The PRDM family has recently spawned considerable interest as it has been implicated in fundamental aspects of cellular differentiation and exhibits expanding ties to human diseases. The PRDMs belong to the SET domain family of histone methyltransferases, however, enzymatic activity has been determined for only few PRDMs suggesting that they act by recruiting co‐factors or, more speculatively, confer methylation of non‐histone targets. Several PRDM family members are deregulated in human diseases, most prominently in hematological malignancies and solid cancers, where they (...) can act as both tumor suppressors or drivers of oncogenic processes. The molecular mechanisms have been delineated for only few PRDMs and little is known about functional redundancy within the family. Future studies should identify target genes of PRDM proteins and the protein complexes in which PRDM proteins reside to provide a more comprehensive understanding of the biological and biochemical functions of this important protein family. (shrink)

Literature on maternal exposures and the risk of epigenetic changes or diseases in the offspring is growing. Paternal contributions are often not considered. However, some animal and epidemiologic studies on various contaminants, nutrition, and lifestyle‐related conditions suggest a paternal influence on the offspring's future health. The phenotypic outcomes may have been attributed to DNA damage or mutations, but increasing evidence shows that the inheritance of environmentally induced functional changes of the genome, and related disorders, are (also) driven by epigenetic components. (...) In this essay we suggest the existence of epigenetic windows of susceptibility to environmental insults during sperm development. Changes in DNA methylation, histone modification, and non‐coding RNAs are viable mechanistic candidates for a non‐genetic transfer of paternal environmental information, from maturing germ cell to zygote. Inclusion of paternal factors in future research will ultimately improve the understanding of transgenerational epigenetic plasticity and health‐related effects in future generations. (shrink)

Since the 1970s, there has been an increased focus on gender in the research literature concerning British philosopher Mary Wollstonecraft, which most likely is caused by the increasing interest in the social aspects of gender inspired by poststructuralist thinking. Although such readings have been illuminative and fruitful, focusing on the social and the interconnections between Wollstonecraft and modernity seems to have brought with them a neglect of two interesting aspects of Wollstonecraft’s notion about gender. On the one hand, her thoughts (...) on the body seem somewhat underexposed, while her impact on the subsequent British romanticists is equally neglected. The article focuses on these two aspects. Here the analyses are based on Wollstonecraft’s discussions with Jean-Jacques Rousseau and Edmund Burke about the relations gender has to nature, bodies, and aesthetics; discussions which inform a conception of gender that the later romantics would take inspiration from. (shrink)

Background: Freezing of gait is a common symptom in Parkinson’s disease and can be difficult to treat with dopaminergic medications or with deep brain stimulation. Novel stimulation paradigms have been proposed to address suboptimal responses to conventional DBS programming methods. Burst-cycling deep brain stimulation delivers current in various frequencies of bursts, while maintaining an intra-burst frequency identical to conventional DBS.Objective: To evaluate the safety and tolerability of BCDBS in PD patients with FOG.Methods: Ten PD subjects with STN or GPi DBS (...) and complaints of FOG were recruited for this single center, single blinded within-subject crossover study. For each subject, we compared 4, 10, and 15 Hz BCDBS to conventional DBS during the PD medication-OFF state.Results: There were no serious adverse events with BCDBS. It was feasible and straightforward to program BCDBS in the clinic setting. The benefit was comparable to conventional DBS in measures of FOG, functional mobility and in PD motor symptoms. BCDBS had lower battery consumption when compared to conventional DBS.Conclusions: BCDBS was feasible, safe and well tolerated and it has potential to be a viable future DBS programming strategy. (shrink)

BackgroundFreezing of gait is a disabling burden for Parkinson’s disease patients with poor response to conventional therapies. Combined deep brain stimulation of the subthalamic nucleus and substantia nigra moved into focus as a potential therapeutic option to treat the parkinsonian gait disorder and refractory FoG. The mechanisms of action of DBS within the cortical-subcortical-basal ganglia network on gait, particularly at the cortical level, remain unclear.MethodsTwelve patients with idiopathic PD and chronically-implanted DBS electrodes were assessed on their regular dopaminergic medication in (...) a standardized stepping in place paradigm. Patients executed the task with DBS switched off, conventional STN DBS and combined STN+SN DBS and were compared to healthy matched controls. Simultaneous high-density EEG and kinematic measurements were recorded during resting-state, effective stepping, and freezing episodes.ResultsClinically, STN+SN DBS was superior to conventional STN DBS in improving temporal stepping variability of the more affected leg. During resting-state and effective stepping, the cortical activity of PD patients in STIM OFF was characterized by excessive over-synchronization in the theta, alpha, and high-beta band compared to healthy controls. Both active DBS settings similarly decreased resting-state alpha power and reduced pathologically enhanced high-beta activity during resting-state and effective stepping compared to STIM OFF. Freezing episodes during STN DBS and STN+SN DBS showed spectrally and spatially distinct cortical activity patterns when compared to effective stepping. During STN DBS, FoG was associated with an increase in cortical alpha and low-beta activity over central cortical areas, while with STN+SN DBS, an increase in high-beta was prominent over more frontal areas.ConclusionsSTN+SN DBS improved temporal aspects of parkinsonian gait impairment compared to conventional STN DBS and differentially affected cortical oscillatory patterns during regular locomotion and freezing suggesting a potential modulatory effect on dysfunctional cortical-subcortical communication in PD. (shrink)

BackgroundThe preferable position of Deep Brain Stimulation electrodes is proposed to be located in the dorsolateral subthalamic nucleus to improve general motor performance. The optimal DBS electrode localization for the post-operative improvement of balance and gait is unknown.MethodsIn this single-center, retrospective analyses, 66 Parkinson’s disease patients were assessed pre- and post-operatively by using MDS-UPDRS, freezing of gait score, Giladi’s gait and falls questionnaire and Berg balance scale. The clinical outcome was related to the DBS electrode coordinates in x, y, z (...) plane as revealed by image-based reconstruction. Binomial generalized linear mixed models with fixed-effect variables electrode asymmetry, parkinsonian subtype, medication, age class and clinical DBS induced changes were analyzed.ResultsSubthalamic nucleus-deep brain stimulation improved all motor, balance and FoG scores in MED OFF condition, however there were heterogeneous results in MED ON condition. DBS electrode reconstructed coordinates impacted the responsiveness of axial symptoms. FoG and balance responders showed slightly more medially located STN electrode coordinates and less medio-lateral asymmetry of the electrode reconstructed coordinates across hemispheres compared to non-responders.ConclusionDeep brain stimulation electrode reconstructed coordinates, particularly electrode asymmetry on the medio-lateral axis affected the post-operative responsiveness of balance and FoG symptoms in PD patients. (shrink)

In a recent paper Savas Tsohatzidis has provided a number of putative counterexamples to the well-attested Kartunnen-Vendler (K-V) thesis that the use of 'tell' with a wh-complement requires that the speaker spoke truthfully. His counterexamples are sentences like: (1) Old John told us who he saw in the fog, but it turned out that he was mistaken. I argue that such examples do not serve to refute the K-V thesis. Rather, they are examples of a more general phenomenon that I (...) label participant projection, which is manifested in sentences like: (2) He gave her a ring studded with diamonds, but they turned out to be glass. Just as the acceptability of (2) does not show that some diamonds are glass, so the acceptability of (1) does not disprove the K-V thesis. (shrink)

TheCulexis now widely recognized as a piece of post-Ovidian, possibly Tiberian, pseudo-juvenilia written by an author impersonating the young Virgil, although it was attached to Virgil's name already in the first centuryc.e., being identified as Virgilian by Statius, Suetonius and Martial. Dedicated to the young Octavian (Octauiin line 1), the poem seems to fill a biographical gap in Virgil's career before his composition of theEclogues. It is introduced as aludus, which Irene Peirano suggests may openly refer to ‘the act of (...) impersonating Virgil’, and, like many of the poems in theAppendix Vergiliana, it seems to have a parodic intent. TheCulexhas been interpreted as a parody of neoteric style and the epyllion, as mock-epic, as Virgil parody (John Henderson called it a ‘spoofAeneidin bucolic drag’), as pointed Augustan satire, as mock Ovidian ‘Weltgedicht’ and as just very bad poetry (Housman's ‘stutterer’). Glenn Most has observed that the poem's three ‘acts’ structurally recapitulate Virgil's three major works in chronological succession. Little attention, however, has been paid to theCulex's final lines, which contain a catalogue of flowers thepastorplaces on the gnat's tomb. Recent scholarship has reintroduced an older interpretation of the gnat's tomb as a political allegory of Augustus’ Mausoleum; in this paper I suggest instead that the tomb and its flowers serve a closural and metapoetic function at the end of the poem. (shrink)

A series of letters between a professor of philosophy and an eleven-year-old girl.

Grush's emulation theory comprises both modality-specific and amodal emulators. I suggest that the amodal variety be replaced by multisensory emulators. The key distinction is that multisensory processing retains the characteristics of individual sensory modalities, in contrast to amodal processing. The latter term is better reserved for conceptual and linguistic systems, rather than perception or emulation.

I wish to discuss symbols concerned with the way we feel about the world and the way we conduct our lives in consequence of those feelings. Our conduct is guided by commands and instructions which for some reason we have to obey. We are guided by our knowledge of the world. The symbols I wish to discuss express and excite desires and preferences and that is how they affect our conduct.

The effects of the vacuum electromagnetic fluctuations and the radiation reaction fields on the time development of a simple microscopic system are identified using a new mathematical method. This is done by studying a charged mechanical oscillator (frequency Ω 0)within the realm of stochastic electrodynamics, where the vacuum plays the role of an energy reservoir. According to our approach, which may be regarded as a simple mathematical exercise, we show how the oscillator Liouville equation is transformed into a Schrödinger-like stochastic (...) equation with a free parameter h′ with dimensions of action. The role of the physical Planck's constant h is introduced only through the zero-point vacuum electromagnetic fields. The perturbative and the exact solutions of the stochastic Schrödinger-like equation are presented for h′>0. The exact solutions for which h′<h are called sub-Heisenberg states. These nonperturbative solutions appear in the form of Gaussian, non-Heisenberg states for which the initial classical uncertainty relation takes the form 〈(δx 2)〉〈(δp) 2 〉=(h′/2) 2,which includes the limit of zero indeterminacy (h → 0). We show how the radiation reaction and the vacuum fields govern the evolution of these non-Heisenberg states in phase space, guaranteeing their decay to the stationary state with average energy hΩ 0 /2 and 〈(δx) 2 〉〈(δp) 2 〉=h 2 /4 at zero temperature. Environmental and thermal effects-are briefly discussed and the connection with similar works within the realm of quantum electrodynamics is also presented. We suggest some other applications of the classical non-Heisenberg states introduced in this paper and we also indicate experiments which might give concrete evidence of these states. (shrink)

Commentary and supercommentary, with text, on Īśvarapratyabhijñā, classical verse work, expounding the Trika philosophy in Kashmir Sivaism, by Utpala, fl. 900-950.

The author of this comment suggests that some of the important points made by Dr Adrian Rogers are vitiated by a tendency to contrast the worst of modern medical practice with an over-idealised view of the past. The state of medical ethics today, the author suggests, is more hopeful than Dr Rogers allows.

The author discusses the contribution of humanities teaching in medical education. Five "qualities of mind" specifically engendered by the humanistic disciplines are isolated, delineated, and illustrated: critical abilities, flexibility of perspective, nondogmatism, discernment of values, and empathy and self-knowledge. Keywords: humanities, humanities and medicine, medical education CiteULike Connotea Del.icio.us What's this?

Open peer commentary on the article “Radical Constructivism and Radical Constructedness: Luhmann’s Sociology of Semantics, Organizations, and Self-Organization” by Loet Leydesdorff. > Upshot: Leydesdorff emphasises the uncertainties involved in the communication of meaning. Luhmann posited three types of media, each of which reduces one type of communicative improbability. The theory of cultural evolution supports Leydesdorff’s emphasis on the uncertainty of communication, and agrees that different media are needed for communication within and across social boundaries. But it highlights the distinction between (...) media and the symbolic codes that give them structure; and it raises the question whether Luhmann’s symbolically generalized communication media are really media at all. (shrink)