core components of the emotion. Thus, nostalgia involves brain activities implicated in self-reflection processing (medial prefrontal cortex, posterior cingulate cortex and precuneus), autobiographical memory processing (hippocampus, medial prefrontal cortex, posterior cingulate cortex and precuneus), emotion regulation processing (anterior cingulate cortex and medial prefrontal cortex) and reward processing (striatum, substantia nigra, ventral tegmental area and ventromedial prefrontal cortex). Nostalgia's potential to modulate activity in these core neural substrates has both theoretical and applied implications.

Thalamocortical Mechanisms for Nostalgia-Induced Analgesia.

As a predominately positive emotion, nostalgia serves various adaptive functions, including a recently revealed analgesic effect. The current fMRI study aimed to explore the neural mechanisms underlying the nostalgia-induced analgesic effect on noxious thermal stimuli of different intensities. Human participants' (males and females) behavior results showed that the nostalgia paradigm significantly reduced participants' perception of pain, particularly at low pain intensities. fMRI analysis revealed that analgesia was related to decreased brain activity in pain-related brain regions, including the lingual and parahippocampal gyrus. Notably, anterior thalamic activation during the nostalgia stage predicted posterior parietal thalamus activation during the pain stage, suggesting that the thalamus might play a key role as a central functional linkage in the analgesic effect. Moreover, while thalamus-PAG functional connectivity was found to be related to nostalgic strength, periaqueductal gray-dorsolateral prefrontal cortex (PAG-dlPFC) functional connectivity was found to be associated with pain perception, suggesting possible analgesic modulatory pathways. These findings demonstrate the analgesic effect of nostalgia and, more importantly, shed light on its neural mechanism.SIGNIFICANCE STATEMENT Nostalgia is known to reduce individuals' perception of physical pain. The underlying brain mechanisms, however, are unclear. Our study found that the thalamus plays a key role as a functional linkage between nostalgia and pain, suggesting a possible analgesic modulatory mechanism of nostalgia. These findings have implications for the underlying brain mechanisms of psychological analgesia.

Why do humans pursue higher social class? Death anxiety matters.

This research examined whether death anxiety motivated individuals to pursue a higher social class. Two studies were conducted to provide supporting evidence. Study 1 (n = 1847) showed that higher chronic death anxiety was associated with stronger motivation to pursue a higher social class. Study 2 (n = 135) showed that situationally induced death anxiety augmented the pursuit of a higher social class and was associated with choosing lower criteria for joining a higher social class. Together, the two studies provided both experimental and correlational evidence for the motivational significance of death anxiety in pursuing a higher social class.

Best research practices for using the Implicit Association Test.

Interest in unintended discrimination that can result from implicit attitudes and stereotypes (implicit biases) has stimulated many research investigations. Much of this research has used the Implicit Association Test (IAT) to measure association strengths that are presumed to underlie implicit biases. It had been more than a decade since the last published treatment of recommended best practices for research using IAT measures. After an initial draft by the first author, and continuing through three subsequent drafts, the 22 authors and 14 commenters contributed extensively to refining the selection and description of recommendation-worthy research practices. Individual judgments of agreement or disagreement were provided by 29 of the 36 authors and commenters. Of the 21 recommended practices for conducting research with IAT measures presented in this article, all but two were endorsed by 90% or more of those who felt knowledgeable enough to express agreement or disagreement; only 4% of the totality of judgments expressed disagreement. For two practices that were retained despite more than two judgments of disagreement (four for one, five for the other), the bases for those disagreements are described in presenting the recommendations. The article additionally provides recommendations for how to report procedures of IAT measures in empirical articles.

Is implicit social cognition developmentally stable? A longitudinal study.

To examine whether implicit social cognition is developmentally stable or variable, this study investigated three primary types of implicit social cognition (self-esteem, the gender-science stereotype, and racial attitude) across 2 years in a sample of Chinese adolescents and emerging adults (N = 608; 56% female; 15- to 27-year-olds). Rank-order stability analyses indicated that implicit self-esteem and implicit racial attitude manifested low stability (r = .16, .19, respectively), whereas implicit gender-science stereotype was highly stable (r = .75). Latent change score model analyses showed that: (a) the mean level of implicit self-esteem decreased across the 2 years, whereas the mean levels of implicit gender-science stereotype and implicit racial attitude manifested no changes; (b) individual changes were heterogeneous for all the three types of implicit social cognition (while some of the participants manifested increasing tendencies, 15%-46%, the others exhibited decreasing tendencies); (c) 30% of participants manifested similar changes across the three types of implicit social cognition (either increasing or decreasing over time on all three), while the remaining participants exhibited distinct changes across them. Together, these findings indicate that, developmentally, implicit social cognition is variable but also stable, though the degree of variability and stability vary across individuals and domains. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Novel Evidence for the Increasing Prevalence of Unique Names in China: A Reply to Ogihara.

In this study, we aimed to address three comments proposed by Ogihara on a recent study where we found that unique names in China have become increasingly popular from 1950 to 2009. Using a large representative sample of Chinese names (N = 2.1 million), we replicated the increase in uniqueness of Chinese names from 1920 to 2005, especially since the 1970s, with multiple uniqueness indices based on name-character frequency and name-length deviation. Over the years, Chinese characters that are rare in daily life or naming practice were more often used in given names, and the length of given names became more deviant from typical practice (i.e., more one-character and three-character given names and higher standard deviation of name length). Taken together, these findings not only reconfirmed the increasing prevalence of unique names but also demonstrated the validity of various indices in assessing name uniqueness in China.

Nostalgia enhances detection of death threat: neural and behavioral evidence.

An experiment examined the potency of nostalgia-a sentimental longing for one's past-to facilitate detection of death-related stimuli, using functional magnetic resonance imaging (fMRI) and behavioral techniques (i.e., judgmental accuracy, reaction times). We hypothesized and found that, at the neural level, nostalgic (relative to control) participants evinced more intense activation in right amygdala in response to death-related (vs. neutral) words. We also hypothesized and found that, at the behavioral level, nostalgic (relative to control) participants manifested greater accuracy in judging whether two death-related (vs. neutral) words belonged in the same category. Exploratory analyses indicated that nostalgic (relative to control) participants did not show faster reaction times to death-related (vs. neutral) words. In all, nostalgia appeared to aid in death threat detection. We consider implications for the relevant literatures.

Dopaminergic and neurotrophic genetic polymorphisms modulate the implicit gender-science stereotype.

Genetic approaches to both the gender-science stereotype and implicit social cognition have received increasing attention in recent years. We explored whether single nucleotide polymorphisms (SNPs) in dopaminergic and neurotrophic systems (i.e., COMT, BDNF genotypes) explain variations in the implicit gender-science stereotype. We genotyped 413 adolescents and assessed their implicit gender-science stereotype with the Implicit Association Test. Replication on a subsample (N = 312) was conducted 2 years later. Results showed that SNP-level variations within the COMT and BDNF genes were consistently associated with the implicit gender-science stereotype in both investigations. These findings suggest that variants in the COMT and BDNF genes may contribute to the variation of implicit gender-science stereotype.

Meaning making helps cope with COVID-19: A longitudinal study.

Meaning making is a useful coping strategy in negative situations. We investigated whether making meaning in negative experiences (MINE) would help people cope with COVID-19. We conducted a three-wave longitudinal study (N = 2364) three months before, during, and after the COVID-19 outbreak in China. Results showed that participants reported increased tendency of MINE during the COVID-19 outbreak than three months before the outbreak. Moreover, both initial MINE and the increased MINE predicted less psychological distress including depression, anxiety and stress, during and three months after the outbreak. Perceived benefits and costs of the COVID-19 mediated the long-term effect of MINE. These findings not only provide novel evidence for meaning making model but also shed light on the underlying mechanism, suggesting an effective strategy to cope with stressful events such as the ongoing COVID-19 pandemic.