Recent studies have shown a critical function for the ubiquitin-proteasome system (UPS) in regulating the signalling network for DNA damage responses and DNA repair. To search for new UPS targets in the DNA damage signalling pathway, we have carried out a non-biased assay to identify fast-turnover proteins induced by various types of genotoxic stress. This endeavour led to the identification of Rad17 as a protein exhibiting a distinctive pattern of upregulation followed by subsequent degradation after exposure to UV radiation in human primary cells. Our characterization showed that UV-induced Rad17 oscillation is mediated by Cdh1/APC, a ubiquitin-protein ligase. Studies using a degradation-resistant Rad17 mutant demonstrated that Rad17 stabilization prevents the termination of checkpoint signalling, which in turn attenuates the cellular re-entry into cell-cycle progression. The findings provide an insight into how the proteolysis of Rad17 by Cdh1/APC regulates the termination of checkpoint signalling and the recovery from genotoxic stress.

Sudden cardiac death (SCD) is a significant issue affecting national health policies. The National Emergency Department Information System for Cardiac Arrest (NEDIS-CA) consortium managed a prospective registry of out-of-hospital cardiac arrest (OHCA) at the emergency department (ED) level. We analyzed the NEDIS-CA data from 29 participating hospitals from January 2008 to July 2009. The primary outcomes were incidence of OHCA and final survival outcomes at discharge. Factors influencing survival outcomes were assessed as secondary outcomes. The implementation of advanced emergency management (drugs, endotracheal intubation) and post-cardiac arrest care (therapeutic hypothermia, coronary intervention) was also investigated. A total of 4,156 resuscitation-attempted OHCAs were included, of which 401 (9.6%) patients survived to discharge and 79 (1.9%) were discharged with good neurologic outcomes. During the study period, there were 1,662,470 ED visits in participant hospitals; therefore, the estimated number of resuscitation-attempted CAs was 1 per 400 ED visits (0.25%). Factors improving survival outcomes included younger age, witnessed collapse, onset in a public place, a shockable rhythm in the pre-hospital setting, and applied advanced resuscitation care. We found that active advanced multidisciplinary resuscitation efforts influenced improvement in the survival rate. Resuscitation by public witnesses improved the short-term outcomes (return of spontaneous circulation, survival admission) but did not increase the survival to discharge rate. Strategies are required to reinforce the chain of survival and high-quality cardiopulmonary resuscitation in Korea.

The Dietary Approaches to Stop Hypertension (DASH) diet is a widely recommended diet for individuals with hypertension. Adherence to the DASH diet has been shown to be effective for controlling hypertension, but it is unclear whether a hypertension diagnosis has an impact on adherence to the diet and nutrient intake. This study examined the association between hypertension diagnosis and the DASH nutrient intake using the multivariate linear regression method. The sample was composed of individuals with hypertension in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2012. The outcome was the DASH accordance score (0 to 9 points), which measures the intake of nine nutrients compared to target amounts. Study findings indicate that a diagnostic status of hypertension was associated with increased consumption of sodium, saturated fat, total fat, and protein. Adherence to the DASH diet was more likely to be associated with health conditions such as obesity and heart diseases and lifestyle behaviors such as current smoking status and physical activity. Individuals diagnosed with hypertension showed less adherence to the DASH diet than those not diagnosed with hypertension, so a diagnosis of hypertension did not seem to provide an incentive to engage in healthy dietary behavior. Overall, regardless of diagnostic status, individuals with hypertension did not seem to follow the DASH guidelines.

Management of men with prostate cancer is fraught with uncertainty as physicians and patients balance efficacy with potential toxicity and diminished quality of life. Utilization of genomics as a prognostic biomarker has improved the informed decision-making process by enabling more rationale treatment choices. Recently investigations have begun to determine whether genomic information from tumor transcriptome data can be used to impact clinical decision-making beyond prognosis. Here we discuss the potential of genomics to alter management of a patient who presented with high-risk prostate adenocarcinoma. We suggest that this information help selecting patients for advanced imaging, chemotherapies, or clinical trial.

Synaptic adhesion molecules regulate diverse aspects of synapse formation and maintenance. Many known synaptic adhesion molecules localize at excitatory synapses, whereas relatively little is known about inhibitory synaptic adhesion molecules. Here we report that IgSF9b is a novel, brain-specific, homophilic adhesion molecule that is strongly expressed in GABAergic interneurons. IgSF9b was preferentially localized at inhibitory synapses in cultured rat hippocampal and cortical interneurons and was required for the development of inhibitory synapses onto interneurons. IgSF9b formed a subsynaptic domain distinct from the GABAA receptor- and gephyrin-containing domain, as indicated by super-resolution imaging. IgSF9b was linked to neuroligin 2, an inhibitory synaptic adhesion molecule coupled to gephyrin, via the multi-PDZ protein S-SCAM. IgSF9b and neuroligin 2 could reciprocally cluster each other. These results suggest a novel mode of inhibitory synaptic organization in which two subsynaptic domains, one containing IgSF9b for synaptic adhesion and the other containing gephyrin and GABAA receptors for synaptic transmission, are interconnected through S-SCAM and neuroligin 2.

Helicobacter fennelliae, a human enterohepatic pathogen, causes bacteremia and colitis. We isolated H. fennelliae strain MRY12-0050 from a female patient; this strain was isolated from 2 other patients from the same hospital during the same period, suggesting human-to-human transmission. This is the first report of an H. fennelliae genome sequence.

Synaptic adhesion molecules regulate synapse development and plasticity through mechanisms that include trans-synaptic adhesion and recruitment of diverse synaptic proteins. We found that the immunoglobulin superfamily member 11 (IgSF11), a homophilic adhesion molecule that preferentially expressed in the brain, is a dual-binding partner of the postsynaptic scaffolding protein PSD-95 and AMPA glutamate receptors (AMPARs). IgSF11 required PSD-95 binding for its excitatory synaptic localization. In addition, IgSF11 stabilized synaptic AMPARs, as determined by IgSF11 knockdown-induced suppression of AMPAR-mediated synaptic transmission and increased surface mobility of AMPARs, measured by high-throughput, single-molecule tracking. IgSF11 deletion in mice led to the suppression of AMPAR-mediated synaptic transmission in the dentate gyrus and long-term potentiation in the CA1 region of the hippocampus. IgSF11 did not regulate the functional characteristics of AMPARs, including desensitization, deactivation or recovery. These results suggest that IgSF11 regulates excitatory synaptic transmission and plasticity through its tripartite interactions with PSD-95 and AMPARs.

Disturbances in circadian rhythms have been suggested as a possible cause of bipolar disorder (BD). Included in this study were 31 mood episodes of 26 BD patients, and 18 controls. Circadian rhythms of BD were evaluated at admission, at 2-week intervals during hospitalization, and at discharge. All participants wore wrist actigraphs during the studies. Saliva and buccal cells were obtained at 8:00, 11:00, 15:00, 19:00, and 23:00 for two consecutive days. Collected saliva and buccal cells were used for analysis of the cortisol and gene circadian rhythm, respectively. Circadian rhythms had different phases during acute mood episodes of BD compared to recovered states. In 23 acute manic episodes, circadian phases were ~7hour advanced (equivalent to ~17hour delayed). Phases of 21 out of these 23 cases returned to normal by ~7hour delay along with treatment, but two out of 23 cases returned to normal by ~17hour advance. In three cases of mixed manic episodes, the phases were ~6-7hour delayed. For five cases of depressive episodes, circadian rhythms phases were ~4-5hour delayed. After treatment, circadian phases resembled those of healthy controls. Circadian misalignment due to circadian rhythm phase shifts might be a pathophysiological mechanism of BD.

Parkinson's disease (PD) is a common, late-onset movement disorder with selective degeneration of dopaminergic (DA) neurons in the substantia nigra (SN). Although the neurotoxin 6-hydroxydopamine (6-OHDA) has been used to induce progressive degeneration of DA neurons in various animal models of PD, the precise molecular pathway and the impact of anti-apoptotic treatment on this neurodegeneration are less understood. Following a striatal injection of 6-OHDA, we observed atrophy and progressive death of DA neurons in wild-type mice. These degenerating DA neurons never exhibited signs of apoptosis (i.e., caspase-3 activation and cytoplasmic release of cytochrome C), but rather show nuclear translocation of apoptosis-inducing factor (AIF), a hallmark of regulated necrosis. However, mice with genetic deletion of the proapoptotic gene Bax (Bax-KO) exhibited a complete absence of 6-OHDA-induced DA neuron death and nuclear translocation of AIF, indicating that 6-OHDA-induced DA neuronal death is mediated by Bax-dependent AIF activation. On the other hand, DA neurons that survived in Bax-KO mice exhibited marked neuronal atrophy, without significant improvement of PD-related behavioral deficits. These findings suggest that anti-apoptotic therapy may not be sufficient for PD treatment, and the prevention of Bax-independent neuronal atrophy may be an important therapeutic target.

Tamalin is a scaffold protein known to regulate membrane trafficking through its interaction with cytohesin-2/ARNO, guanine nucleotide exchange factor (GEF) on ADP-ribosylation factor (Arf) 1/6, and induces actin reorganization. However, the neuronal function of Tamalin is not well understood. Here, we report that Tamalin participates in neurite development through the association with exchange factor for Arf6 (EFA6A)/Arf6 signaling. In immature hippocampal neuron, Tamalin knockdown markedly reduced the dendritic outgrowth, the number of dendritic tips and the levels of filamentous actin (F-actin) and microtubule-associated protein 2 (MAP2) in dendrites. In addition, Tamalin colocalized with EFA6A and Arf6 in the dendritic shaft. Tamalin knockdown reduced the number, size, and intensity of endogenous EFA6A cluster, whereas overexpression of Tamalin showed opposite effects compared with those of knockdown. These results suggest that Tamalin is responsible for neuronal dendritic development via regulation of EFA6A/Arf6-mediated cytoskeleton dynamics.

It is generally believed that after memory consolidation, memory-encoding synaptic circuits are persistently modified and become less plastic. This, however, may hinder the remaining capacity of information storage in a given neural circuit. Here we consider the hypothesis that memory-encoding synaptic circuits still retain reversible plasticity even after memory consolidation. To test this, we employed a protocol of auditory fear conditioning which recruited the vast majority of the thalamic input synaptic circuit to the lateral amygdala (T-LA synaptic circuit; a storage site for fear memory) with fear conditioning-induced synaptic plasticity. Subsequently the fear memory-encoding synaptic circuits were challenged with fear extinction and re-conditioning to determine whether these circuits exhibit reversible plasticity. We found that fear memory-encoding T-LA synaptic circuit exhibited dynamic efficacy changes in tight correlation with fear memory strength even after fear memory consolidation. Initial conditioning or re-conditioning brought T-LA synaptic circuit near the ceiling of their modification range (occluding LTP and enhancing depotentiation in brain slices prepared from conditioned or re-conditioned rats), while extinction reversed this change (reinstating LTP and occluding depotentiation in brain slices prepared from extinguished rats). Consistently, fear conditioning-induced synaptic potentiation at T-LA synapses was functionally reversed by extinction and reinstated by subsequent re-conditioning. These results suggest reversible plasticity of fear memory-encoding circuits even after fear memory consolidation. This reversible plasticity of memory-encoding synapses may be involved in updating the contents of original memory even after memory consolidation.

How innate T cells (ITC), including invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, and γδ T cells, maintain a poised effector state has been unclear. Here we address this question using low-input and single-cell RNA-seq of human lymphocyte populations. Unbiased transcriptomic analyses uncover a continuous 'innateness gradient', with adaptive T cells at one end, followed by MAIT, iNKT, γδ T and natural killer cells at the other end. Single-cell RNA-seq reveals four broad states of innateness, and heterogeneity within canonical innate and adaptive populations. Transcriptional and functional data show that innateness is characterized by pre-formed mRNA encoding effector functions, but impaired proliferation marked by decreased baseline expression of ribosomal genes. Together, our data shed new light on the poised state of ITC, in which innateness is defined by a transcriptionally-orchestrated trade-off between rapid cell growth and rapid effector function.

Polymer-based biomedical electronics provide a tunable platform to interact with nervous tissue both in vitro and in vivo. Ultimately, the ability to control functional properties of neural interfaces may provide important advantages to study the nervous system or to restore function in patients with neurodegenerative disorders. Liquid crystal elastomers (LCEs) are a class of smart materials that reversibly change shape when exposed to a variety of stimuli. Our interest in LCEs is based on leveraging this shape change to deploy electrode sites beyond the tissue regions exhibiting inflammation associated with chronic implantation. As a first step, we demonstrate that LCEs are cellular compatible materials that can be used as substrates for fabricating microelectrode arrays (MEAs) capable of recording single unit activity in vitro. Extracts from LCEs are non-cytotoxic (>70% normalized percent viability), as determined in accordance to ISO protocol 10993-5 using fibroblasts and primary murine cortical neurons. LCEs are also not functionally neurotoxic as determined by exposing cortical neurons cultured on conventional microelectrode arrays to LCE extract for 48 h. Microelectrode arrays fabricated on LCEs are stable, as determined by electrochemical impedance spectroscopy. Examination of the impedance and phase at 1 kHz, a frequency associated with single unit recording, showed results well within range of electrophysiological recordings over 30 days of monitoring in phosphate-buffered saline (PBS). Moreover, the LCE arrays are shown to support viable cortical neuronal cultures over 27 days in vitro and to enable recording of prominent extracellular biopotentials comparable to those achieved with conventional commercially-available microelectrode arrays.

Neural stem cells (NSCs) in the adult subventricular zone (SVZ) are regionally specified and have distinct molecular gene expression signatures. Recently, we identified the subcallosal zone (SCZ) as a novel brain region where adult NSCs maintain and spontaneously produce neuroblasts. In an attempt to isolate genes specifically expressed in the SCZ or SVZ, microarray analyses of their differentially expressing transcripts were done. The comparison between neurospheres generated from SVZ and SCZ revealed differential expression >1.5-fold in two groups in only 83 genes, representing <0.03% of the genes examined, suggesting that these two populations are largely similar. The differential expression patterns SCZ and SVZ genes were confirmed by RT-PCR and Western blots. The selective expressions of two genes (CRBP1, HMGA1) in SVZ-NSCs were further confirmed by immunohistochemistry. These molecular markers could be useful for further molecular and cellular characterization of NSCs.

Inositol 1,4,5-trisphosphate 3-kinase A (IP3K-A) regulates the level of the inositol polyphosphates, inositol trisphosphate (IP3) and inositol tetrakisphosphate to modulate cellular signaling and intracellular calcium homeostasis in the central nervous system. IP3K-A binds to F-actin in an activity-dependent manner and accumulates in dendritic spines, where it is involved in the regulation of synaptic plasticity. IP3K-A knockout mice exhibit deficits in some forms of hippocampus-dependent learning and synaptic plasticity, such as long-term potentiation in the dentate gyrus synapses of the hippocampus. In the present study, to further elucidate the role of IP3K-A in the brain, we developed a transgenic (Tg) mouse line in which IP3K-A is conditionally overexpressed approximately 3-fold in the excitatory neurons of forebrain regions, including the hippocampus. The Tg mice showed an increase in both presynaptic release probability of evoked responses, along with bigger synaptic vesicle pools, and miniature excitatory postsynaptic current amplitude, although the spine density or the expression levels of the postsynaptic density-related proteins NR2B, synaptotagmin 1, and PSD-95 were not affected. Hippocampal-dependent learning and memory tasks, including novel object recognition and radial arm maze tasks, were partially impaired in Tg mice. Furthermore, (R,S)-3,5-dihydroxyphenylglycine-induced metabotropic glutamate receptor long-term depression was inhibited in Tg mice and this inhibition was dependent on protein kinase C but not on the IP3 receptor. Long-term potentiation and depression dependent on N-methyl-d-aspartate receptor were marginally affected in Tg mice. In summary, this study shows that overexpressed IP3K-A plays a role in some forms of hippocampus-dependent learning and memory tasks as well as in synaptic transmission and plasticity by regulating both presynaptic and postsynaptic functions.

Mania causes symptoms of hyperactivity, impulsivity, elevated mood, reduced anxiety and decreased need for sleep, which suggests that the dysfunction of the striatum, a critical component of the brain motor and reward system, can be causally associated with mania. However, detailed molecular pathophysiology underlying the striatal dysfunction in mania remains largely unknown. In this study, we aimed to identify the molecular pathways showing alterations in the striatum of SH3 and multiple ankyrin repeat domains 3 (Shank3)-overexpressing transgenic (TG) mice that display manic-like behaviors. The results of transcriptome analysis suggested that mammalian target of rapamycin complex 1 (mTORC1) signaling may be the primary molecular signature altered in the Shank3 TG striatum. Indeed, we found that striatal mTORC1 activity, as measured by mTOR S2448 phosphorylation, was significantly decreased in the Shank3 TG mice compared to wild-type (WT) mice. To elucidate the potential underlying mechanism, we re-analyzed previously reported protein interactomes, and detected a high connectivity between Shank3 and several upstream regulators of mTORC1, such as tuberous sclerosis 1 (TSC1), TSC2 and Ras homolog enriched in striatum (Rhes), via 94 common interactors that we denominated "Shank3-mTORC1 interactome". We noticed that, among the 94 common interactors, 11 proteins were related to actin filaments, the level of which was increased in the dorsal striatum of Shank3 TG mice. Furthermore, we could co-immunoprecipitate Shank3, Rhes and Wiskott-Aldrich syndrome protein family verprolin-homologous protein 1 (WAVE1) proteins from the striatal lysate of Shank3 TG mice. By comparing with the gene sets of psychiatric disorders, we also observed that the 94 proteins of Shank3-mTORC1 interactome were significantly associated with bipolar disorder (BD). Altogether, our results suggest a protein interaction-mediated connectivity between Shank3 and certain upstream regulators of mTORC1 that might contribute to the abnormal striatal mTORC1 activity and to the manic-like behaviors of Shank3 TG mice.

Although eating disorders (EDs) are common in bipolar disorder (BD), little is known regarding their longitudinal consequences. We assessed prevalence, clinical correlates, and longitudinal depressive severity in BD patients with vs. without EDs.

Recent molecular genetic studies have identified 100s of risk genes for various neurodevelopmental and neuropsychiatric disorders. As the number of risk genes increases, it is becoming clear that different mutations of a single gene could cause different types of disorders. One of the best examples of such a gene is SHANK3, which encodes a core scaffold protein of the neuronal excitatory post-synapse. Deletions, duplications, and point mutations of SHANK3 are associated with autism spectrum disorders, intellectual disability, schizophrenia, bipolar disorder, and attention deficit hyperactivity disorder. Nevertheless, how the different mutations of SHANK3 can lead to such phenotypic diversity remains largely unknown. In this study, we investigated whether Shank3 could form protein complexes in a brain region-specific manner, which might contribute to the heterogeneity of neuronal pathophysiology caused by SHANK3 mutations. To test this, we generated a medial prefrontal cortex (mPFC) Shank3 in vivo interactome consisting of 211 proteins, and compared this protein list with a Shank3 interactome previously generated from mixed hippocampal and striatal (HP+STR) tissues. Unexpectedly, we found that only 47 proteins (about 20%) were common between the two interactomes, while 164 and 208 proteins were specifically identified in the mPFC and HP+STR interactomes, respectively. Each of the mPFC- and HP+STR-specific Shank3 interactomes represents a highly interconnected network. Upon comparing the brain region-enriched proteomes, we found that the large difference between the mPFC and HP+STR Shank3 interactomes could not be explained by differential protein expression profiles among the brain regions. Importantly, bioinformatic pathway analysis revealed that the representative biological functions of the mPFC- and HP+STR-specific Shank3 interactomes were different, suggesting that these interactors could mediate the brain region-specific functions of Shank3. Meanwhile, the same analysis on the common Shank3 interactors, including Homer and GKAP/SAPAP proteins, suggested that they could mainly function as scaffolding proteins at the post-synaptic density. Lastly, we found that the mPFC- and HP+STR-specific Shank3 interactomes contained a significant number of proteins associated with neurodevelopmental and neuropsychiatric disorders. These results suggest that Shank3 can form protein complexes in a brain region-specific manner, which might contribute to the pathophysiological and phenotypic diversity of disorders related to SHANK3 mutations.

The identification of predictive biomarkers or models is necessary for the selection of patients who might benefit the most from immunotherapy. Seven histological features (signet ring cell [SRC], fibrous stroma, myxoid stroma, tumor-infiltrating lymphocytes [TILs], necrosis, tertiary lymphoid follicles, and ulceration) detected in surgically resected tissues (N = 44) were used to train a model. The presence of SRC became an optimal decision parameter for pathology alone (AUC = 0.78). Analysis of differentially expressed genes (DEGs) for the prediction of genomic markers showed that C-X-C motif chemokine ligand 11 (CXCL11) was high in responders (P < 0.001). Immunohistochemistry (IHC) was performed to verify its potential as a biomarker. IHC revealed that the expression of CXCL11 was associated with responsiveness (P = 0.003). The response prediction model was trained by integrating the results of the analysis of pathological factors and RNA sequencing (RNA-seq). When trained with the C5.0 decision tree model, the categorical level of the expression of CXCL11, a single variable, was shown to be the best model (AUC = 0.812). The AUC of the model trained with the random forest was 0.944. Survival analysis revealed that the C5.0-trained model (log-rank P = 0.01 for progression-free survival [PFS]; log-rank P = 0.012 for overall survival [OS]) and the random forest-trained model (log-rank P < 0.001 for PFS; log-rank P = 0.001 for OS) predicted prognosis more accurately than the PD-L1 test (log-rank P = 0.031 for PFS; log-rank P = 0.107 for OS).

Hyperbaric oxygen therapy (HBOT) has been used to provide oxygen to underperfused organs following ischemia or carbon monoxide intoxication. Various beneficial consequences of HBOT have been reported, including wound healing, anti-inflammatory action, and cell survival; however, the molecular mechanisms underlying these effects have not been elucidated yet. We applied a single HBOT program consisting of administration of 2.8 atmospheres absolute (ATA) for 45 min, followed by 2.0 ATA for 55 min, to 10 male volunteers without any metabolic disease. Within 1 week of HBOT, there was no alteration in serum biochemical variables, except for an increase in triglyceride content. As a mitochondrial stress indicator, the serum concentration of growth differentiation factor 15 was reduced by HBOT. The circulating level of γ-glutamyltransferase was also decreased by HBOT, suggesting an attenuation of oxidative stress. HBOT increased adiponectin and reduced leptin levels in the serum, leading to an elevated adiponectin/leptin ratio. This is the first study to investigate the effect of HBOT on serum levels of metabolic stress-related biomarkers. We suggest that HBOT attenuates mitochondrial and oxidative stresses, and relieves metabolic burdens, indicating its potential for use in therapeutic applications to metabolic diseases.