NMR Studies of the Interactions between Sialyllactoses and the Polysialytransferase Domain for Polysialylation Inhibition.

It is known that sialyllactose (SL) in mammalians is a major source of sialic acid (Sia), which can further form cytidine monophosphate sialic acid (CMP-Sia), and the final product is polysialic acid (polySia) using polysialyltransferases (polySTs) on the neural cell adhesion molecule (NCAM). This process is called NCAM polysialylation. The overexpression of polysialylation is strongly related to cancer cell migration, invasion, and metastasis. In order to inhibit the overexpression of polysialylation, in this study, SL was selected as an inhibitor to test whether polysialylation could be inhibited. Our results suggest that the interactions between the polysialyltransferase domain (PSTD) in polyST and CMP-Siaand the PSTD and polySia could be inhibited when the 3'-sialyllactose (3'-SL) or 6'-sialyllactose (6'-SL) concentration is about 0.5 mM or 6'-SL and 3 mM, respectively. The results also show that SLs (particularly for 3'-SL) are the ideal inhibitors compared with another two inhibitors, low-molecular-weight heparin (LMWH) and cytidine monophosphate (CMP), because 3'-SL can not only be used to inhibit NCAM polysialylation, but is also one of the best supplements for infant formula and the gut health system.

The Graphical Studies of the Major Molecular Interactions for Neural Cell Adhesion Molecule (NCAM) Polysialylation by Incorporating Wenxiang Diagram into NMR Spectroscopy.

Polysialylation is a process of polysialic acid (polySia) addition to neural cell adhesion molecule (NCAM), which is associated with tumor cell migration and progression in many metastatic cancers and neurocognition. Polysialylation can be catalyzed by two highly homologous mammalian polysialyltransferases (polySTs), ST8Sia II (STX) and ST8Sia IV (PST). It has been proposed that two polybasic domains, polybasic region (PBR) and polysialyltransferase domain (PSTD) in polySTs, are possible binding sites for the intermolecular interactions of polyST-NCAM and polyST-polySia, respectively, as well as the intramolecular interaction of PSTD-PBR. In this study, Chou's wenxiang diagrams of the PSTD and PBR are used to determine the key amino acids of these intermolecular and intramolecular interactions, and thus it may be helpful for the identification of the crucial amino acids in the polyST and for the understanding of the molecular mechanism of NCAM polysialylation by incorporating the wenxiang diagram and molecular modeling into NMR spectroscopy.

Mindfulness and Posttraumatic Stress Disorder Symptom Severity in Urban African-American High School Students.

OBJECTIVES: The aim of the current study was to examine the relations among mindfulness, posttraumatic stress disorder (PTSD) symptom severity, and stressful life events (SLEs) in African-American urban adolescents. Another aim was to examine mindfulness as a moderator of the relation between SLEs and PTSD symptom severity in this population. METHOD: Eighty-eight African-American high school students from a low-income urban community completed measures of demographics, PTSD symptom severity, SLEs, and mindfulness. RESULTS: Mindfulness was significantly negatively related to PTSD symptom severity, r(86) = -.70, p < .001, 95% CI [-.58, -79], and SLEs were significantly positively related to PTSD symptom severity, r(86) = .29, p = .003, 95% CI [.09, .47]. Mindfulness was an independent predictor of PTSD symptom severity after accounting for SLEs, B = -1.16, t(84) = -9.06, p < .001, 95% CI [-1.41, -0.90], and SLEs were an independent predictor of PTSD symptom severity after accounting for mindfulness, B = 0.49, t(84) = 2.92, p = .004, 95% CI [0.16, 0.82]. Mindfulness did not moderate the relation between SLEs and PTSD symptom severity, B = -.003, t(84) = -0.15, p = .89, 95% CI [-.04, .03]. IMPLICATIONS: This study has implications for both mindfulness as a potential protective factor against PTSD symptom severity and SLEs as a potential risk factor for increased PTSD symptom severity in African-American urban adolescents.

Molecular Interactions of the Polysialytransferase Domain (PSTD) in ST8Sia IV with CMP-Sialic Acid and Polysialic Acid Required for Polysialylation of the Neural Cell Adhesion Molecule Proteins: An NMR Study.

Polysialic acid (polySia) is an unusual glycan that posttranslational modifies neural cell adhesion molecule (NCAM) proteins in mammalian cells. The up-regulated expression of polySia-NCAM is associated with tumor progression in many metastatic human cancers and in neurocognitive processes. Two members of the ST8Sia family of α2,8-polysialyltransferases (polySTs), ST8Sia II (STX) and ST8Sia IV (PST) both catalyze synthesis of polySia when activated cytidine monophosphate(CMP)-Sialic acid (CMP-Sia) is translocate into the lumen of the Golgi apparatus. Two key polybasic domains in the polySTs, the polybasic region (PBR) and the polysialyltransferase domain (PSTD) areessential forpolysialylation of the NCAM proteins. However, the precise molecular details to describe the interactions required for polysialylation remain unknown. In this study, we hypothesize that PSTD interacts with both CMP-Sia and polySia to catalyze polysialylation of the NCAM proteins. To test this hypothesis, we synthesized a 35-amino acid-PSTD peptide derived from the ST8Sia IV gene sequence and used it to study its interaction with CMP-Sia, and polySia. Our results showed for the PSTD-CMP-Sia interaction,the largest chemical-shift perturbations (CSP) were in amino acid residues V251 to A254 in the short H1 helix, located near the N-terminus of PSTD. However, larger CSP values for the PSTD-polySia interaction were observed in amino acid residues R259 to T270 in the long H2 helix. These differences suggest that CMP-Sia preferentially binds to the domain between the short H1 helix and the longer H2 helix. In contrast, polySia was principally bound to the long H2 helix of PSTD. For the PSTD-polySia interaction, a significant decrease in peak intensity was observed in the 20 amino acid residues located between the N-and C-termini of the long H2 helix in PSTD, suggesting a slower motion in these residues when polySia bound to PSTD. Specific features of the interactions between PSTD-CMP-Sia, and PSTD-polySia were further confirmed by comparing their 800 MHz-derived HSQC spectra with that of PSTD-Sia, PSTD-TriSia (DP 3) and PSTD-polySia. Based on the interactions between PSTD-CMP-Sia, PSTD-polySia, PBR-NCAM and PSTD-PBR, these findingsprovide a greater understanding of the molecular mechanisms underlying polySia-NCAM polysialylation, and thus provides a new perspective for translational pharmacological applications and development by targeting the two polysialyltransferases.

Modeling the sub-diffraction focusing phenomenon of light propagation through scattering medium.

Optical techniques are assuming greater importance in biomedical applications, however, due to extreme complexity involved in light propagation through scattering medium, it is very challenging to analyze experimentally. Here we report a two-stage simulation technique to simulate phase-conjugated light propagation through scattering medium with macroscopic dimensions. The reported simulation yields accurate information with flexibility to access research parameters. The proposed simulation method is suitable for finite-difference time-domain (FDTD) technique, pseudospectral time-domain (PSTD) technique, and other simulation techniques based upon numerical solutions of Maxwell's equations. We demonstrate modeling phase-conjugated light propagation through a scattering medium. The reported simulation technique is applicable to model the propagation of continuous-wave (CW) light with specific amplitude and phase through a scattering medium of macroscopic dimensions. More importantly, the flexibility of simulation enables analysis of research factors that are challenging to access experimentally.

Examining the relationship and clinical management between traumatic brain injury and pain in military and civilian populations.

In this review, we discuss the comorbidity of traumatic brain injury (TBI) and pain among civilians and military members, the common causes of pain resulting from TBI, and offer insight about the therapeutic management of TBI symptoms and pain. Traumatic brain injury (TBI) is a debilitating health problem and one of the most common post-TBI symptoms is pain, which can contribute to psychological issues such as Post-traumatic stress disorder (PTSD) and depression. Headache pain appears to be the most common type of pain that results from TBI, yet pain can also be more widespread. Managing TBI symptoms and pain simultaneously is difficult because extensive randomized control and clinical studies assessing the effectiveness of therapeutic approaches are lacking. Pharmacological agents such as antidepressants and Triptans and nonpharmacological therapies such as cognitive rehabilitation and physical therapies are commonly used yet it is unknown how effective these therapies are in the long-term. A combination of pharmacological and non-pharmacological therapies is often more effective for managing TBI symptoms and pain than either treatment alone. However, future research is needed to determine the most therapeutic approaches for managing the comorbidity of pain and TBI symptoms in the long term. This review offers suggestions for such future studies.

A Scoping Review of Trauma, Mental Health and First Responders in Australia.

Exposure to traumatic and/or violent events is an inherent part of the first responder role, which increases the risk of developing acute and chronic mental health symptoms and conditions. Suicidality for Australian first responders have recently increased with prevalence considered much higher compared with the general population. To inform specific recommendations for Australian first responders, there is a need to establish what evidence is available regarding these issues within the Australian context. The aim of this scoping review was to explore the impacts of trauma on the mental health of Australian first responders, the strategies recommended to address these issues and any unique needs in rural contexts. A scoping review was undertaken following PRISMA guidelines for scoping reviews. Peer-reviewed articles on Australian first responder mental health from seven databases were screened for inclusion. This review highlights that despite available evidence on the types of traumas and adverse mental health outcomes experienced, less evidence exists pertaining to intervention effectiveness. There are major gaps in evidence within rural and remote contexts which hinders effective planning and delivery of support for rural and regional first responders. Clinicians such as mental health nurses, particularly in rural areas, need to be aware of these gaps which impact planning and delivery of support and are in prime position to ensure screening, interventions and strategies are used and evaluated to determine their suitability for rural first responders.

Brain activation during an emotional task in participants with PTSD and borderline and/or cluster C personality disorders.

INTRODUCTION: Although comorbidity of post-traumatic stress disorder (PTSD) with borderline personality disorder (BPD) and/or cluster C personality disorders (CPD) is common, neural correlates of this comorbidity are unknown. METHODS: We acquired functional MRI scans during an emotional face task in participants with PTSD + CPD (n = 34), PTSD + BPD (n = 24), PTSD + BPD + CPD (n = 18) and controls (n = 30). We used ANCOVAs and Bayesian analyses on specific ROIs in a fearful vs. scrambled faces contrast. We also investigated associations with clinical measures. RESULTS: There were no robust differences in brain activation between the groups with ANCOVAs. Transdiagnostically, we found a negative association between severity of dissociation and right insula and right dmPFC activation, and emotion regulation problems with right dmPFC activation. Bayesian analyses showed credible evidence for higher activation in all ROIs in the PTSD + BPD + CPD group compared to PTSD + BPD and PTSD + CPD. DISCUSSION: Our Bayesian and correlation analyses support new dimensional conceptualizations of personality disorders.

Having permission not to remember: perspectives on interventions for post-traumatic stress disorder in the absence of trauma memory.

Background: It is possible for people to have post-traumatic stress disorder (PTSD) without memory of the trauma event, such as in drug-facilitated sexual assault. However, there is little evidence available on treatment provision for this population. Objective: This study aimed to address this gap by exploring the experiences of people who have had psychological intervention for PTSD without memories (PwM). Method: Interpretative phenomenological analysis was used to explore the lived experience of nine women with PwM, who had sought psychological assessment/therapy. Participants were recruited via social media and completed semi-structured interviews online/via telephone. Results: Identified themes concerned two broad areas: (i) the challenges of having therapy whilst lacking memories and (ii) what was helpful in therapy. Challenges included: delayed help-seeking; having emotional/sensory reactions in the absence of recognisable triggers; experiencing therapy as more applicable to remembered trauma (vs. unremembered); and difficulty discussing and processing unremembered trauma. However, participants also described helpful aspects of therapy including: feeling safe and supported; working with emotional and sensory forms of experience; having scientific explanations for trauma and memory; and having 'permission' from therapists not to remember. Conclusions: Recommendations for clinicians included: being aware that clients with PwM may have more difficulty accessing treatment and perceive it as less applicable to them; focussing on clients' emotions and sensations (not cognitive memories) in therapy; and supporting clients to develop a more self-compassionate understanding of their experiences and lack of memory, thus supporting them to accept that not remembering is 'permitted'. HIGHLIGHTS: • Having therapy for unremembered trauma involves unique challenges, but aspects of therapy can still be helpful.• Suggested 'dos and don'ts' for therapists include recognising the additional barriers to treatment, focussing on emotions (not memories), and normalising memory loss.

Antecedentes: Es posible que las personas tengan un trastorno de estrés postraumático (TEPT) sin recordar el evento traumático, como en una agresión sexual facilitada por drogas. Sin embargo, hay poca evidencia disponible sobre la provisión de tratamiento para esta población.Objetivo: Este estudio tuvo como objetivo abordar esta brecha mediante la exploración de las experiencias de las personas que han tenido una intervención psicológica para TEPT sin recuerdos (PwM en su sigla en inglés).Método: Se usó análisis fenomenológico interpretativo para explorar la experiencia vivida de nueve mujeres con PwM, quienes habían buscado una evaluación/terapia psicológica. Las participantes fueron reclutadas a través de redes sociales y completaron entrevistas semiestructuradas en línea o por teléfono.Resultados: Los temas identificados se referían a dos grandes áreas: (i) los desafíos de tener terapia mientras se carece de memoria; y (ii) lo que fue útil en la terapia. Los desafíos incluyeron: búsqueda de ayuda retardada; tener reacciones emocionales/sensoriales en ausencia de desencadenantes reconocibles; experimentar la terapia como más aplicable al trauma recordado (frente no recordado); y dificultad en discutir y procesar el trauma no recordado. Sin embargo, los participantes tambien describieron aspectos útiles de la terapia incluidos: sentirse seguros y apoyados; trabajar con formas de experiencia emocional y sensorial; tener explicaciones científicas para el trauma y el recuerdo; y tener 'permiso' de los terapeutas para no recordar.Conclusiones: Las recomendaciones para el clínico incluyeron: ser conscientes de que los clientes con PwM pueden tener más dificultades para acceder al tratamiento y percibirlo como menos aplicable a ellos; en la terapia centrarse en las emociones y sensaciones de los clientes (no en los recuerdos cognitivos); y apoyar a los clientes a desarrollar una comprensión más compasiva de sus experiencias y falta de recuerdos, apoyando así que acepten que no recordar está 'permitido'.

Presenting symptoms as prognostic measures of mental health recovery among service members with concussion.

Background: Comorbid mental illness may negatively impact recovery from concussion. This study evaluated whether the level of symptom clusters at clinic intake contribute to poor mental health recovery in concussed patients during treatment, which may in turn serve as a target intervention. Objective: The objective of this study is to examine the association between the level of initial symptoms and mental health symptoms among service members with concussion. Methods: Data were obtained from 483 active duty service members treated in interdisciplinary treatment programs for traumatic brain injury, all of which were concussions. Pre-treatment symptom clusters included self-reported hyperarousal, dissociation/depression, cognitive dysfunction/headache and neurological symptoms. The outcomes, clinically-relevant decreases in depressive symptoms (assessed by the 8-item Patient Health Questionnaire, PHQ-8) and PTSD symptoms (assessed by the PTSD Checklist for DSM-5, PCL-5), were defined as a decrease in PHQ-8 > 5 and PCL-5 > 7, respectively. Poisson regression with robust error variance was used to evaluate the relationship between the level of each symptom cluster and clinically-relevant decrease in outcomes. Results: Participants with higher (vs. lower) levels of pre-treatment hyperarousal and dissociation/depression symptom cluster were less likely to improve in depressive and PTSD symptoms during treatment. The level of cognitive/headache and neurological symptom clusters were not significantly associated with any symptom changes. Conclusion: These findings support the need for individualized treatment for symptoms identified and treated after determining concussion history, with particular attention to high levels of hyperarousal and dissociation/depression prior to treatment.

The psychological impact of COVID-19 pandemic on healthcare workers.

Background: As unprecedented and prolonged crisis, healthcare workers (HCWs) are at high risk of developing psychological disorders. We investigated the psychological impact of COVID-19 pandemic on HCWs. Methods: This cross-sectional study randomly recruited 439 HCWs in Hunan Cancer Hospital via a web-based sampling method from June 1st 2021 to March 31st 2022. Anxiety and depression levels were measured using Hospital Anxiety and Depression Scale (HADS). The Post Traumatic Stress Disorder (PTSD) Checklist for DSM-5 (PCL-5) was used to assess the presence and severity of PTSD. Fear was measured by modified scale of SARS. Data were collected based on these questionnaires. Differences in fear, anxiety, depression and PTSD among HCWs with different clinical characteristics were analyzed using a multivariate analysis of variance. The Cronbach's alpha scores in our samples were calculated to evaluate the internal consistency of HADS, fear scale and PCL-5. Results: The prevalence of anxiety, depression, and PTSD in HCWs was 15.7, 9.6, and 12.8%, respectively. Females and nurses were with higher fear level (P < 0.05) and higher PTSD levels (P < 0.05). Further analysis of female HCWs revealed that PTSD levels in the 35-59 years-old age group were higher than that in other groups; while married female HCWs were with increased fear than single HCWs. The internal consistency was good, with Cronbach's α = 0.88, 0.80 and 0.84 for HADS, fear scale, and PCL, respectively. Conclusion: Gender, marital status, and age are related to different level of psychological disorders in HCWs. Clinical supportive care should be implemented for specific group of HCWs.

Impaired functional cortical networks in the theta frequency band of patients with post-traumatic stress disorder during auditory-cognitive processing.

Impaired cognitive function related to intrusive memories of traumatic experiences is the most noticeable characteristic of post-traumatic stress disorder (PTSD); nevertheless, the brain mechanism involved in the cognitive processing is still elusive. To improve the understanding of the neuropathology in PTSD patients, we investigated functional cortical networks that are based on graph theory, by using electroencephalogram (EEG). EEG signals, elicited by an auditory oddball paradigm, were recorded from 53 PTSD patients and 39 healthy controls (HCs). Source signals in 68 regions of interests were estimated using EEG data for each subject using minimum-norm estimation. Then, using source signals of each subject, time-frequency analysis was conducted, and a functional connectivity matrix was constructed using the imaginary part of coherence, which was used to evaluate three global-level (strength, clustering coefficient, and path length) and two nodal-level (strength and clustering coefficients) network indices in four frequency bands (theta, alpha, low-beta, and high-beta). The relationships between the network indices and symptoms were evaluated using Pearson's correlation. Compared with HCs, PTSD patients showed significantly reduced spectral powers around P300 periods and significantly altered network indices (diminished strength and clustering coefficient, and prolonged path length) in theta frequency band. In addition, the nodal strengths and nodal clustering coefficients in theta band of PTSD patients were significantly reduced, compared with those of HCs, and the reduced nodal clustering coefficients in parieto-temporo-occipital regions had negative correlations with the symptom scores (Impact of Event Scale-Revises, Beck Depression Inventory, and Beck Anxiety Inventory). The characterization of this disrupted pattern improves the understanding of the neuropathophysiology underlying the impaired cognitive function in PTSD patients.

Perception and determinants of Social Networking Sites (SNS) on spreading awareness and panic during the COVID-19 pandemic in Bangladesh.

Introduction: The COVID-19 pandemic is an unprecedented and unique fallout worldwide and creates colossal disruption in human survival. During the pandemic, social networking sites (SNS) played a significant role in disseminating news related to the pandemic. Methods: This research is based on primary data collected from 400 successful respondents via online Google Form. Bivariate Pearson's Chi-square and multivariate binary logistic regression analysis were performed to determine the impact of the explanatory variables on the study variables. Results: This study reveals that most respondents (n = 360, 90 %) use SNS to get up-to-date news, and 72.5 % (n = 290) read health-related information. The highest number of participants (n = 386, 96.5 %) were Facebook users. Multivariate binary logistic regression reveals that "reading news on SNS" and "sharing information related to COVID-19 on social media" significantly influence the spread of awareness of COVID-19. "Unauthentic news sources" and "stop using social media to stay away from panic" also have a substantial impact on the spread of panic during the COVID-19 pandemic. Conclusion: SNS has become an inevitable medium of information carrier nowadays. Social media users are found significantly aware of the COVID-19 pandemic. The findings of this study might assist the concerned persons in taking the necessary steps to propagate authentic news and regulate appropriate policies to prevent spreading misinformation.

Comorbid depression and treatment of anxiety disorders, OCD, and PTSD: Diagnosis versus severity.

BACKGROUND: Although anxiety and depression are highly comorbid disorders, it remains unclear whether and how a concurrent depression affects the outcome of anxiety treatment. METHOD: Using anonymized routine outcome monitoring (ROM) data of 740 patients having received specialized treatment for an anxiety disorder, OCD, or PTSD, this study investigates whether a comorbid diagnosis of depression and/or self-reported depression severity levels relate to the patients' improvement following anxiety treatment. RESULTS: The results show that both the patients with and those without comorbid depression had profited similarly from the anxiety, OCD, or PTSD treatment, regardless of whether depression was merely diagnosed prior to treatment or based on self-reported severity (and assuming a smallest effect size of interest of d = 0.35/r = .2). Importantly, the post-treatment reductions in self-reported depressive symptoms were strongly and positively related to the reductions in self-reported anxiety symptoms and disorder-related disability. LIMITATIONS: Causal inferences cannot be made due to the retrospective cross-sectional design. CONCLUSIONS: The outcomes obtained in a naturalistic patient sample support current treatment guidelines recommending evidence-based treatment for anxiety disorders, OCD, and PTSD in patients with and without a comorbid depression. Future treatment studies are recommended for investigate the (bi)directionality of anxiety and depressive symptoms throughout treatment.

The Impact of Co-occurring Post-traumatic Stress Disorder and Substance Use Disorders on Craving: A Systematic Review of the Literature.

The frequent co-occurrence of post-traumatic stress disorder (PTSD) and substance use disorders (SUDs) leads to manifestations of both conditions that are more severe and more resistance to treatment than single disorders. One hypothesis to explain this synergy is the impact of intrusive memories on craving which, in turn, increases the risk of relapse among patients with substance use disorders. The aim of this systematic review is to examine this possibility by assessing the impact of PTSD and its symptoms on craving among dual disorder patients. Using PRISMA criteria, four databases were comprehensively searched up to June, 2021, in order to identify all candidate studies based on broad key words. Resulting studies were then selected if they examined the impact of PTSD or PTSD symptoms on craving, and if they used standardized assessments of PTSD, SUD, and craving. Twenty-seven articles matched the selection criteria and were included in this review. PTSD was found to be significantly associated with increased craving levels among patients with alcohol, cannabis, cocaine, tobacco, and other substance use disorders. Exposition to traumatic cues among dual disorder patients was also shown to trigger craving, with an additive effect on craving intensity when exposure to substance-related cues occurred. In addition, certain studies observed a correlation between PTSD symptom severity and craving intensity. Concerning mechanisms underlying these associations, some findings suggest that negative emotional states or emotion dysregulation may play a role in eliciting craving after traumatic exposure. Moreover, these studies suggest that PTSD symptoms may, independently of emotions, act as powerful cues that trigger craving. These findings argue for the need of dual disorder treatment programs that integrate PTSD-focused approaches and emotion regulation strategies, in addition to more traditional interventions for craving management.

Molecular Mechanism of Inhibition of Polysialyltransferase Domain (PSTD) by Heparin.

The polysialic acid (polySia) is a unique carbohydrate polymer produced on the surface of Neuronal Cell Adhesion Molecule (NCAM) in a number of cancer cells, and strongly correlates with the migration and invasion of tumor cells and with aggressive, metastatic disease and poor clinical prognosis in the clinic. Its synthesis is catalyzed by two polysialyltransferases (polySTs), ST8SiaIV (PST) and ST8SiaII (STX). Selective inhibition of polySTs, therefore, presents a therapeutic opportunity to inhibit tumor invasion and metastasis due to NCAM polysialylation. It has been proposed that NCAM polysialylation could be inhibited by two types of heparin inhibitors, low molecular heparin (LMWH) and heparin tetrasaccharide (DP4). This review summarizes how the interactions between Polysialyltransferase Domain (PSTD) in ST8SiaIV and CMP-Sia, and between the PSTD and polySia take place, and how these interactions are inhibited by LMWH and DP4. Our NMR studies indicate that LMWH is a more effective inhibitor than DP4 for inhibition of NCAM polysialylation. The NMR identification of heparin-binding sites in the PSTD may provide insight into the design of specific inhibitors of polysialylation.

Sex-Specific Differences in Rodents Following a Single Primary Blast Exposure: Focus on the Monoamine and Galanin Systems.

Most blast-induced traumatic brain injuries (bTBI) are mild in severity and culpable for the lingering and persistent neuropsychological complaints in affected individuals. There is evidence that the prevalence of symptoms post-exposure may be sex-specific. Our laboratory has focused on changes in the monoamine and the neuropeptide, galanin, systems in male rodents following primary bTBI. In this study, we aimed to replicate these findings in female rodents. Brainstem sections from the locus coeruleus (LC) and dorsal raphe nuclei (DRN) were processed for in situ hybridisation at 1 and 7 days post-bTBI. We investigated changes in the transcripts for tyrosine hydroxylase (TH), tryptophan hydroxylase two (TPH2) and galanin. Like in males, we found a transient increase in TH transcript levels bilaterally in the female LC. Changes in TPH2 mRNA were more pronounced and extensive in the DRN of females compared to males. Galanin mRNA was increased bilaterally in the LC and DRN, although this increase was not apparent until day 7 in the LC. Serum analysis revealed an increase in corticosterone, but only in exposed females. These changes occurred without any visible signs of white matter injury, cell death, or blood-brain barrier breakdown. Taken together, in the apparent absence of visible structural damage to the brain, the monoamine and galanin systems, two key players in emotional regulation, are activated deferentially in males and females following primary blast exposure. These similarities and differences should be considered when developing and evaluating diagnostic and therapeutic interventions for bTBI.

The Inhibition of Polysialyltranseferase ST8SiaIV Through Heparin Binding to Polysialyltransferase Domain (PSTD).

BACKGROUND: The polysialic acid (polySia) is a unique carbohydrate polymer produced on the surface Of Neuronal Cell Adhesion Molecule (NCAM) in a number of cancer cells, and strongly correlates with the migration and invasion of tumor cells and with aggressive, metastatic disease and poor clinical prognosis in the clinic. Its synthesis is catalyzed by two polysialyltransferases (polySTs), ST8SiaIV (PST) and ST8SiaII (STX). Selective inhibition of polySTs, therefore, presents a therapeutic opportunity to inhibit tumor invasion and metastasis due to NCAM polysialylation. Heparin has been found to be effective in inhibiting the ST8Sia IV activity, but no clear molecular rationale. It has been found that polysialyltransferase domain (PSTD) in polyST plays a significant role in influencing polyST activity, and thus it is critical for NCAM polysialylation based on the previous studies. OBJECTIVE: To determine whether the three different types of heparin (unfractionated hepain (UFH), low molecular heparin (LMWH) and heparin tetrasaccharide (DP4)) is bound to the PSTD; and if so, what are the critical residues of the PSTD for these binding complexes? METHODS: Fluorescence quenching analysis, the Circular Dichroism (CD) spectroscopy, and NMR spectroscopy were used to determine and analyze interactions of PSTD-UFH, PSTD-LMWH, and PSTD-DP4. RESULTS: The fluorescence quenching analysis indicates that the PSTD-UFH binding is the strongest and the PSTD-DP4 binding is the weakest among these three types of the binding; the CD spectra showed that mainly the PSTD-heparin interactions caused a reduction in signal intensity but not marked decrease in α-helix content; the NMR data of the PSTD-DP4 and the PSTDLMWH interactions showed that the different types of heparin shared 12 common binding sites at N247, V251, R252, T253, S257, R265, Y267, W268, L269, V273, I275, and K276, which were mainly distributed in the long α-helix of the PSTD and the short 3-residue loop of the C-terminal PSTD. In addition, three residues K246, K250 and A254 were bound to the LMWH, but not to DP4. This suggests that the PSTD-LMWH binding is stronger than the PSTD-DP4 binding, and the LMWH is a more effective inhibitor than DP4. CONCLUSION: The findings in the present study demonstrate that PSTD domain is a potential target of heparin and may provide new insights into the molecular rationale of heparin-inhibiting NCAM polysialylation.

A Possible Modulation Mechanism of Intramolecular and Intermolecular Interactions for NCAM Polysialylation and Cell Migration.

Polysialic acid (polySia) is a novel glycan that posttranslationally modifies neural cell adhesion molecules (NCAMs) in mammalian cells. Up-regulation of polySia-NCAM expression or NCAM polysialylation is associated with tumor cell migration and progression in many metastatic cancers and neurocognition. It has been known that two highly homologous mammalian polysialyltransferases (polySTs), ST8Sia II (STX) and ST8Sia IV (PST), can catalyze polysialylation of NCAM, and two polybasic domains, polybasic region (PBR) and polysialyltransferase domain (PSTD) in polySTs play key roles in affecting polyST activity or NCAM polysialylation. However, the molecular mechanisms of NCAM polysialylation and cell migration are still not entirely clear. In this minireview, the recent research results about the intermolecular interactions between the PBR and NCAM, the PSTD and cytidine monophosphate-sialic acid (CMP-Sia), the PSTD and polySia, and as well as the intramolecular interaction between the PBR and the PSTD within the polyST, are summarized. Based on these cooperative interactions, we have built a novel model of NCAM polysialylation and cell migration mechanisms, which may be helpful to design and develop new polysialyltransferase inhibitors.

The Cooperative Effect between Polybasic Region (PBR) and Polysialyltransferase Domain (PSTD) within Tumor-Target Polysialyltranseferase ST8Sia II.

ST8Sia II (STX) is a highly homologous mammalian polysialyltransferase (polyST), which is a validated tumor-target in the treatment of cancer metastasis reliant on tumor cell polysialylation. PolyST catalyzes the synthesis of α2,8-polysialic acid (polySia) glycans by carrying out the activated CMP-Neu5Ac (Sia) to N- and O-linked oligosaccharide chains on acceptor glycoproteins. In this review article, we summarized the recent studies about intrinsic correlation of two polybasic domains, Polysialyltransferase domain (PSTD) and Polybasic region (PBR) within ST8Sia II molecule, and suggested that the critical amino acid residues within the PSTD and PBR motifs of ST8Sia II for polysialylation of Neural cell adhesion molecules (NCAM) are related to ST8Sia II activity. In addition, the conformational changes of the PSTD domain due to point mutations in the PBR or PSTD domain verified an intramolecular interaction between the PBR and the PSTD. These findings have been incorporated into Zhou's NCAM polysialylation/cell migration model, which will provide new perspectives on drug research and development related to the tumor-target ST8Sia II.