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Abstract Protein/protein interactions (PPI) play crucial roles in neuronal functions. Yet, their potential as drug targets for brain disorders remains underexplored. The fibroblast growth factor 14 (FGF14)/voltage-gated Na+ channel 1.6 (Nav1.6) complex regulates excitability of medium spiny neurons (MSN) of the nucleus accumbens (NAc), a central hub of reward circuitry that controls motivated behaviors. Here, we identified compound 1028 (IUPAC: ethyl 3-(2-(3-(hydroxymethyl)-1H-indol-1-yl)acetamido)benzoate), a brain-permeable small molecule that targets FGF14R117, a critical residue located within a druggable pocket at the FGF14/Nav1.6 PPI interface. We found that 1028 modulates FGF14/Nav1.6 complex assembly and depolarizes the voltage-dependence of Nav1.6 channel inactivation with nanomolar potency by modulating the intramolecular interaction between the III-IV linker and C-terminal domain of the Nav1.6 channel. Consistent with the compound’s effects on Nav1.6 channel inactivation, 1028 enhances MSN excitability ex vivo and accumbal neuron firing rate in vivo in murine models. Systemic administration of 1028 maintains behavioral motivation preferentially during motivationally deficient conditions in murine models. These behavioral effects were abrogated by in vivo gene silencing of Fgf14 in the NAc and were accompanied by a selective reduction in accumbal dopamine levels during reward consumption in murine models. These findings underscore the potential to selectively regulate complex behaviors associated with neuropsychiatric disorders through targeting of PPIs in neurons.

Abstract Background Excess tumor necrosis factor (TNF) is implicated in the pathogenesis of hyperinflammatory experimental cerebral malaria (eCM), including gliosis, increased levels of fibrin(ogen) in the brain, behavioral changes, and mortality. However, the role of TNF in eCM within the brain parenchyma, particularly directly on neurons, remains underdefined. Here, we investigate electrophysiological consequences of eCM on neuronal excitability and cell signaling mechanisms that contribute to observed phenotypes. Methods The split-luciferase complementation assay (LCA) was used to investigate cell signaling mechanisms downstream of tumor necrosis factor receptor 1 (TNFR1) that could contribute to changes in neuronal excitability in eCM. Whole-cell patch-clamp electrophysiology was performed in brain slices from eCM mice to elucidate consequences of infection on CA1 pyramidal neuron excitability and cell signaling mechanisms that contribute to observed phenotypes. Involvement of identified signaling molecules in mediating behavioral changes and sickness behavior observed in eCM were investigated in vivo using genetic silencing. Results Exploring signaling mechanisms that underlie TNF-induced effects on neuronal excitability, we found that the complex assembly of fibroblast growth factor 14 (FGF14) and the voltage-gated Na+ (Nav) channel 1.6 (Nav1.6) is increased upon tumor necrosis factor receptor 1 (TNFR1) stimulation via Janus Kinase 2 (JAK2). On account of the dependency of hyperinflammatory experimental cerebral malaria (eCM) on TNF, we performed patch-clamp studies in slices from eCM mice and showed that Plasmodium chabaudi infection augments Nav1.6 channel conductance of CA1 pyramidal neurons through the TNFR1–JAK2–FGF14–Nav1.6 signaling network, which leads to hyperexcitability. Hyperexcitability of CA1 pyramidal neurons caused by infection was mitigated via an anti-TNF antibody and genetic silencing of FGF14 in CA1. Furthermore, knockdown of FGF14 in CA1 reduced sickness behavior caused by infection. Conclusions FGF14 may represent a therapeutic target for mitigating consequences of TNF-mediated neuroinflammation.

Cocaine use disorder (CUD) is a prevalent neuropsychiatric disorder with few existing treatments. Thus, there is an unmet need for the identification of new pharmacological targets for CUD. Previous studies using environmental enrichment versus isolation paradigms have found that the latter induces increased cocaine self-administration with correlative increases in the excitability of medium spiny neurons (MSN) of the nucleus accumbens shell (NAcSh). Expanding upon these findings, we sought in the present investigation to elucidate molecular determinants of these phenomena. To that end, we first employed a secondary transcriptomic analysis and found that cocaine self-administration differentially regulates mRNA for fibroblast growth factor 13 (FGF13), which codes for a prominent auxiliary protein of the voltage-gated Na+ (Nav) channel, in the NAcSh of environmentally enriched rats (i.e., resilient behavioral phenotype) compared to environmentally isolated rats (susceptible phenotype). Based upon this finding, we used in vivo genetic silencing to study the causal functional and behavioral consequences of knocking down FGF13 in the NAcSh. Functional studies revealed that knockdown of FGF13 in the NAcSh augmented excitability of MSNs by increasing the activity of Nav channels. These electrophysiological changes were concomitant with a decrease in cocaine demand elasticity (i.e., susceptible phenotype). Taken together, these data support FGF13 as being protective against cocaine self-administration, which positions it well as a pharmacological target for CUD.

Chan chuang, a psychophysical practice renowned for its beneficial effects, has been favored by martial artists and traditional Chinese medicine practitioners since ancient times. With the onset of the COVID-19 pandemic, chan chuang has garnered increased attention and recognition. However, existing research primarily focuses on the efficacy of chan chuang, rather than exploring the practice itself. Consequently, there is a dearth of scientific and experiential guidance available to current practitioners of chan chuang. To address this gap, the present study employs an in-depth interview method within a qualitative research framework, conducting follow-up interviews with eight martial artists who regularly engage in chan chuang practice. By gaining insights into the physical and mental states of these practitioners, this paper aims to elucidate their embodied experiences of chan chuang from the perspective of “body perception”. The findings reveal that the practitioners’ perception of their bodies during chan chuang practice can be characterized by three key aspects: stillness, naturalness, and qi. The sense of stillness signifies a state of tranquility in both body and mind. The sense of naturalness represents a harmonious equilibrium of body and mind, at times even resulting in a loss of self-awareness. Finally, the sense of qi conveys a serene mental state accompanied by the smooth flow of life energy and blood. These three dimensions guide chan chuang practitioners toward attaining physical and mental well-being.

Traditional martial art is a pivotal part of Chinese folk culture. However, due to the impact of modern culture, the inheritance of various martial arts is threatened. Therefore, many efforts have been made by the Chinese government to protect this unique culture in the late 20th century. To provide practical indications for the safeguard of intangible cultural heritage, we conducted a literature review for the Chinese strategies concerning the safeguard of traditional martial arts (TMA) in the past 30 years, also tried to identify the advantages and shortcomings of current safeguard of TMA. Existing evidence indicates that the legislative safeguarding of Chinese TMA has gradually evolved into a system for preservation. Modern devices are important to maintain the current form of the intangible cultural heritage. Inviting inheritors of the TMA to teach relevant skills and knowledge in university campuses may play an important role in the dynamic safeguard of inheritance. On the other hand, shortcomings are also noticed. For instance, younger generations are not fully aware of the importance of TMA, thus specific education is needed. The means of transmission of TMA is still insufficient in the current information era.

Summary: Resilience and vulnerability to neuropsychiatric disorders are linked to molecular changes underlying excitability that are still poorly understood. Here, we identify glycogen-synthase kinase 3β (GSK3β) and voltage-gated Na+ channel Nav1.6 as regulators of neuroplasticity induced by environmentally enriched (EC) or isolated (IC) conditions—models for resilience and vulnerability. Transcriptomic studies in the nucleus accumbens from EC and IC rats predicted low levels of GSK3β and SCN8A mRNA as a protective phenotype associated with reduced excitability in medium spiny neurons (MSNs). In vivo genetic manipulations demonstrate that GSK3β and Nav1.6 are molecular determinants of MSN excitability and that silencing of GSK3β prevents maladaptive plasticity of IC MSNs. In vitro studies reveal direct interaction of GSK3β with Nav1.6 and phosphorylation at Nav1.6T1936 by GSK3β. A GSK3β-Nav1.6T1936 competing peptide reduces MSNs excitability in IC, but not EC rats. These results identify GSK3β regulation of Nav1.6 as a biosignature of MSNs maladaptive plasticity. : Scala et al. show how vulnerability to reward-related behaviors associates with maladaptive plasticity of medium spiny neurons through phosphorylation of the voltage-gated Na+ channel Nav1.6 by the enzyme GSK3β. Keywords: GSK3β, Nav1.6, enriched environment, isolated condition, persistent sodium current, neuronal firing, medium spiny neurons, reward pathway, plasticity

Qualitative research in the social sciences typically requires a personal engagement with resource persons. The widely used participant-observation method requires that the researcher assume as far as possible the role of community member. Even when participant observation is not the chosen method, group members assign identities to investigators. Role assignment in martial contexts may range from the “intruder” who disrupts ongoing events (e.g., outsiders may not see “secret techniques”) to one who is allowed insider access, usually after having gone through some test or rite of passage. Data collected in “natural context” is ideal. The primary problem here is that act of observation inevitably changes phenomena under examination. The most effective means of gathering information in a natural context is by engaging in what is known in the Intelligence community as “deep cover” actually joining a community for the purpose of secretly gathering information. This, of course, brings with it serious ethical dilemmas. While it is clear that we must all address the issue of transparency vs. efficiency, most decisions actually are made on a case by case basis. I suggest that it may be time to develop a general set of guidelines to help us keep faith with informants and accomplish our academic goals of accurately depicting the martial cultures with which we engage.

In this panel, five experts present their personal experiences in martial arts and combat sports (MA&CS) research. These experiences represent the two classic approaches to our studies: the quantitative and the qualitative. Above all, the panel aims to foster debate and reflection on the complementarity of these methods when trying to embrace the complexity of MA&CS.

Future food production will be constrained by the scarcity of fossil fuel and fresh water as well as increasing intensity and unpredictability of weather events and climate changes. The assurance of food security and equity for many consumers is complicated by concentration of ownership of land and other production resources, as well as a global corporate food systems model that is driven by profit at the expense of people and the environment. To assess potential alternatives to the contemporary global food chain, well focused research is needed on local food production and food webs where small- and midscale family farms provide economic viability for rural communities and their regions. We suggest multiple and integrative research priorities in production, enterprise, and farm economics, environmental impacts of farming at different scales, and social and community consequences of value adding and economic multipliers in local food webs and systems as well as the structure of agriculture. Research into key questions on food security and how it relates to increased food sovereignty is clearly needed to assess creative food system alternatives for the future.

Meihuaquan (“Plum Blossom Fist [Boxing]”) has traditionally been practiced as vernacular (folk) art practiced among the Han ethnic group residing in the Shandong, Henan and Hebei Provinces of China. Historical documentation dates Plum Blossom Boxing to the seventeenth century. The classic Chinese novel, Shuǐhǔ Zhuàn (Marsh Chronicles) recounts the martial exploits of Shandong’s twelfth century outlaw heroes who may have been Mei Boxers, also. Thus, for perhaps a millennium, the region has been noted for vernacular martial arts and social banditry. The region’s rampant lawlessness promoted highly-developed martial prowess among both lawbreakers and those who were required to protect themselves against the brigands. Cultural, economic, and environmental factors in the region gave rise to heterodox political and religious beliefs that frequently served as a catalyst for martial sects, most notably the “Boxers” who at the turn of the twentieth century, came into conflict with the imperial government. These factors laid the groundwork for the “character traits” of the art while Taoism, the Five Elements theory, and a concept of predictable change shaped Plum Boxing’s strategic and mechanical principles. In the past decade, there have been efforts to globalize this vernacular martial art. Rather than driving Plum Boxing to extinction it is likely that the folk and the “larger than local” will co-exist.

Prior research demonstrated that environmental enrichment creates individual differences in behavior leading to a protective addiction phenotype in rats. Understanding the mechanisms underlying this phenotype will guide selection of targets for much-needed novel pharmacotherapeutics. The current study investigates differences in proteome expression in the nucleus accumbens of enriched and isolated rats and the proteomic response to cocaine self-administration using a liquid chromatography mass spectrometry (LCMS) technique to quantify 1917 proteins. Results of complementary Ingenuity Pathways Analyses (IPA) and gene set enrichment analyses (GSEA), both performed using protein quantitative data, demonstrate that cocaine increases vesicular transporters for dopamine and glutamate as well as increasing proteins in the RhoA pathway. Further, cocaine regulates proteins related to ERK, CREB and AKT signaling. Environmental enrichment altered expression of a large number of proteins implicated in a diverse number of neuronal functions (e.g., energy production, mRNA splicing and ubiquitination), molecular cascades (e.g., protein kinases), psychiatric disorders (e.g., mood disorders), and neurodegenerative diseases (e.g., Huntington's and Alzheimer’s diseases). Upregulation of energy metabolism components in EC rats was verified using RNA sequencing. Most of the biological functions and pathways listed above were also identified in the Cocaine X Enrichment interaction analysis, providing clear evidence that enriched and isolated rats respond quite differently to cocaine exposure. The overall impression of the current results is that enriched saline-administering rats have a unique proteomic complement compared to enriched cocaine-administering rats as well as saline and cocaine-taking isolated rats. These results identify possible mechanisms of the protective phenotype and provide fertile soil for developing novel pharmacotherapeutics.

El meihuaquan (“Puño [Boxeo] de la Flor del Ciruelo”) se ha practicado tradicionalmente como arte vernáculo (folclórico) en el grupo étnico de los Han de las provincias chinas de Shandong, Henan y Hebei. Los registros históricos datan al boxeo de la flor del ciruelo del s. XVII. La novela clásica china Shuihu Zhuan (Las crónicas del pantano) relata las proezas marciales de los héroes proscritos de Shandong durante el siglo XII, quienes también podían haber sido boxeadores mei. Así, durante posiblemente un milenio, la región ha sido célebre por sus artes marciales vernáculas y el bandolerismo social. La rampante anarquía de la región promovió habilidades marciales altamente desarrolladas tanto entre los criminales como entre aquellos que necesitaban defenderse frente a los bandidos. Los factores culturales, económicos y ambientales de la región dieron lugar a creencias políticas y religiosas heterodoxas que sirvieron frecuentemente como catalizadoras de sectas marciales, muy destacadamente los “Bóxers”, que en el cambio al s. XX entraron en conflicto con el gobierno imperial. Estos factores sentaron las bases de los “rasgos de carácter” del arte, mientras que el taoísmo, la teoría de los cinco elementos y un concepto del cambio predecible conformaron los principios estratégicos y mecánicos del boxeo de la flor del ciruelo. Durante la última década se han realizado esfuerzos para globalizar este arte marcial vernáculo. Es probable que esta circunstancia, en vez de conducir al boxeo de la flor del ciruelo a la extinción, consiga que lo tradicional y lo “más amplio que lo local” lleguen a coexistir.

Stereoselective reduction of ketones to alcohols using baker's yeast is a classic experiment in the undergraduate laboratory. Here we illustrate the reduction of racemic ethyl 2-fluoro-3-oxobutanoate to the corresponding alcohol using a set of four commercially available ketoreductases (KREDs). The reaction sets two stereocenters with four stereoisomers possible, with different KREDs selecting for different stereoisomers. Products are characterized by [superscript 1]H and [superscript 19]F NMR spectroscopy to establish diastereomeric and enantiomeric excess. Students learn about dynamic reductive kinetic resolution (DYRKR) and perform NMR Mosher ester analysis for stereochemical assignments.