Elevated representational similarity of voluntary action and inhibition in Tourette syndrome.

Many people with Tourette syndrome are able to volitionally suppress tics, under certain circumstances. To understand better the neural mechanisms that underlie this ability, we used functional magnetic resonance neuroimaging to track regional brain activity during performance of an intentional inhibition task. On some trials, Tourette syndrome and comparison participants internally chose to make or withhold a motor action (a button press), while on other trials, they followed 'Go' and 'NoGo' instructions to make or withhold the same action. Using representational similarity analysis, a functional magnetic resonance neuroimaging multivariate pattern analysis technique, we assessed how Tourette syndrome and comparison participants differed in neural activity when choosing to make or to withhold an action, relative to externally cued responses on Go and NoGo trials. Analyses were pre-registered, and the data and code are publicly available. We considered similarity of action representations within regions implicated as critical to motor action release or inhibition and to symptom expression in Tourette syndrome, namely the pre-supplementary motor area, inferior frontal gyrus, insula, caudate nucleus and primary motor cortex. Strikingly, in the Tourette syndrome compared to the comparison group, neural activity within the pre-supplementary motor area displayed greater representational similarity across all action types. Within the pre-supplementary motor area, there was lower response-specific differentiation of activity relating to action and inhibition plans and to internally chosen and externally cued actions, implicating the region as a functional nexus in the symptomatology of Tourette syndrome. Correspondingly, patients with Tourette syndrome may experience volitional tic suppression as an effortful and tiring process because, at the top of the putative motor decision hierarchy, activity within the population of neurons facilitating action is overly similar to activity within the population of neurons promoting inhibition. However, not all pre-supplementary motor area group differences survived correction for multiple comparisons. Group differences in representational similarity were also present in the primary motor cortex. Here, representations of internally chosen and externally cued inhibition were more differentiated in the Tourette syndrome group than in the comparison group, potentially a consequence of a weaker voluntary capacity earlier in the motor hierarchy to suppress actions proactively. Tic severity and premonitory sensations correlated with primary motor cortex and caudate nucleus representational similarity, but these effects did not survive correction for multiple comparisons. In summary, more rigid pre-supplementary motor area neural coding across action categories may constitute a central feature of Tourette syndrome, which can account for patients' experience of 'unvoluntary' tics and effortful tic suppression.

Addressing alpine plant phylogeography using integrative distributional, demographic and coalescent modeling.

Phylogeographic studies of alpine plants have evolved considerably in the last two decades from ad hoc interpretations of genetic data to statistical model-based approaches. In this review we outline the developments in alpine plant phylogeography focusing on the recent approach of integrative distributional, demographic and coalescent (iDDC) modeling. By integrating distributional data with spatially explicit demographic modeling and subsequent coalescent simulations, the history of alpine species can be inferred and long-standing hypotheses, such as species-specific responses to climate change or survival on nunataks during the last glacial maximum, can be efficiently tested as exemplified by available case studies. We also discuss future prospects and improvements of iDDC.

A cross-sectional study of auditory verbal hallucinations experienced by people with a diagnosis of borderline personality disorder.

BACKGROUND: The presence of auditory verbal hallucinations (AVHs) does not currently feature in the main diagnostic criteria for borderline personality disorder (BPD). However, there is accumulating evidence that a high proportion of BPD patients report longstanding and frequent AVHs which constitute a significant risk factor for suicide plans and attempts, and hospitalization. AIM: This study addressed questions about the validity and phenomenology of AVHs in the context of BPD. The longer-term aim is to facilitate the development and translation of treatment approaches to address the unmet need of this population. METHOD: This was a cross-sectional study, combining phenomenological and psychological assessments administered in person and online. We explored the experiences of 48 patients with a diagnosis of BPD who were hearing AVHs. RESULTS: Participants gave 'consistent' reports on the measure of AVH phenomenology, suggesting that these experiences were legitimate. Similar to AVHs in a psychosis context, AVHs were experienced as distressing and appraised as persecutory. AVHs were found to be weakly associated with BPD symptoms. AVHs were also rated highly as a treatment priority by the majority of participants. CONCLUSION: The findings suggest that AVH is a legitimate and distressing symptom of BPD and a treatment priority for some patients. The relative independence of AVHs from other BPD symptoms and emotional states suggests that psychological treatment may need to be targeted specifically at the symptom of AVHs. This treatment could be adapted from cognitive behaviour therapy, the psychological intervention that is recommended for the treatment of AVHs in the context of psychosis.

Voice Hearing in Borderline Personality Disorder Across Perceptual, Subjective, and Neural Dimensions.

BACKGROUND: Auditory verbal hallucinations (AVH) commonly occur in the context of borderline personality disorder (BPD) yet remain poorly understood. AVH are often perceived by patients with BPD as originating from inside the head and hence viewed clinically as "pseudohallucinations," but they nevertheless have a detrimental impact on well-being. METHODS: The current study characterized perceptual, subjective, and neural expressions of AVH by using an auditory detection task, experience sampling and questionnaires, and functional neuroimaging, respectively. RESULTS: Perceptually, reported AVH correlated with a bias for reporting the presence of a voice in white noise. Subjectively, questionnaire measures indicated that AVH were significantly distressing and persecutory. In addition, AVH intensity, but not perceived origin (i.e., inside vs outside the head), was associated with greater concurrent anxiety. Neurally, fMRI of BPD participants demonstrated that, relative to imagining or listening to voices, periods of reported AVH induced greater blood oxygenation level-dependent activity in anterior cingulate and bilateral temporal cortices (regional substrates for language processing). AVH symptom severity was associated with weaker functional connectivity between anterior cingulate and bilateral insular cortices. CONCLUSION: In summary, our results indicate that AVH in participants with BPD are (1) underpinned by aberrant perceptual-cognitive mechanisms for signal detection, (2) experienced subjectively as persecutory and distressing, and (3) associated with distinct patterns of neural activity that inform proximal mechanistic understanding. Our findings are like analogous observations in patients with schizophrenia and validate the clinical significance of the AVH experience in BPD, often dismissed as "pseudohallucinations." These highlight a need to reconsider this experience as a treatment priority.

Sensitivity to changes in rate of heartbeats as a measure of interoceptive ability.

Individuals vary in their ability to perceive, as conscious sensations, signals like the beating of the heart. Tests of such interoceptive ability are, however, constrained in nature and reliability. Performance of the heartbeat tracking task, a widely used test of cardiac interoception, often corresponds well with individual differences in emotion and cognition, yet is susceptible to reporting bias and influenced by higher-order knowledge, e.g., of expected heart rate. The present study introduces a new way of assessing cardiac interoceptive ability, focusing on sensitivity to short-term, naturalistic changes in frequency of heartbeats. At rest, such heart rate variability typically reflects the dominant influence of respiration on vagus parasympathetic control of the sinoatrial pacemaker. We observed an overall tendency of healthy participants to report feeling fewer heartbeats during increases in heart rate, which we speculate reflects a reduction in heartbeat strength and salience during inspiratory periods when heart rate typically increases to maintain a stable cardiac output. Within-participant performance was more variable on this measure of cardiac interoceptive sensitivity relative to the "classic" heartbeat tracking task. Our findings indicate that cardiac interoceptive ability, rather than reflecting the veridical monitoring of subtle variations in physiology, appears to involve more interpolation wherein interoceptive decisions are informed by dynamic working estimates derived from the integration of afferent signaling and higher-order predictions.NEW & NOTEWORTHY This study presents a new method for evaluating cardiac interoceptive ability, measuring sensitivity to naturalistic changes in the number of heartbeats over time periods. Results show participants have an overall tendency toward sensing fewer heartbeats during higher heart rates. This likely reflects the influence of changing heartbeat strength on cardiac interoception at rest, which should be taken into account when evaluating cardiac interoceptive ability and its relationship to anxiety and psychosomatic conditions.

Inhibition of CYP27B1 and CYP24 Increases the Anti-proliferative Effects of 25-Hydroxyvitamin D3 in LNCaP Cells.

BACKGROUND/AIM: Growing evidence suggests that vitamin D3 exerts anticancer effects. The present study aimed to evaluate 25-hydroxyvitamin D3 (25(OH)D3) as a potential endocrine factor regulating proliferation and vitamin D receptor expression in LNCaP prostate cancer cells. MATERIALS AND METHODS: Cell counting after treatment was utilized to assess the effect of 25(OH)D3 on cell proliferation. Changes in mRNA expression of the vitamin D receptors, VDR and PDIA3, were evaluated using droplet digital polymerase chain reaction (ddPCR). RESULTS: 25(OH)D3 inhibited cell proliferation in a dose- and time-dependent manner. The inhibitory effect of 25(OH)D3 on cell proliferation was potentiated after inhibition of CYP17B1 and CYP24 by genistein, preventing further metabolism of 25(OH)D3 to 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3). Expression of PDIA3 and VDR mRNA increased after treatment with 25(OH)D3, whereas the ratio between PDIA3 and VDR mRNA remained unchanged. CONCLUSION: 25(OH)D3 has a direct inhibitory effect on cell proliferation, which is enhanced and accelerated when the metabolism of 25(OH)D3 to 1,25(OH)2D3 and 24,25(OH)2D3 was inhibited by the CYP17B1 and CYP24 inhibitor genistein. Furthermore, treatment with 25(OH)D3 increased receptor transcript expression, suggesting an increased VDR stability and sensibility of the treated cells.

Interoceptive training to target anxiety in autistic adults (ADIE): A single-center, superiority randomized controlled trial.

BACKGROUND: This trial tested if a novel therapy, Aligning Dimensions of Interoceptive Experience (ADIE), reduces anxiety in autistic adults. ADIE targets the association of anxiety with mismatch between subjective and behavioral measures of an individual's interoceptive sensitivity to bodily signals, including heartbeats. METHODS: In this superiority randomized controlled trial, autistic adults (18-65 years) from clinical and community settings in Southern England were randomly assigned (1:1) to receive six sessions of ADIE or an active 'exteroceptive' control therapy (emotional prosody identification). Researchers conducting outcome assessments were blind to allocation. ADIE combines two modified heartbeat detection tasks with performance feedback and physical activity manipulation that transiently increases cardiac arousal. Participants were followed-up one-week (T1) and 3-months post-intervention (T2). The primary outcome was Spielberger Trait Anxiety Score (STAI-T) at T2. Outcomes were assessed on an intention-to-treat basis using multiple imputation for dealing with missing values. This trial was registered at International Standard Randomized Controlled Trial Registry, ISRCTN14848787. FINDINGS: Between July 01, 2017, and December 31, 2019, 121 participants were randomly allocated to ADIE (n = 61) or prosody (n = 60) intervention groups. Data at T1 was provided by 85 (70%) participants (46 [75%] ADIE; 39 [65%] prosody). Data at T2 was provided by 61 (50%) participants (36 [59%] ADIE; 25 [42%] prosody). One adverse event (cardiac anxiety following ADIE) was recorded. A statistically significant group effect of ADIE on trait anxiety continued at T2 (estimated mean difference 3•23 [95% CI 1•13 to 5•29]; d = 0•30 [95% CI 0•09 to 0•51]; p = 0•005) with 31% of ADIE group participants meeting trial criteria for recovery (compared to 16% in the control group). INTERPRETATION: ADIE can reduce anxiety in autistic adults, putatively improving regulatory control over internal stimuli. With little reliance on language and emotional insight, ADIE may constitute an inclusive intervention. FUNDING MQ: Transforming Mental Health PsyImpact Grant.

Cis-regulatory elements in conserved non-coding sequences of nuclear receptor genes indicate for crosstalk between endocrine systems.

Nuclear receptors (NRs) are ligand-activated transcription factors that regulate gene expression when bound to specific DNA sequences. Crosstalk between steroid NR systems has been studied for understanding the development of hormone-driven cancers but not to an extent at a genetic level. This study aimed to investigate crosstalk between steroid NRs in conserved intron and exon sequences, with a focus on steroid NRs involved in prostate cancer etiology. For this purpose, we evaluated conserved intron and exon sequences among all 49 members of the NR Superfamily (NRS) and their relevance as regulatory sequences and NR-binding sequences. Sequence conservation was found to be higher in the first intron (35%), when compared with downstream introns. Seventy-nine percent of the conserved regions in the NRS contained putative transcription factor binding sites (TFBS) and a large fraction of these sequences contained splicing sites (SS). Analysis of transcription factors binding to putative intronic and exonic TFBS revealed that 5 and 16%, respectively, were NRs. The present study suggests crosstalk between steroid NRs, e.g., vitamin D, estrogen, progesterone, and retinoic acid endocrine systems, through cis-regulatory elements in conserved sequences of introns and exons. This investigation gives evidence for crosstalk between steroid hormones and contributes to novel targets for steroid NR regulation.

Differential expression of protein disulfide-isomerase A3 isoforms, PDIA3 and PDIA3N, in human prostate cancer cell lines representing different stages of prostate cancer.

Prostate cancer (PCa) is a highly heterogeneous and unpredictable progressive disease. Sensitivity of PCa cells to androgens play a central role in tumor aggressiveness but biomarkers with high sensitivity and specificity that follow the progression of the disease has not yet been verified. The vitamin D endocrine system and its receptors, the Vitamin D Receptor (VDR) and the Protein Disulfide-Isomerase A3 (PDIA3), are related to anti-tumoral effects as well as carcinogenesis and have therefore been suggested as potential candidates for the prevention and therapy of several cancer forms, including PCa. In this study, we evaluated the mRNA expression of VDR and PDIA3 involved in vitamin D signaling in cell lines representing different stages of PCa (PNT2, P4E6, LNCaP, DU145 and PC3). This study further aimed to evaluate vitamin D receptors and their isoforms as potential markers for clinical diagnosis of PCa. A novel transcript isoform of PDIA3 (PDIA3N) was identified and found to be expressed in all PCa cell lines analyzed. Androgen-independent cell lines showed a higher mRNA expression ratio between PDIA3N/PDIA3 contrary to androgen-dependent cell lines that showed a lower mRNA expression ratio between PDIA3N/PDIA3. The structure of PDIA3N differed from PDIA3. PDIA3N was found to be a N-truncated isoform of PDIA3 and differences in protein structure suggests an altered protein function i.e. cell location, thioredoxin activity and affinity for 1,25(OH)2D3. Collectively, PDIA3 transcript isoforms, the ratio between PDIA3N/PDIA3 and especially PDIA3N, are proposed as candidate markers for future studies with different stages of PCa progression.

Impact of cardiac interoception cues and confidence on voluntary decisions to make or withhold action in an intentional inhibition task.

Interoceptive signals concerning the internal physiological state of the body influence motivational feelings and action decisions. Cardiovascular arousal may facilitate inhibition to mitigate risks of impulsive actions. Baroreceptor discharge at ventricular systole underpins afferent signalling of cardiovascular arousal. In a modified Go/NoGo task, decisions to make or withhold actions on 'Choose' trials were not influenced by cardiac phase, nor individual differences in heart rate variability. However, cardiac interoceptive awareness and insight predicted how frequently participants chose to act, and their speed of action: Participants with better awareness and insight tended to withhold actions and respond slower, while those with poorer awareness and insight tended to execute actions and respond faster. Moreover, self-reported trait urgency correlated negatively with intentional inhibition rates. These findings suggest that lower insight into bodily signals is linked to urges to move the body, putatively by engendering noisier sensory input into motor decision processes eliciting reactive behaviour.

Amplified engagement of prefrontal cortex during control of voluntary action in Tourette syndrome.

Tourette syndrome is characterized by 'unvoluntary' tics, which are compulsive, yet often temporarily suppressible. The inferior frontal gyrus is implicated in motor control, including inhibition of pre-potent actions through influences on downstream subcortical and motor regions. Although tic suppression in Tourette syndrome also engages the inferior frontal gyrus, it is unclear whether such prefrontal control of action is also dysfunctional: Tic suppression studies do not permit comparison with control groups, and neuroimaging studies of motor inhibition can be confounded by the concurrent expression or suppression of tics. Here, patients with Tourette syndrome were directly compared to control participants when performing an intentional inhibition task during functional MRI. Tic expression was recorded throughout for removal from statistical models. Participants were instructed to make a button press in response to Go cues, withhold responses to NoGo cues, and decide whether to press or withhold to 'Choose' cues. Overall performance was similar between groups, for both intentional inhibition rates (% Choose-Go) and reactive NoGo inhibition commission errors. A subliminal face prime elicited no additional effects on intentional or reactive inhibition. Across participants, the task activated prefrontal and motor cortices and subcortical nuclei, including pre-supplementary motor area, inferior frontal gyrus, insula, caudate nucleus, thalamus and primary motor cortex. In Tourette syndrome, activity was elevated in the inferior frontal gyrus, insula and basal ganglia, most notably within the right inferior frontal gyrus during voluntary action and inhibition (Choose-Go and Choose-NoGo), and reactive inhibition (NoGo-correct). Anatomically, the locus of this inferior frontal gyrus hyperactivation during control of voluntary action matched that previously reported for tic suppression. In Tourette syndrome, activity within the caudate nucleus was also enhanced during both intentional (Choose-NoGo) and reactive (NoGo-correct) inhibition. Strikingly, despite the absence of overt motor behaviour, primary motor cortex activity increased in patients with Tourette syndrome but decreased in controls during both reactive and intentional inhibition. Additionally, severity of premonitory sensations scaled with functional connectivity of the pre-supplementary motor area to the caudate nucleus, globus pallidus and thalamus when choosing to respond (Choose-Go). Together, these results suggest that patients with Tourette syndrome use equivalent prefrontal mechanisms to suppress tics and withhold non-tic actions, but require greater inferior frontal gyrus engagement than controls to overcome motor drive from hyperactive downstream regions, notably primary motor cortex. Moreover, premonitory sensations may cue midline motor regions to generate tics through interactions with the basal ganglia.

Duplication of the bodily self: a perceptual illusion of dual full-body ownership and dual self-location.

Previous research has shown that it is possible to use multisensory stimulation to induce the perceptual illusion of owning supernumerary limbs, such as two right arms. However, it remains unclear whether the coherent feeling of owning a full-body may be duplicated in the same manner and whether such a dual full-body illusion could be used to split the unitary sense of self-location into two. Here, we examined whether healthy human participants can experience simultaneous ownership of two full-bodies, located either close in parallel or in two separate spatial locations. A previously described full-body illusion, based on visuo-tactile stimulation of an artificial body viewed from the first-person perspective (1PP) via head-mounted displays, was adapted to a dual-body setting and quantified in five experiments using questionnaires, a behavioural self-location task and threat-evoked skin conductance responses. The results of experiments 1-3 showed that synchronous visuo-tactile stimulation of two bodies viewed from the 1PP lying in parallel next to each other induced a significant illusion of dual full-body ownership. In experiment 4, we failed to find support for our working hypothesis that splitting the visual scene into two, so that each of the two illusory bodies was placed in distinct spatial environments, would lead to dual self-location. In a final exploratory experiment (no. 5), we found preliminary support for an illusion of dual self-location and dual body ownership by using dynamic changes between the 1PPs of two artificial bodies and/or a common third-person perspective in the ceiling of the testing room. These findings suggest that healthy people, under certain conditions of multisensory perceptual ambiguity, may experience dual body ownership and dual self-location. These findings suggest that the coherent sense of the bodily self located at a single place in space is the result of an active and dynamic perceptual integration process.

Heart rate variability as a biomarker in health and affective disorders: A perspective on neuroimaging studies.

The dynamic embodiment of psychological processes is evident in the association of health outcomes, behavioural traits and psychological functioning with Heart Rate Variability (HRV). The dominant high-frequency component of HRV is an index of the central neural control of heart rhythm, mediated via the parasympathetic vagus nerve. HRV provides a potential objective measure of action policies for the adaptive and predictive allostatic regulation of homeostasis within the cardiovascular system. In its support, a network of brain regions (referred to as the 'central autonomic network') maps internal state, and controls autonomic responses. This network includes regions of prefrontal cortex, anterior cingulate cortex, insula, amygdala, periaqueductal grey, pons and medulla. Human neuroimaging studies of neural activation and functional connectivity broadly endorse this architecture, and its link with cardiac regulation at rest and dysregulation in clinical states that include affective disorders. In this review, we appraise neuroimaging research and related evidence for HRV as an informative marker of autonomic integration with affect and cognition, taking a perspective on function and organisation. We consider evidence for the utility of HRV as a metric to inform targeted interventions to improve autonomic and affective dysregulation, and suggest research questions for further investigation.

Multisensory correlations-Not tactile expectations-Determine the sense of body ownership.

Can the mere expectation of a sensory event being about to occur on an artificial limb be sufficient to elicit an illusory sense of ownership over said limb? This issue is currently under debate and studies using two different paradigms have presented conflicting results. Here, we employed the two relevant paradigms, namely, the magnetic touch illusion and the "tactile expectation" version of the rubber hand illusion, to clarify the role of tactile expectations in the process of attributing ownership to limbs. The illusory senses of ownership and 'magnetic touch' were quantified using questionnaires, threat-evoked skin conductance responses and a combination of motion tracking synchronized with real-time subjective ratings and skin conductance. The results showed that the magnetic touch illusion was dependent on concurrent visual and tactile stimulation and that visually induced tactile expectations alone were insufficient. Moreover, in this study, tactile expectations were not associated with the rubber hand illusion, neither in terms of subjective ratings nor skin conductance changes. Together, these findings contradict the notion that the brain uses predictions of upcoming sensory events to determine whether or not a limb belongs to the self, and, instead, emphasize the importance of correlated multisensory information.

Dimensions of interoception predict premonitory urges and tic severity in Tourette syndrome.

Interoceptive processes in Tourette syndrome may foster the premonitory urges that commonly precede tics. Twenty-one adults with TS and 22 controls completed heartbeat tracking and discrimination tasks. Three dimensions of interoception were examined: objective accuracy, metacognitive awareness, and subjective (self-report) sensibility. Trait interoceptive prediction error was calculated as the discrepancy between accuracy and sensibility. Participants with TS had numerically lower interoceptive accuracy on the heartbeat tracking task, and increased self-reported interoceptive sensibility. While these group differences were not significant, the discrepancy between lower interoceptive accuracy and heightened sensibility, i.e. the trait interoceptive prediction error, was significantly greater in TS compared to controls. This suggests a heightened higher-order sensitivity to bodily sensations in TS, relative to a noisier perceptual representation of afferent bodily signals. Moreover, interoceptive sensibility predicted the severity of premonitory sensations and tics. This suggests interventions that work to align dimensions of interoceptive experience in TS hold therapeutic potential.

Subjective embodiment during the rubber hand illusion predicts severity of premonitory sensations and tics in Tourette Syndrome.

In Tourette Syndrome, the expression of tics and commonly preceding premonitory sensations is associated with perturbed subjective feelings of self-control and agency. We compared responses to the Rubber Hand Illusion in 23 adults with TS and 22 controls. Both TS and control participants reported equivalent subjective embodiment of the artificial hand: feelings of ownership, location, and agency were greater during synchronous visuo-tactile stimulation, compared to asynchronous. However, individuals with TS did not manifest greater proprioceptive drift, an objective marker of embodiment observed in controls. An 'embodiment prediction error' index of the difference between subjective embodiment and objective proprioceptive drift correlated with severity of premonitory sensations. Feelings of ownership also correlated with premonitory sensation severity, and feelings of agency with tic severity. These findings suggest that subjective bodily ownership, as measured by the rubber hand illusion, contributes to susceptibility to the premonitory sensations that may be a precipitating factor in tics.

Exceptionally prolonged tooth formation in elasmosaurid plesiosaurians.

Elasmosaurid plesiosaurians were globally prolific marine reptiles that dominated the Mesozoic seas for over 70 million years. Their iconic body-plan incorporated an exceedingly long neck and small skull equipped with prominent intermeshing 'fangs'. How this bizarre dental apparatus was employed in feeding is uncertain, but fossilized gut contents indicate a diverse diet of small pelagic vertebrates, cephalopods and epifaunal benthos. Here we report the first plesiosaurian tooth formation rates as a mechanism for servicing the functional dentition. Multiple dentine thin sections were taken through isolated elasmosaurid teeth from the Upper Cretaceous of Sweden. These specimens revealed an average of 950 daily incremental lines of von Ebner, and infer a remarkably protracted tooth formation cycle of about 2-3 years-other polyphyodont amniotes normally take ~1-2 years to form their teeth. Such delayed odontogenesis might reflect differences in crown length and function within an originally uneven tooth array. Indeed, slower replacement periodicity has been found to distinguish larger caniniform teeth in macrophagous pliosaurid plesiosaurians. However, the archetypal sauropterygian dental replacement system likely also imposed constraints via segregation of the developing tooth germs within discrete bony crypts; these partly resorbed to allow maturation of the replacement teeth within the primary alveoli after displacement of the functional crowns. Prolonged dental formation has otherwise been linked to tooth robustness and adaption for vigorous food processing. Conversely, elasmosaurids possessed narrow crowns with an elongate profile that denotes structural fragility. Their apparent predilection for easily subdued prey could thus have minimized this potential for damage, and was perhaps coupled with selective feeding strategies that ecologically optimized elasmosaurids towards more delicate middle trophic level aquatic predation.

Assessing chronic pelvic pain syndrome patients: blood plasma factors and cortisol saliva.

OBJECTIVE: The aim of this study was to identify changes in inflammatory molecules in the blood (plasma) of patients with chronic prostatitis/chronic pelvic syndrome (CP/CPPS) compared with controls. Altered levels indicate a systemic component by possible involvement of the prostate and/or the inner pelvic floor musculature. MATERIAL AND METHODS: In 32 patients with CP/CPPS and 37 controls, blood plasma levels of testosterone, macrophage migration inhibitory factor (MIF), tumour necrosis factor-α (TNF-α), TNF-ß, interleukin-2 (IL-2) and IL-1ß were measured by enzyme-linked immunosorbent assay. Cortisol in saliva samples was measured in the morning and late evening. All participants answered a questionnaire regarding their health profile. RESULTS: Significantly higher levels of MIF (p = 0.012) were detected in patients. The testosterone level was, contrary to other studies, little lower in patients (p = 0.014; age adjusted). When controls with health issues and patients with a parallel disease were excluded, the MIF and TNF-α levels were higher in the patients (p = 0.007, p = 0.016, respectively) than in controls, and the testosterone was slightly lower in patients (p = 0.047). CONCLUSIONS: The findings show an immune response extending to the circulatory system, in which MIF makes a significant contribution to CP/CPPS. This study also indicates TNF-α as a circulatory component when excluding subjects with concomitant diseases. Both MIF and TNF-α have previously been highlighted for other diseases related to chronic pain and here also for CP/CPPS. These results provide further insights into the immunological basis of CP/CPPS.

Vitamin D and prostate cancer: the role of membrane initiated signaling pathways in prostate cancer progression.

1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) has been demonstrated to mediate both genomic and non-genomic responses in prostate cancer (CaP) cells. Here, we give an overview of membrane initiated 1,25(OH)2D3 signaling in prostate cancer cell progression. The presence of PDIA3 was investigated and homologous modeling of the putative PDIA3 receptor complex was conducted. Furthermore, the cellular distribution of nVDR was analyzed. We could show that both nVDR and PDIA3 are expressed in the prostate cancer cell lines investigated. The homologous modeling of PDIA3 showed that the receptor complex exists in a trimer formation, which suggests for allosteric activity. Our findings support previous reports and suggest that 1,25(OH)2D3 is an important therapeutic agent in inhibiting prostate cancer progression. Furthermore, our data show that 1,25(OH)2D3 regulate prostate cell biology via multiple pathways and targeting specific pathways for 1,25(OH)2D3 might provide more effective therapies compared to the vitamin D therapies currently clinically tested.

Spatial insulin signalling in isolated skeletal muscle preparations.

During in vitro incubation in the absence or presence of insulin, glycogen depletion occurs in the inner core of the muscle specimen, concomitant with increased staining of hypoxia-induced-factor-1-alpha and caspase-3, markers of hypoxia and apoptosis, respectively. The aim of this study was to determine whether insulin is able to diffuse across the entire muscle specimen in sufficient amounts to activate signalling cascades to promote glucose uptake and glycogenesis within isolated mouse skeletal muscle. Phosphoprotein multiplex assay on lysates from muscle preparation was performed to detect phosphorylation of insulin-receptor on Tyr(1146), Akt on Ser(473) and glycogen-synthases-kinase-3 on Ser(21)/Ser(9). To address the spatial resolution of insulin signalling, immunohistochemistry studies on cryosections were performed. Our results provide evidence to suggest that during the in vitro incubation, insulin sufficiently diffuses into the centre of tubular mouse muscles to promote phosphorylation of these signalling events. Interestingly, increased insulin signalling was observed in the core of the incubated muscle specimens, correlating with the location of oxidative fibres. In conclusion, insulin action was not restricted due to insufficient diffusion of the hormone during in vitro incubation in either extensor digitorum longus or soleus muscles from mouse under the specific experimental settings employed in this study. Hence, we suggest that the glycogen depleted core as earlier observed is not due to insufficient insulin action.