Targeting Pin1 renders pancreatic cancer eradicable by synergizing with immunochemotherapy.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by notorious resistance to current therapies attributed to inherent tumor heterogeneity and highly desmoplastic and immunosuppressive tumor microenvironment (TME). Unique proline isomerase Pin1 regulates multiple cancer pathways, but its role in the TME and cancer immunotherapy is unknown. Here, we find that Pin1 is overexpressed both in cancer cells and cancer-associated fibroblasts (CAFs) and correlates with poor survival in PDAC patients. Targeting Pin1 using clinically available drugs induces complete elimination or sustained remissions of aggressive PDAC by synergizing with anti-PD-1 and gemcitabine in diverse model systems. Mechanistically, Pin1 drives the desmoplastic and immunosuppressive TME by acting on CAFs and induces lysosomal degradation of the PD-1 ligand PD-L1 and the gemcitabine transporter ENT1 in cancer cells, besides activating multiple cancer pathways. Thus, Pin1 inhibition simultaneously blocks multiple cancer pathways, disrupts the desmoplastic and immunosuppressive TME, and upregulates PD-L1 and ENT1, rendering PDAC eradicable by immunochemotherapy.

Family Cohesion Moderates the Relation between Parent-Child Neural Connectivity Pattern Similarity and Youth's Emotional Adjustment.

Despite a recent surge in research examining parent-child neural similarity using fMRI, there remains a need for further investigation into how such similarity may play a role in children's emotional adjustment. Moreover, no prior studies explored the potential contextual factors that may moderate the link between parent-child neural similarity and children's developmental outcomes. In this study, 32 parent-youth dyads (parents: M age = 43.53 years, 72% female; children: M age = 11.69 years, 41% female) watched an emotion-evoking animated film while being scanned using fMRI. We first quantified how similarly emotion network interacts with other brain regions in responding to the emotion-evoking film between parents and their children. We then examined how such parent-child neural similarity is associated with children's emotional adjustment, with attention to the moderating role of family cohesion. Results revealed that higher parent-child similarity in functional connectivity pattern during movie viewing was associated with better emotional adjustment, including less negative affect, lower anxiety, and greater ego resilience in youth. Moreover, such associations were significant only among families with higher cohesion, but not among families with lower cohesion. The findings advance our understanding of the neural mechanisms underlying how children thrive by being in sync and attuned with their parents, and provide novel empirical evidence that the effects of parent-child concordance at the neural level on children's development are contextually dependent.SIGNIFICANCE STATEMENT What neural processes underlie the attunement between children and their parents that helps children thrive? Using a naturalistic movie-watching fMRI paradigm, we find that greater parent-child similarity in how emotion network interacts with other brain regions during movie viewing is associated with youth's better emotional adjustment including less negative affect, lower anxiety, and greater ego resilience. Interestingly, these associations are only significant among families with higher cohesion, but not among those with lower cohesion. Our findings provide novel evidence that parent-child shared neural processes to emotional situations can confer benefits to children, and underscore the importance of considering specific family contexts in which parent-child neural similarity may be beneficial or detrimental to children's development, highlighting a crucial direction for future research.

Parental warmth buffers the negative impact of weaker fronto-striatal connectivity on early adolescents' academic achievement.

In past decades, the positive role of self-control in students' academic success has attracted plenty of scholarly attention. However, fewer studies have examined the link between adolescents' neural development of the inhibitory control system and their academic achievement, especially using a longitudinal approach. Moreover, less is known about the role of parents in this link. Using large-scale longitudinal data from the Adolescent Brain Cognitive Development (ABCD) study (N = 9574; mean age = 9.94 years at baseline, SD = .63; 50% girls), the current study took an integrative biopsychosocial approach to explore the longitudinal link between early adolescents' fronto-striatal connectivity and their academic achievement, with attention to the moderating role of parental warmth. Results showed that weaker intrinsic connectivity between the frontoparietal network and the striatum was associated with early adolescents' worse academic achievement over 2 years during early adolescence. Notably, parental warmth moderated the association between fronto-striatal connectivity and academic achievement, such that weaker fronto-striatal connectivity was only predictive of worse academic achievement among early adolescents who experienced low levels of parental warmth. Taken together, the findings demonstrate weaker fronto-striatal connectivity as a risk factor for early adolescents' academic development and highlight parental warmth as a protective factor for academic development among those with weaker connectivity within the inhibitory control system.

Caffeinated Soda Intake in Children Is Associated with Neurobehavioral Risk Factors for Substance Misuse.

BACKGROUND AND OBJECTIVES: Use of psychotropic substances in childhood has been associated with both impulsivity and other manifestations of poor executive function as well as escalation over time to use of progressively stronger substances. However, how this relationship may start in earlier childhood has not been well explored. Here, we investigated the neurobehavioral correlates of daily caffeinated soda consumption in preadolescent children and examined whether caffeinated soda intake is associated with a higher risk of subsequent alcohol initiation. METHODS: Using Adolescent Brain Cognitive Development study data (N = 2,092), we first investigated cross-sectional relationships between frequent caffeinated soda intake and well-known risk factors of substance misuse: impaired working memory, high impulsivity, and aberrant reward processing. We then examined whether caffeinated soda intake at baseline predicts more alcohol sipping at 12 months follow-up using a machine learning algorithm. RESULTS: Daily consumption of caffeinated soda was cross-sectionally associated with neurobehavioral risk factors for substance misuse such as higher impulsivity scores and lower working memory performance. Furthermore, caffeinated soda intake predicted a 2.04 times greater likelihood of alcohol sipping after 12 months, even after controlling for rates of baseline alcohol sipping rates. CONCLUSIONS: These findings suggest that previous linkages between caffeine and substance use in adolescence also extend to younger initiation, and may stem from core neurocognitive features thought conducive to substance initiation.

The impact of bone marrow stimulation on arthroscopic rotator cuff repair for small to large rotator cuff tears: a randomized controlled trial.

BACKGROUND: Bone marrow stimulation (BMS), a procedure involving the creation of multiple channels in the greater tuberosity, is often performed alongside arthroscopic rotator cuff repair (ARCR). This study evaluated the effect of BMS on clinical and structural outcomes following ARCR. METHOD: This study involved 204 patients with small, medium, and large full-thickness rotator cuff tears. In all, 103 patients who underwent BMS and ARCR made up the BMS group, while the 101 patients who only had ARCR made up the control group with randomization. Clinical and functional outcomes were assessed before and at 3 months, 6 months, 1 year, and 2 years after surgery, using parameters such as range of motion, functional scores (American Shoulder and Elbow Surgeons and Constant score), and clinical scores (Visual Analogue Scale). Tendon integrity was also examined postoperatively via ultrasound at 6 months and 2 years. RESULTS: There were no significant differences between the two groups concerning range of motion, functional scores (American Shoulder and Elbow Surgeons score and Constant score), and clinical score (Visual Analogue Scale) during the 2-year postsurgery period (all P > .05). Similarly, the rotator cuff retear rate, as assessed using ultrasonographic tendon integrity checks over 2 years postsurgery, did not significantly vary between the groups (all P > .05). CONCLUSION: There were no significant disparities in functional scores and clinical outcomes between the BMS and control groups. Further, no significant differences were observed in tendon integrity postsurgery. Therefore, the inclusion or exclusion of BMS is not anticipated to influence the postoperative outcome in ARCR for patients with small, medium, or large rotator cuff tears.

Selection of Catechin Biosynthesis-Related Genes and Functional Analysis from Chromosome-Level Genome Assembly in C. sinensis L. Variety 'Sangmok'.

Camellia is an important plant genus that includes well-known species such as C. sinensis, C. oleifera, and C. japonica. The C. sinensis cultivar 'Sangmok', one of Korea's standard types of tea landraces, is a small evergreen tree or shrub. Genome annotation has shown that Korean tea plants have special and unique benefits and superior components, such as catechin. The genome of Camellia sinensis cultivar 'Sangmok' was assembled on the chromosome level, with a length of 2678.62 Mbp and GC content of 38.16%. Further, 15 chromosome-scale scaffolds comprising 82.43% of the assembly (BUSCO completeness, 94.3%) were identified. Analysis of 68,151 protein-coding genes showed an average of 5.003 exons per gene. Among 82,481 coding sequences, the majority (99.06%) were annotated by Uniprot/Swiss-Prot. Further analysis revealed that 'Sangmok' is closely related to C. sinensis, with a divergence time of 60 million years ago. A total of 3336 exclusive gene families in 'Sangmok' were revealed by gene ontology analysis to play roles in auxin transport and cellular response mechanisms. By comparing these exclusive genes with 551 similar catechin genes, 17 'Sangmok'-specific catechin genes were identified by qRT-PCR, including those involved in phytoalexin biosynthesis and related to cytochrome P450. The 'Sangmok' genome exhibited distinctive genes compared to those of related species. This comprehensive genomic investigation enhances our understanding of the genetic architecture of 'Sangmok' and its specialized functions. The findings contribute valuable insights into the evolutionary and functional aspects of this plant species.

Emotion Downregulation Targets Interoceptive Brain Regions While Emotion Upregulation Targets Other Affective Brain Regions.

Researchers generally agree that when upregulating and downregulating emotion, control regions in the prefrontal cortex turn up or down activity in affect-generating brain areas. However, the "affective dial hypothesis" that turning up and down emotions produces opposite effects in the same affect-generating regions is untested. We tested this hypothesis by examining the overlap between the regions activated during upregulation and those deactivated during downregulation in 54 male and 51 female humans. We found that upregulation and downregulation both recruit regulatory regions, such as the inferior frontal gyrus and dorsal anterior cingulate gyrus, but act on distinct affect-generating regions. Upregulation increased activity in regions associated with emotional experience, such as the amygdala, anterior insula, striatum, and anterior cingulate gyrus as well as in regions associated with sympathetic vascular activity, such as periventricular white matter, while downregulation decreased activity in regions receiving interoceptive input, such as the posterior insula and postcentral gyrus. Nevertheless, participants' subjective sense of emotional intensity was associated with activity in overlapping brain regions (dorsal anterior cingulate, insula, thalamus, and frontal pole) across upregulation and downregulation. These findings indicate that upregulation and downregulation rely on overlapping brain regions to control and assess emotions but target different affect-generating brain regions.SIGNIFICANCE STATEMENT Many contexts require modulating one's own emotions. Identifying the brain areas implementing these regulatory processes should advance understanding emotional disorders and designing potential interventions. The emotion regulation field has an implicit assumption we call the affective dial hypothesis: both emotion upregulation and downregulation modulate the same emotion-generating brain areas. Countering the hypothesis, our findings indicate that up- and down-modulating emotions target different brain areas. Thus, the mechanisms underlying emotion regulation might differ more than previously appreciated for upregulation versus downregulation. In addition to their theoretical importance, these findings are critical for researchers attempting to target activity in particular brain regions during an emotion regulation intervention.

Association of Intrinsic Functional Connectivity between the Locus Coeruleus and Salience Network with Attentional Ability.

The locus coeruleus (LC) is a brainstem region associated with broad neural arousal because of norepinephrine production, but it has increasingly been associated with specific cognitive processes. These include sustained attention, with deficits associated with various neuropsychological disorders. Neural models of attention deficits have focused on interrupted dynamics between the salience network (SAL) with the frontoparietal network, which has been associated with task-switching and processing of external stimuli, respectively. Conflicting findings for these regions suggest the possibility of upstream signaling leading to attention dysfunction, and recent research suggests LC involvement. In this study, resting-state functional connectivity and behavioral performance on an attention task was examined within 584 individuals. Analysis revealed significant clusters connected to LC activity in the SAL. Given previous findings that attention deficits may be caused by SAL network switching dysfunctions, findings here further suggest that dysfunction in LC-SAL connectivity may impair attention.

Essential role for the prolyl isomerase Pin1 in Toll-like receptor signaling and type I interferon-mediated immunity.

Toll-like receptors (TLRs) shape innate and adaptive immunity to microorganisms. The enzyme IRAK1 transduces signals from TLRs, but mechanisms for its activation and regulation remain unknown. We found here that TLR7 and TLR9 activated the isomerase Pin1, which then bound to IRAK1; this resulted in activation of IRAK1 and facilitated its release from the receptor complex to activate the transcription factor IRF7 and induce type I interferons. Consequently, Pin1-deficient cells and mice failed to mount TLR-mediated, interferon-dependent innate and adaptive immune responses. Given the critical role of aberrant activation of IRAK1 and type I interferons in various immune diseases, controlling IRAK1 activation via inhibition of Pin1 may represent a useful therapeutic approach.

Global Trends in Social Prescribing: Web-Based Crawling Approach.

BACKGROUND: Social loneliness is a prevalent issue in industrialized countries that can lead to adverse health outcomes, including a 26% increased risk of premature mortality, coronary heart disease, stroke, depression, cognitive impairment, and Alzheimer disease. The United Kingdom has implemented a strategy to address loneliness, including social prescribing-a health care model where physicians prescribe nonpharmacological interventions to tackle social loneliness. However, there is a need for evidence-based plans for global social prescribing dissemination. OBJECTIVE: This study aims to identify global trends in social prescribing from 2018. To this end, we intend to collect and analyze words related to social prescribing worldwide and evaluate various trends of related words by classifying the core areas of social prescribing. METHODS: Google's searchable data were collected to analyze web-based data related to social prescribing. With the help of web crawling, 3796 news items were collected for the 5-year period from 2018 to 2022. Key topics were selected to identify keywords for each major topic related to social prescribing. The topics were grouped into 4 categories, namely Healthy, Program, Governance, and Target, and keywords for each topic were selected thereafter. Text mining was used to determine the importance of words collected from new data. RESULTS: Word clouds were generated for words related to social prescribing, which collected 3796 words from Google News databases, including 128 in 2018, 432 in 2019, 566 in 2020, 748 in 2021, and 1922 in 2022, increasing nearly 15-fold between 2018 and 2022 (5 years). Words such as health, prescribing, and GPs (general practitioners) were the highest in terms of frequency in the list for all the years. Between 2020 and 2021, COVID, gardening, and UK were found to be highly related words. In 2022, NHS (National Health Service) and UK ranked high. This dissertation examines social prescribing-related term frequency and classification (2018-2022) in Healthy, Program, Governance, and Target categories. Key findings include increased "Healthy" terms from 2020, "gardening" prominence in "Program," "community" growth across categories, and "Target" term spikes in 2021. CONCLUSIONS: This study's discussion highlights four key aspects: (1) the "Healthy" category trends emphasize mental health, cancer, and sleep; (2) the "Program" category prioritizes gardening, community, home-schooling, and digital initiatives; (3) "Governance" underscores the significance of community resources in social prescribing implementation; and (4) "Target" focuses on 4 main groups: individuals with long-term conditions, low-level mental health issues, social isolation, or complex social needs impacting well-being. Social prescribing is gaining global acceptance and is becoming a global national policy, as the world is witnessing a sharp rise in the aging population, noncontagious diseases, and mental health problems. A successful and sustainable model of social prescribing can be achieved by introducing social prescribing schemes based on the understanding of roles and the impact of multisectoral partnerships.

Potential Implications of miRNAs in the Pathogenesis, Diagnosis, and Therapeutics of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex multifactorial disorder that poses a substantial burden on patients, caregivers, and society. Considering the increased aging population and life expectancy, the incidence of AD will continue to rise in the following decades. However, the molecular pathogenesis of AD remains controversial, superior blood-based biomarker candidates for early diagnosis are still lacking, and effective therapeutics to halt or slow disease progression are urgently needed. As powerful genetic regulators, microRNAs (miRNAs) are receiving increasing attention due to their implications in the initiation, development, and theranostics of various diseases, including AD. In this review, we summarize miRNAs that directly target microtubule-associated protein tau (MAPT), amyloid precursor protein (APP), and ß-site APP-cleaving enzyme 1 (BACE1) transcripts and regulate the alternative splicing of tau and APP. We also discuss related kinases, such as glycogen synthase kinase (GSK)-3ß, cyclin-dependent kinase 5 (CDK5), and death-associated protein kinase 1 (DAPK1), as well as apolipoprotein E, that are directly targeted by miRNAs to control tau phosphorylation and amyloidogenic APP processing leading to Aß pathologies. Moreover, there is evidence of miRNA-mediated modulation of inflammation. Furthermore, circulating miRNAs in the serum or plasma of AD patients as noninvasive biomarkers with diagnostic potential are reviewed. In addition, miRNA-based therapeutics optimized with nanocarriers or exosomes as potential options for AD treatment are discussed.

Ablation of Death-Associated Protein Kinase 1 Changes the Transcriptomic Profile and Alters Neural-Related Pathways in the Brain.

Death-associated protein kinase 1 (DAPK1), a Ca2+/calmodulin-dependent serine/threonine kinase, mediates various neuronal functions, including cell death. Abnormal upregulation of DAPK1 is observed in human patients with neurological diseases, such as Alzheimer's disease (AD) and epilepsy. Ablation of DAPK1 expression and suppression of DAPK1 activity attenuates neuropathology and behavior impairments. However, whether DAPK1 regulates gene expression in the brain, and whether its gene profile is implicated in neuronal disorders, remains elusive. To reveal the function and pathogenic role of DAPK1 in neurological diseases in the brain, differential transcriptional profiling was performed in the brains of DAPK1 knockout (DAPK1-KO) mice compared with those of wild-type (WT) mice by RNA sequencing. We showed significantly altered genes in the cerebral cortex, hippocampus, brain stem, and cerebellum of both male and female DAPK1-KO mice compared to those in WT mice, respectively. The genes are implicated in multiple neural-related pathways, including: AD, Parkinson's disease (PD), Huntington's disease (HD), neurodegeneration, glutamatergic synapse, and GABAergic synapse pathways. Moreover, our findings imply that the potassium voltage-gated channel subfamily A member 1 (Kcna1) may be involved in the modulation of DAPK1 in epilepsy. Our study provides insight into the pathological role of DAPK1 in the regulatory networks in the brain and new therapeutic strategies for the treatment of neurological diseases.

The Pin1-CaMKII-AMPA Receptor Axis Regulates Epileptic Susceptibility.

Pin1 is a unique isomerase that regulates protein conformation and function after phosphorylation. Pin1 aberration contributes to some neurological diseases, notably Alzheimer's disease, but its role in epilepsy is not fully understood. We found that Pin1-deficient mice had significantly increased seizure susceptibility in multiple chemical inducing models and developed age-dependent spontaneous epilepsy. Electrophysiologically, Pin1 ablation enhanced excitatory synaptic transmission to prefrontal cortex (PFC) pyramidal neurons without affecting their intrinsic excitability. Biochemically, Pin1 ablation upregulated AMPA receptors and GluA1 phosphorylation by acting on phosphorylated CaMKII. Clinically, Pin1 was decreased significantly, whereas phosphorylated CaMKII and GluA1 were increased in the neocortex of patients with epilepsy. Moreover, Pin1 expression restoration in the PFC of Pin1-deficient mice using viral gene transfer significantly reduced phosphorylated CaMKII and GluA1 and effectively suppressed their seizure susceptibility. Thus, Pin1-CaMKII-AMPA receptors are a novel axis controlling epileptic susceptibility, highlighting attractive new therapeutic strategies.

Perinatal Outcomes According to Accessibility to Maternal-Fetal and Neonatal Intensive Care Units by Region in Korea.

BACKGROUND: Herein, we aimed to evaluate the maternal mortality ratio and perinatal mortality rate for different perinatal medical care service areas (PMCSAs), which were established by considering their geographical accessibility to maternal-fetal intensive care units (MFICUs) and neonatal intensive care units (NICUs), and to compare the PMCSAs according to their accessibility to these perinatal care services. METHODS: Based on the 70 hospital service areas (HSAs) across the country confirmed through the Dartmouth Atlas methodology analysis and gathering of expert opinions, the PMCSAs were designated by merging HSAs without MFICUs and NICUs to the nearest HSA that contained MFICUs and NICUs, based on which MFICU and NICU could be reached within the shortest amount of time from population-weighted centroids in HSAs. PMCSAs where 30% or more of the population could not access MFICUs and NICUs within 60 minutes were identified using the service module ArcGIS and were defined as having access vulnerability. RESULTS: Thirty-three of 70 HSAs in the country did not contain MFICUs and NICUs, and 39 PMCSAs were finally derived by merging 70 HSAs. Ten of 39 PMCSAs (25.6%) were classified as having access vulnerability to MFICUs and NICUs. The national maternal mortality ratio was 9.42, with the highest ratio seen in the region of Wonju (25.86) and the lowest in Goyang (2.79). The national perinatal mortality rate was 2.86, with the highest and lowest rates observed in the Gunsan (4.04) and Sejong (1.99) regions, respectively. The perinatal mortality rates for areas vulnerable and invulnerable to maternal and neonatal healthcare accessibility were 2.97 and 2.92, respectively, but there was no statistically significant difference in this rate (P = 0.789). The maternal mortality ratio for areas vulnerable and invulnerable to maternal and neonatal healthcare accessibility were 14.28 and 9.48, respectively; this ratio was significantly higher in areas vulnerable to accessibility (P = 0.022). CONCLUSION: Of the PMCSAs across the country, 25.6% (10/39) were deemed to be vulnerable to MFICU and NICU accessibility. There was no difference in the perinatal mortality rate between the vulnerable and invulnerable areas, but the maternal mortality ratio in vulnerable areas was significantly higher than that in invulnerable areas.

Graft isometry during anatomical ACL reconstruction has little effect on surgical outcomes.

PURPOSE: To investigate the surgical outcomes of anatomical anterior cruciate ligament (ACL) reconstruction according to the graft isometry measured during surgery. METHODS: Electrical medical records of patients who underwent an arthroscopic ACL reconstruction through the transportal technique using hamstring tendon autograft between 2012 and 2016 were retrospectively reviewed. The patients were classified into two groups based on the graft length change throughout the knee range of motion measured just before graft fixation (Group 1, graft length change ≤ 2 mm; Group 2, graft length change > 2 mm). Comparative analyses, including a non-inferiority trial, were performed regarding the clinical scores, knee laxity, and radiographic parameters between the groups. RESULTS: A total of 67 patients were included in the study. The total change in the length of ACL graft throughout the knee range of motion was 1.4 ± 0.4 mm in Group 1 (range, 0.2-2.0 mm), and 3.0 ± 0.7 mm in Group 2 (range, 2.2-5.0 mm). Group 1 showed a relatively high (proximal) femoral tunnel and shallow (anterior) tibial tunnel compared to Group 2 (P < 0.001 and P = 0.028, respectively), but there were no apparent differences in the macroscopic view. There were no statistically significant differences in the clinical outcomes between groups at 2 years after surgery, which satisfied the non-inferiority criterion of Group 1 in terms of clinical scores and knee laxity compared to Group 2. CONCLUSION: The surgical outcomes of anatomical ACL reconstruction in patients with non-isometric ACL graft were not inferior in terms of clinical scores and knee laxity, compared to those with nearly-isometric ACL graft. The graft tunnel placement in the isometric position during anatomical ACL reconstruction, which is technically challenging in the clinical setting, is not a crucial factor in terms of clinical outcomes. LEVEL OF EVIDENCE: Level IV.

Bamboo Salt and Triple Therapy Synergistically Inhibit Helicobacter pylori-Induced Gastritis In Vivo: A Preliminary Study.

Helicobacter pylori infections are a major cause of gastrointestinal disorders, including gastric ulcers, gastritis, and gastric cancer. Triple therapy, using two antibiotics and a proton pump inhibitor, is recommended for the treatment of H. pylori infections. However, antibiotic resistance in H. pylori is an emerging issue. Bamboo salt, a traditional Korean salt made by baking solar sea salt in bamboo barrels, can ameliorate the symptoms of various gastrointestinal diseases. Herein, we compared the anti-H. pylori activity of triple therapy (clarithromycin, metronidazole, and omeprazole), solar salt, and bamboo salt in vivo as a preliminary study. Four-week-old C57BL/6 male mice were inoculated for eight weeks with the H. pylori Sydney Strain 1 (SS-1) and orally administered triple therapy drugs and salts for five days. The transcript levels of the H. pylori-expressed gene CagA and inflammatory cytokines Tnfα and Il-1ß significantly decreased in the bamboo salt treated mice than those in the H. pylori-infected control group. This effect was further enhanced by using triple therapy and bamboo salt together. Solar salt caused modest inhibition of H. pylori-induced inflammation. We also demonstrated the synergistic effects of bamboo salt and triple therapy against H. pylori. Thus, bamboo salt may be a potential candidate agent against the treatment of H. pylori-associated gastritis.

Blocking ERK-DAPK1 Axis Attenuates Glutamate Excitotoxicity in Epilepsy.

Glutamate excitotoxicity induces neuronal cell death during epileptic seizures. Death-associated protein kinase 1 (DAPK1) expression is highly increased in the brains of epilepsy patients; however, the underlying mechanisms by which DAPK1 influences neuronal injury and its therapeutic effect on glutamate excitotoxicity have not been determined. We assessed multiple electroencephalograms and seizure grades and performed biochemical and cell death analyses with cellular and animal models. We applied small molecules and peptides and knocked out and mutated genes to evaluate the therapeutic efficacy of kainic acid (KA), an analog of glutamate-induced neuronal damage. KA administration increased DAPK1 activity by promoting its phosphorylation by activated extracellular signal-regulated kinase (ERK). DAPK1 activation increased seizure severity and neuronal cell death in mice. Selective ERK antagonist treatment, DAPK1 gene ablation, and uncoupling of DAPK1 and ERK peptides led to potent anti-seizure and anti-apoptotic effects in vitro and in vivo. Moreover, a DAPK1 phosphorylation-deficient mutant alleviated glutamate-induced neuronal apoptosis. These results provide novel insight into the pathogenesis of epilepsy and indicate that targeting DAPK1 may be a potential therapeutic strategy for treating epilepsy.

miR-143-3p Inhibits Aberrant Tau Phosphorylation and Amyloidogenic Processing of APP by Directly Targeting DAPK1 in Alzheimer's Disease.

The neuropathology of Alzheimer's disease (AD) is characterized by intracellular aggregation of hyperphosphorylated tau and extracellular accumulation of beta-amyloid (Aß). Death-associated protein kinase 1 (DAPK1), as a novel therapeutic target, shows promise for the treatment of human AD, but the regulatory mechanisms of DAPK1 expression in AD remain unclear. In this study, we identified miR-143-3p as a promising candidate for targeting DAPK1. miR-143-3p directly bound to the 3' untranslated region of human DAPK1 mRNA and inhibited its translation. miR-143-3p decreased tau phosphorylation and promoted neurite outgrowth and microtubule assembly. Moreover, miR-143-3p attenuated amyloid precursor protein (APP) phosphorylation and reduced the generation of Aß40 and Aß42. Furthermore, restoring DAPK1 expression with miR-143-3p antagonized the effects of miR-143-3p in attenuating tau hyperphosphorylation and Aß production. In addition, the miR-143-3p levels were downregulated and correlated inversely with the expression of DAPK1 in the hippocampus of AD patients. Our results suggest that miR-143-3p might play critical roles in regulating both aberrant tau phosphorylation and amyloidogenic processing of APP by targeting DAPK1 and thus offer a potential novel therapeutic strategy for AD.

Comparative Transcriptome Analysis between Two Potato Cultivars in Tuber Induction to Reveal Associated Genes with Anthocyanin Accumulation.

Anthocyanins are generally accumulated within a few layers, including the epidermal cells of leaves and stems in plants. Solanum tuberosum cv. 'Jayoung' (hereafter, JY) is known to accumulate anthocyanin both in inner tissues and skins. We discovered that anthocyanin accumulation in the inner tissues of JY was almost diminished (more than 95% was decreased) in tuber induction condition. To investigate the transcriptomic mechanism of anthocyanin accumulation in JY flesh, which can be modulated by growth condition, we performed mRNA sequencing with white-colored flesh tissue of Solanum tuberosum cv. 'Atlantic' (hereafter, 'Daeseo', DS) grown under canonical growth conditions, a JY flesh sample grown under canonical growth conditions, and a JY flesh sample grown under tuber induction conditions. We could identify 36 common DEGs (differentially expressed genes) in JY flesh from canonical growth conditions that showed JY-specifically increased or decreased expression level. These genes were enriched with flavonoid biosynthetic process terms in GO analysis, as well as gene set enrichment analysis (GSEA) analysis. Further in silico analysis on expression levels of anthocyanin biosynthetic genes including rate-limiting genes such as StCHS and StCHI followed by RT-PCR and qRT-PCR analysis showed a strong positive correlation with the observed phenotypes. Finally, we identified StWRKY44 from 36 common DEGs as a possible regulator of anthocyanin accumulation, which was further supported by network analysis. In conclusion, we identified StWRKY44 as a putative regulator of tuber-induction-dependent anthocyanin accumulation.

The Graft Insertion Length in the Femoral Tunnel During Anterior Cruciate Ligament Reconstruction With Suspensory Fixation and Tibialis Anterior Allograft Does Not Affect Surgical Outcomes but Is Negatively Correlated With Tunnel Widening.

PURPOSE: To investigate the surgical outcomes of anterior cruciate ligament (ACL) reconstruction using a low-dose irradiated tibialis anterior allograft with a fixed-loop cortical suspension device for the femur based on the graft insertion length (GIL) in the femoral tunnel. METHODS: Between January 2010 and January 2018, the medical records of consecutive patients who underwent arthroscopic ACL reconstruction with a tibialis anterior allograft fixed with the EndoButton CL for the femur and who had at least 2 years of follow-up were retrospectively evaluated. Patients were classified into 3 groups based on the GIL in the femoral tunnel (group 1, GIL < 15 mm; group 2, GIL of 15-20 mm; and group 3, GIL > 20 mm), and their functional scores, knee laxity, and radiographic parameters were evaluated. RESULTS: A total of 91 patients were analyzed. There were no statistically significant differences in the functional scores and knee laxity between the 3 groups at 2 years postoperatively. However, significant differences were observed in tunnel widening at 1 year postoperatively in the femur (P = .045 for absolute value and P = .004 for relative value) and the tibia (P = .014 for absolute value and P = .012 for relative value), revealing that both the femoral and tibial tunnels widened as the GIL decreased. Additional linear regression analyses were performed to identify whether the GIL independently affects tunnel widening. Consequently, the femoral tunnel depth, tunnel diameter, and GIL were found to independently influence femoral tunnel widening (P = .008, P = .019, and P < .001, respectively), whereas the tunnel diameter and GIL affected tibial tunnel widening (P < .001 and P = .004, respectively). CONCLUSIONS: The GIL in the femoral tunnel during ACL reconstruction using a tibialis anterior allograft with a fixed-loop cortical suspension device for the femur has no significant association with the postoperative functional outcomes and knee laxity, but it has a negative correlation with tunnel widening in the femur and the tibia. LEVEL OF EVIDENCE: Level III, retrospective cohort study.