MFN2 coordinates mitochondria motility with α-tubulin acetylation and this regulation is disrupted in CMT2A.

Mitofusin-2 (MFN2), a large GTPase residing in the mitochondrial outer membrane and mutated in Charcot-Marie-Tooth type 2 disease (CMT2A), is a regulator of mitochondrial fusion and tethering with the ER. The role of MFN2 in mitochondrial transport has however remained elusive. Like MFN2, acetylated microtubules play key roles in mitochondria dynamics. Nevertheless, it is unknown if the α-tubulin acetylation cycle functionally interacts with MFN2. Here, we show that mitochondrial contacts with microtubules are sites of α-tubulin acetylation, which occurs through MFN2-mediated recruitment of α-tubulin acetyltransferase 1 (ATAT1). This activity is critical for MFN2-dependent regulation of mitochondria transport, and axonal degeneration caused by CMT2A MFN2 associated R94W and T105M mutations may depend on the inability to release ATAT1 at sites of mitochondrial contacts with microtubules. Our findings reveal a function for mitochondria in α-tubulin acetylation and suggest that disruption of this activity plays a role in the onset of MFN2-dependent CMT2A.

Evaluation of methamphetamine assist packs: As-needed antipsychotics for self-management of methamphetamine-associated psychiatric toxicity.

BACKGROUND: Methamphetamine frequently causes substance-induced psychosis and related symptoms. There are currently no interventions to prevent or assist in self-management of these symptoms. METHODS: We evaluated a program providing "Methamphetamine Assist Packs" to patients who were seen in a psychiatric emergency services program for methamphetamine-induced psychosis. Methamphetamine Assist Packs included a small number of tablets of an antipsychotic medication (olanzapine), administration instructions, and referral information. We reviewed medical charts of patients who received Methamphetamine Assist Packs from January 2022 through May 2023 for sociodemographic and emergency visit characteristics. We assessed the changes between the number of psychiatric emergency visits before and after Methamphetamine Assist Pack receipt at two, six, and 12 months using generalized estimating equations. RESULTS: Ninety-two patients received a Methamphetamine Assist Pack, with a mean age of 40 years; 79 % were male and 49 % Black/African American; 77 % experienced housing instability or homelessness. The most common symptoms were suicidal ideation (54 %), paranoia or delusions (45 %), and hallucinations (40 %); 55 % were on involuntary psychiatric hold, 38 % required medications for agitation, and 18 % required seclusion or physical restraints. The rate of psychiatric emergency visits after Methamphetamine Assist Pack receipt was 0.68 and 0.87 times the rate prior to receipt at two and six months, respectively (p < 0.001). There was no difference at 12 months. CONCLUSIONS: Methamphetamine Assist Packs were associated with fewer psychiatric emergency visits for six months after receipt, and represent a promising intervention to address acute psychiatric toxicity from methamphetamine in need of further research.

Perception and Correlates of Opioid Overdose Risk Among Overdose Survivors Who Use Nonprescribed Opioids in San Francisco and Boston.

BACKGROUND: Understanding opioid overdose risk perception may inform overdose prevention strategies. METHODS: We used baseline data from a randomized overdose prevention trial, in San Francisco, CA, and Boston, MA, among people who used nonprescribed opioids, survived an overdose in the past 3 years, and had received naloxone. Participants were asked how likely they were to overdose in the next 4 months. We combined "extremely likely" and "likely" (higher risk perception) and "neutral," "unlikely," and "extremely unlikely" (lower risk perception). We performed bivariate analyses and separate multivariable logistic regression models of risk perception across (1) sociodemographic, (2) substance use, and (3) overdose risk behavior measures. Covariates were selected a priori or significant in bivariate analyses. RESULTS: Among 268 participants, 88% reported at least 1 overdose risk behavior; however, only 21% reported higher risk perception. The adjusted odds ratio (AOR) of higher risk perception was 2.41 (95% confidence interval [CI]: 1.10-5.30) among those unhoused in the past 4 months, 2.06 (95% CI: 1.05-4.05) among those using opioids in a new place, and 5.61 (95% CI: 2.82-11.16) among those who had overdosed in the past 4 months. Living in Boston was associated with higher risk perception in all 3 models (AOR = 2.00-2.46, 95% CI: 1.04-4.88). CONCLUSIONS: Despite prevalent risk behaviors, a minority of participants perceived themselves to be at higher risk of overdose. Nonetheless, some known risk factors for overdose were appropriately associated with risk perception. Fentanyl has been prevalent in Boston for longer than San Francisco, which may explain the higher risk perception there.

HCR spectral imaging: 10-plex, quantitative, high-resolution RNA and protein imaging in highly autofluorescent samples.

Signal amplification based on the mechanism of hybridization chain reaction (HCR) provides a unified framework for multiplex, quantitative, high-resolution imaging of RNA and protein targets in highly autofluorescent samples. With conventional bandpass imaging, multiplexing is typically limited to four or five targets owing to the difficulty in separating signals generated by fluorophores with overlapping spectra. Spectral imaging has offered the conceptual promise of higher levels of multiplexing, but it has been challenging to realize this potential in highly autofluorescent samples, including whole-mount vertebrate embryos. Here, we demonstrate robust HCR spectral imaging with linear unmixing, enabling simultaneous imaging of ten RNA and/or protein targets in whole-mount zebrafish embryos and mouse brain sections. Further, we demonstrate that the amplified and unmixed signal in each of the ten channels is quantitative, enabling accurate and precise relative quantitation of RNA and/or protein targets with subcellular resolution, and RNA absolute quantitation with single-molecule resolution, in the anatomical context of highly autofluorescent samples.

Factors affecting female college students' intention to use digital technology in wearable devices to stimulate health monitoring.

In this study, we measured female college students' mental health and physical activities to identify factors that affect their intention to use wearable health-monitoring devices. Specifically, the study derived correlations between female students' health-related quality of life (HRQoL) including, physical activity, stress level, attitudes toward eating, and self-esteem. Using this information, we ascertained the relationship between female college students' use of wearable devices and physical activity and examined the requirements for smartphone applications for healthcare. We collected data from 308 female college students in the Republic of Korea over four months starting in July 2021 using an anonymous online survey. We then analyzed the data using descriptive statistics and linear regression. The results showed that the factors that caused stress in female college students during the past six months were fatigue, COVID-19, grades, worries about getting a full-time job, menstruation, and being overweight. This paper found a negative correlation between stress and self-esteem and a positive correlation between physical activity and self-esteem. People with experience using wearable devices reported a higher intensity in physical activity. More than half the participants recorded biometric information for their menstrual cycles and menstrual cramps regardless of whether they were using wearable devices. Currently, healthcare applications can suggest diets and track nutritional intake, menstrual cycles, and amount of exercise, which users want simultaneously. Therefore, there is a market demand for a mobile application linked with a wearable device and tailored for female college students that could combine and manage all these data. In the future, application developers should consider the needs of female college students.

Regulated alternative splicing of Dscam2 is required for somatosensory circuit wiring.

Axon and dendrite placement and connectivity is guided by a wide range of secreted and surface molecules in the developing nervous system. Nevertheless, the extraordinary complexity of connections in the brain requires that this repertoire be further diversified to precisely and uniquely regulate cell-cell interactions. One important mechanism for molecular diversification is alternative splicing. Drosophila Down syndrome cell adhesion molecule (Dscam2) undergoes cell type-specific alternative splicing to produce two isoform-specific homophilic binding proteins. Regulated alternative splicing of Dscam2 is important for dendrite and axon patterning, but how this translates to circuit wiring and animal behavior is not well understood. Here, we examined the role of cell-type specific expression of Dscam2 isoforms in regulating synaptic partner selection in the larval somatosensory system. We found that synaptic partners in the nociceptive circuit express different Dscam2 isoforms. Forcing synaptic partners to express a common isoform resulted in nociceptive axon patterning defects and attenuated nocifensive behaviors, indicating that a role for Dscam2 alternative splicing is to ensure that synaptic partners do not express matching isoforms. These results point to a model in which regulated alternative splicing of Dscam2 across populations of neurons restricts connectivity to specific partners and prevents inappropriate synaptic connections.

MFN2-dependent recruitment of ATAT1 coordinates mitochondria motility with alpha-tubulin acetylation and is disrupted in CMT2A.

Acetylated microtubules play key roles in the regulation of mitochondria dynamics. It has however remained unknown if the machinery controlling mitochondria dynamics functionally interacts with the alpha-tubulin acetylation cycle. Mitofusin-2 (MFN2), a large GTPase residing in the mitochondrial outer membrane and mutated in Charcot-Marie-Tooth type 2 disease (CMT2A), is a regulator of mitochondrial fusion, transport and tethering with the endoplasmic reticulum. The role of MFN2 in regulating mitochondrial transport has however remained elusive. Here we show that mitochondrial contacts with microtubules are sites of alpha-tubulin acetylation, which occurs through the MFN2-mediated recruitment of alpha-tubulin acetyltransferase 1 (ATAT1). We discover that this activity is critical for MFN2-dependent regulation of mitochondria transport, and that axonal degeneration caused by CMT2A MFN2 associated mutations, R94W and T105M, may depend on the inability to release ATAT1 at sites of mitochondrial contacts with microtubules. Our findings reveal a function for mitochondria in regulating acetylated alpha-tubulin and suggest that disruption of the tubulin acetylation cycle play a pathogenic role in the onset of MFN2-dependent CMT2A.

Dendrite remodeling according to GARP.

Disruptions in membrane trafficking are associated with neurodevelopmental disorders, but underlying pathological mechanisms remain largely unknown. In this issue, O'Brien et al. (2023. J. Cell Biol.https://doi.org/10.1083/jcb.202112108) show how GARP regulates sterol transfer critical for remodeling of dendrites in flies.

Towards a mechanistic understanding of axon transport and endocytic changes underlying paclitaxel-induced peripheral neuropathy.

Paclitaxel is a common chemotherapeutic agent widely used to treat solid cancer. However, it frequently causes peripheral sensory neuropathy, resulting in sensory abnormalities and pain in patients receiving treatment for cancer. As one of the most widely used chemotherapeutics, many preclinical studies on paclitaxel-induced peripheral neuropathy (PIPN) have been performed. Yet, there remain no effective options for treatment or prevention. Due to paclitaxel's ability to bind to and stabilize microtubules, a change in microtubule dynamics and subsequent disruptions in axonal transport has been predicted as a major underlying cause of paclitaxel-induced toxicity. However, the systemic understanding of PIPN mechanisms is largely incomplete, and various phenotypes have not been directly attributed to microtubule-related effects. This review aims to provide an overview of the literature involving paclitaxel-induced alteration in microtubule dynamics, axonal transport, and endocytic changes. It also aims to provide insights into how the microtubule-mediated hypothesis may relate to various phenotypes reported in PIPN studies.

Cellular Pathogenesis of Chemotherapy-Induced Peripheral Neuropathy: Insights From Drosophila and Human-Engineered Skin Models.

Chemotherapy-induced peripheral neuropathy (CIPN) is a highly prevalent and complex condition arising from chemotherapy cancer treatments. Currently, there are no treatment or prevention options in the clinic. CIPN accompanies pain-related sensory functions starting from the hands and feet. Studies focusing on neurons in vitro and in vivo models significantly advanced our understanding of CIPN pathological mechanisms. However, given the direct toxicity shown in both neurons and non-neuronal cells, effective in vivo or in vitro models that allow the investigation of neurons in their local environment are required. No single model can provide a complete solution for the required investigation, therefore, utilizing a multi-model approach would allow complementary advantages of different models and robustly validate findings before further translation. This review aims first to summarize approaches and insights from CIPN in vivo models utilizing small model organisms. We will focus on Drosophila melanogaster CIPN models that are genetically amenable and accessible to study neuronal interactions with the local environment in vivo. Second, we will discuss how these findings could be tested in physiologically relevant vertebrate models. We will focus on in vitro approaches using human cells and summarize the current understanding of engineering approaches that may allow the investigation of pathological changes in neurons and the skin environment.

Elevated skin senescence in young mice causes delayed wound healing.

Although there is growing evidence that cellular senescence influences wound healing, a clear understanding of how senescence can be beneficial and/or detrimental to wound healing is unknown. Wound healing may also be influenced by the baseline tissue senescence, which is elevated in aging and chronic wounds, both of which have significant healing delays. To study the effects of skin senescence on wound healing, we developed an elevated skin senescence model based on the subcutaneous transfer of irradiated fibroblasts into young 8-week-old wild-type C57BL/6 male mice. This senescent cell transfer significantly increased skin senescence levels compared to control transfers of non-irradiated fibroblasts. There was an increased presence of SA-ß-Gal- and p21-positive senescent cells throughout the skin. Furthermore, the entire skin showed significantly elevated gene expression of senescence (p16, p21) and SASP markers (IL-6, MCP-1, MMP-3, MMP-9, and TGF-ß). Subsequent wound healing in the skin with elevated senescence was markedly delayed and had similar kinetics to naturally aged 2-year-old mice. After the wounds had healed, the skin developed persistently elevated senescence. Our results demonstrate that states of elevated skin senescence can delay wound healing and result in sustained senescence after healing. Therefore, the accumulation of senescent cells in aged skin or chronic wounds may be a driver of delayed healing and can be considered a potential target to improve healing.

Skin diseases in Asian individuals that you do not want to miss: A selection of unique or relatively more common conditions in Asian populations.

The Asian population currently constitutes a simple majority of the global population, comprising nearly 60%. The percentage of the US population that identifies as Asian is expected to grow to 41 million by the year 2050, making up an eventual 9% of the US population. As the world and US populations of Asian individuals increase, the demand for dermatologic care from this population will increase, requiring dermatologists to become more familiar with the diagnosis and treatment of Asian-specific skin characteristics and diseases. In this contribution, we review skin conditions specific to or relatively more common in Asian patients to help recognition and management of diseases in an increasing Asian patient population. We discuss prurigo pigmentosa, primary cutaneous plasmacytosis, lipodystrophia centrifugalis abdominalis infantilis, Epstein-Barr viru-positive T- and natural killer-cell lymphoproliferative disorders, acquired bilateral nevus of Ota-like macules, and BehÒ«et disease.

An Insight into Aging, Senescence, and Their Impacts on Wound Healing.

Cellular senescence has been found to have beneficial roles in development, tissue regeneration, and wound healing. However, in aging senescence increases, and the ability to properly repair and heal wounds significantly declines across multiple tissues. This age-related accumulation of senescent cells may cause loss of tissue homeostasis leading to dysregulation of normal and timely wound healing processes. The delays in wound healing of aging have widespread clinical and economic impacts, thus novel strategies to improve wound healing in aging are needed and targeting senescence may be a promising area.

Integrins protect sensory neurons in models of paclitaxel-induced peripheral sensory neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect from cancer treatment with no known method for prevention or cure in clinics. CIPN often affects unmyelinated nociceptive sensory terminals. Despite the high prevalence, molecular and cellular mechanisms that lead to CIPN are still poorly understood. Here, we used a genetically tractable Drosophila model and primary sensory neurons isolated from adult mouse to examine the mechanisms underlying CIPN and identify protective pathways. We found that chronic treatment of Drosophila larvae with paclitaxel caused degeneration and altered the branching pattern of nociceptive neurons, and reduced thermal nociceptive responses. We further found that nociceptive neuron-specific overexpression of integrins, which are known to support neuronal maintenance in several systems, conferred protection from paclitaxel-induced cellular and behavioral phenotypes. Live imaging and superresolution approaches provide evidence that paclitaxel treatment causes cellular changes that are consistent with alterations in endosome-mediated trafficking of integrins. Paclitaxel-induced changes in recycling endosomes precede morphological degeneration of nociceptive neuron arbors, which could be prevented by integrin overexpression. We used primary dorsal root ganglia (DRG) neuron cultures to test conservation of integrin-mediated protection. We show that transduction of a human integrin ß-subunit 1 also prevented degeneration following paclitaxel treatment. Furthermore, endogenous levels of surface integrins were decreased in paclitaxel-treated mouse DRG neurons, suggesting that paclitaxel disrupts recycling in vertebrate sensory neurons. Altogether, our study supports conserved mechanisms of paclitaxel-induced perturbation of integrin trafficking and a therapeutic potential of restoring neuronal interactions with the extracellular environment to antagonize paclitaxel-induced toxicity in sensory neurons.

Pathogenic role of delta 2 tubulin in bortezomib-induced peripheral neuropathy.

The pathogenesis of chemotherapy-induced peripheral neuropathy (CIPN) is poorly understood. Here, we report that the CIPN-causing drug bortezomib (Bort) promotes delta 2 tubulin (D2) accumulation while affecting microtubule stability and dynamics in sensory neurons in vitro and in vivo and that the accumulation of D2 is predominant in unmyelinated fibers and a hallmark of bortezomib-induced peripheral neuropathy (BIPN) in humans. Furthermore, while D2 overexpression was sufficient to cause axonopathy and inhibit mitochondria motility, reduction of D2 levels alleviated both axonal degeneration and the loss of mitochondria motility induced by Bort. Together, our data demonstrate that Bort, a compound structurally unrelated to tubulin poisons, affects the tubulin cytoskeleton in sensory neurons in vitro, in vivo, and in human tissue, indicating that the pathogenic mechanisms of seemingly unrelated CIPN drugs may converge on tubulin damage. The results reveal a previously unrecognized pathogenic role for D2 in BIPN that may occur through altered regulation of mitochondria motility.

The "Let's Talk!" Conference: A Culture-Specific Community Intervention for Asian and Asian American Student Mental Health.

Asian and Asian American students face culture-specific mental health risk factors, and the current study aims to examine whether a culture-specific community intervention in the form of a conference is an effective modality for psychoeducation in the Asian American community. Participants were assessed for reported changes in knowledge, attitudes, and behavior intentions related to mental health after attending the conference. A total of 118 conference participants filled out the survey. Participants reported changes in knowledge regarding mental health issues, generational differences, and the effects of culture. Participants also reported having a more open attitude towards mental health, having greater acceptance of mental health issues in themselves and others, and realizing that mental health issues are a community issue. Lastly, participants reported changes in behavior intentions such as communicating more with friends and family, engaging in perspective-taking, participating in advocacy and activism on mental health issues, and taking care of themselves and others.

A Thorough Analysis of the Current State of Cancer Education in Medical Schools and Application of Experimental Teaching Techniques and Their Efficacy.

Newly diagnosed cases of cancer are expected to double by the year 2040. Although many different oncology teaching initiatives have been implemented, many students continue to report uncertainty when dealing with patients with cancer. Through this review, we aim to find the most effective teaching methods to better prepare future physicians. Papers studying different methods of teaching oncology were identified through a thorough review of specific electronic databases. Each study was analyzed and sorted into one of ten unique categories created by the authors specifically for this review. If portions of the study fit into multiple categories, relevant results would be analyzed in all applicable areas. Additionally, papers were separated and analyzed by country of origin, preclinical or clinical interventional basis, and quantitative versus qualitative form of statistical analysis. A total of 115 papers from 26 different countries and regions were included in the final analysis. 91.4% of papers analyzing Lecture and Small Group Discussions indicated a positive impact. 97.1% of papers analyzing Clinical Practice and Simulation indicated a positive impact. 100% of papers analyzing Early Experience and Mentorship, Summer Programs and Voluntary Electives, use of Multidisciplinary Teams, and Role Play stated that these methods had a positive impact. 50% of papers analyzing Computer/Web Based Programs indicated a positive impact. Clinical Practice and Simulation, Role Play, Summer/Elective Programs and interventions involving Multidisciplinary Team Work all appeared to be most effective. Intensive Block Programs, Didactic Lectures/Small Group Discussions, and Computer/Web Based Education tools as a whole were variable. General Review papers showed continued variability in domestic and international oncology curricula. Incorporation of effective teaching interventions should be highly considered in the future creation of standardized oncology curricula in order to best prepare the next generation of physicians. Future studies could explore the differing efficacies of teaching interventions in the postgraduate versus graduate realms.

Investigating the impact of daily life context on physical activity in terms of steps information generated by wearable activity tracker.

OBJECTIVES: This study used ecological momentary assessment (EMA) to understand how the contextual factors of everyday life affect physical activity in terms of steps measured by wearable activity tracking devices and to identify what factors increase physical activity. In addition, this study investigated and analyzed the user environment and resulting contextual factors in a typical office setting. METHODS: A total of 27 office workers of Korea (70.4 % male, aged 19-44, 51.9 % married, and mostly from an information technology company) participated in this study and provided five-day EMA diary data (morning and evening) in the form of activity log data from a wearable device and attended a 45-60 min qualitative interview. In this study, a mixed-method approach (qualitative and quantitative) was used. RESULTS: This study demonstrated that contextual factors such as mood state (e.g., tired, p < 0.01), level of physical activity (e.g., vigorous, p < 0.01), and types of physical activity (e.g., using the stairs instead of elevators, p < 0.05) could affect the physical activity of the users of wearable devices in everyday life. CONCLUSION: The study contributed to a better understanding of how the contextual and environmental factors affect the physical activity of user of wearable activity trackers (WATs). These findings have practical implications for designers of such devices. In addition, these results could guide future research agendas.

Dscam2 suppresses synaptic strength through a PI3K-dependent endosomal pathway.

Dscam2 is a cell surface protein required for neuronal development in Drosophila; it can promote neural wiring through homophilic recognition that leads to either adhesion or repulsion between neurites. Here, we report that Dscam2 also plays a post-developmental role in suppressing synaptic strength. This function is dependent on one of two distinct extracellular isoforms of the protein and is autonomous to motor neurons. We link the PI3K enhancer, Centaurin gamma 1A, to the Dscam2-dependent regulation of synaptic strength and show that changes in phosphoinositide levels correlate with changes in endosomal compartments that have previously been associated with synaptic strength. Using transmission electron microscopy, we find an increase in synaptic vesicles at Dscam2 mutant active zones, providing a rationale for the increase in synaptic strength. Our study provides the first evidence that Dscam2 can regulate synaptic physiology and highlights how diverse roles of alternative protein isoforms can contribute to unique aspects of brain development and function.