Low-rate firing limit for neurons with axon, soma and dendrites driven by spatially distributed stochastic synapses

Analytical forms for neuronal firing rates are important theoretical tools for the analysis of network states. Since the 1960s, the majority of approaches have treated neurons as being electrically compact and therefore isopotential. These approaches have yielded considerable insight into how single-cell properties affect network activity; however, many neuronal classes, such as cortical pyramidal cells, are electrically extended objects. Calculation of the complex flow of electrical activity driven by stochastic spatio-temporal synaptic input streams in these structures has presented a significant analytical challenge. Here we demonstrate that an extension of the level-crossing method of Rice, previously used for compact cells, provides a general framework for approximating the firing rate of neurons with spatial structure. Even for simple models, the analytical approximations derived demonstrate a surprising richness including: independence of the firing rate to the electrotonic length for certain models, but with a form distinct to the point-like leaky integrate-and-fire model; a non-monotonic dependence of the firing rate on the number of dendrites receiving synaptic drive; a significant effect of the axonal and somatic load on the firing rate; and the role that the trigger position on the axon for spike initiation has on firing properties. The approach necessitates only calculating the mean and variances of the non-thresholded voltage and its rate of change in neuronal structures subject to spatio-temporal synaptic fluctuations. The combination of simplicity and generality promises a framework that can be built upon to incorporate increasing levels of biophysical detail and extend beyond the low-rate firing limit treated in this paper

Hfq binding changes the structure of Escherichia coli small noncoding RNAs OxyS and RprA, which are involved in the riboregulation of rpoS

OxyS and RprA are two small noncoding RNAs (sRNAs) that modulate the expression of rpoS, encoding an alternative sigma factor that activates transcription of multiple Escherichia coli stress-response genes. While RprA activates rpoS for translation, OxyS down-regulates the transcript. Crucially, the RNA binding protein Hfq is required for both sRNAs to function, although the specific role played by Hfq remains unclear. We have investigated RprA and OxyS interactions with Hfq using biochemical and biophysical approaches. In particular, we have obtained the molecular envelopes of the Hfq–sRNA complexes using small-angle scattering methods, which reveal key molecular details. These data indicate that Hfq does not substantially change shape upon complex formation, whereas the sRNAs do. We link the impact of Hfq binding, and the sRNA structural changes induced, to transcript stability with respect to RNase E degradation. In light of these findings, we discuss the role of Hfq in the opposing regulatory functions played by RprA and OxyS in rpoS regulation

Alpha-synuclein aggregates increase the conductance of substantia nigra dopamine neurons, an effect partly reversed by the KATP channel inhibitor glibenclamide

Dopaminergic neurons in the substantia nigra pars compacta (SNpc) form an important part of the basal ganglia circuitry, playing key roles in movement initiation and co-ordination. A hallmark of Parkinson’s disease (PD) is the degeneration of these SNpc dopaminergic neurons leading to akinesia, bradykinesia and tremor. There is gathering evidence that oligomeric alpha synuclein (α-syn) is one of the major pathological species in PD, with its deposition in Lewy bodies closely correlated with disease progression. However the precise mechanisms underlying the effects of oligomeric α-syn on dopaminergic neuron function have yet to be fully defined. Here we have combined electrophysiological recording and detailed analysis to characterise the time-dependent effects of α-syn aggregates (consisting of oligomers and possibly small fibrils) on the properties of SNpc dopaminergic neurons. The introduction of α-syn aggregates into single dopaminergic neurons via the patch electrode significantly reduced both the input resistance and the firing rate without changing the membrane potential. These effects occurred after 8-16 minutes of dialysis but did not occur with the monomeric form of α-syn. The effects of α-syn aggregates could be significantly reduced by pre-incubation with the ATP-sensitive potassium channel (KATP) inhibitor glibenclamide. This data suggests that accumulation of α-syn aggregates in dopaminergic neurons may chronically activate KATP channels leading to a significant loss of excitability and dopamine release

The critical window for the classical Ramsey-Tur\'an problem

The first application of Szemer\'edi's powerful regularity method was the following celebrated Ramsey-Tur\'an result proved by Szemer\'edi in 1972: any K_4-free graph on N vertices with independence number o(N) has at most (1/8 + o(1)) N^2 edges. Four years later, Bollob\'as and Erd\H{o}s gave a surprising geometric construction, utilizing the isoperimetric inequality for the high dimensional sphere, of a K_4-free graph on N vertices with independence number o(N) and (1/8 - o(1)) N^2 edges. Starting with Bollob\'as and Erd\H{o}s in 1976, several problems have been asked on estimating the minimum possible independence number in the critical window, when the number of edges is about N^2 / 8. These problems have received considerable attention and remained one of the main open problems in this area. In this paper, we give nearly best-possible bounds, solving the various open problems concerning this critical window.Comment: 34 page

An examination of autism spectrum traits in adolescents with anorexia nervosa and their parents

There may be a link between anorexia nervosa and autism spectrum disorders. The aims of this study were to examine whether adolescents with anorexia nervosa have autism spectrum and/or obsessive-compulsive traits, how many would meet diagnostic criteria for autism spectrum disorder, and whether these traits are shared by parents

Cross-talk between human airway epithelial cells and 3T3-J2 feeder cells involves partial activation of human MET by murine HGF

There is considerable interest in the ex vivo propagation of primary human basal epithelial stem/progenitor cells with a view to their use in drug development, toxicity testing and regenerative medicine. These cells can be expanded in co-culture with mitotically inactivated 3T3-J2 murine embryonic feeder cells but, similar to other epithelial cell culture systems employing 3T3-J2 cells, the aspects of cross-talk between 3T3-J2 cells and human airway basal cells that are critical for their expansion remain largely unknown. In this study, we investigated secreted growth factors that are produced by 3T3-J2 cells and act upon primary human airway basal cells. We found robust production of hepatocyte growth factor (HGF) from fibroblast feeder cells following mitotic inactivation. Consistent with the limited cross-species reactivity of murine HGF on the human HGF receptor (MET; HGFR), MET inhibition did not affect proliferative responses in human airway basal cells and HGF could not replace feeder cells in this culture system. However, we found that murine HGF is not completely inactive on human airway epithelial cells or cancer cell lines but stimulates the phosphorylation of GRB2-associated-binding protein 2 (GAB2) and signal transducer and activator of transcription 6 (STAT6). Although HGF induces phosphorylation of STAT6 tyrosine 641 (Y641), there is no subsequent STAT6 nuclear translocation or STAT6-driven transcriptional response. Overall, these findings highlight the relevance of cross-species protein interactions between murine feeder cells and human epithelial cells in 3T3-J2 co-culture and demonstrate that STAT6 phosphorylation occurs in response to MET activation in epithelial cells. However, STAT6 nuclear translocation does not occur in response to HGF, precluding the transcriptional activity of STAT6

Bounds for graph regularity and removal lemmas

We show, for any positive integer k, that there exists a graph in which any equitable partition of its vertices into k parts has at least ck^2/\log^* k pairs of parts which are not \epsilon-regular, where c,\epsilon>0 are absolute constants. This bound is tight up to the constant c and addresses a question of Gowers on the number of irregular pairs in Szemer\'edi's regularity lemma. In order to gain some control over irregular pairs, another regularity lemma, known as the strong regularity lemma, was developed by Alon, Fischer, Krivelevich, and Szegedy. For this lemma, we prove a lower bound of wowzer-type, which is one level higher in the Ackermann hierarchy than the tower function, on the number of parts in the strong regularity lemma, essentially matching the upper bound. On the other hand, for the induced graph removal lemma, the standard application of the strong regularity lemma, we find a different proof which yields a tower-type bound. We also discuss bounds on several related regularity lemmas, including the weak regularity lemma of Frieze and Kannan and the recently established regular approximation theorem. In particular, we show that a weak partition with approximation parameter \epsilon may require as many as 2^{\Omega(\epsilon^{-2})} parts. This is tight up to the implied constant and solves a problem studied by Lov\'asz and Szegedy.Comment: 62 page

Treatment of psychoses in patients with epilepsy: an update.

Psychotic disorders represent a relatively rare but serious comorbidity in epilepsy. Current epidemiological studies are showing a point prevalence of 5.6% in unselected samples of people with epilepsy going up to 7% in patients with temporal lobe epilepsy, with a pooled odds ratio of 7.8 as compared with the general population. This is a narrative review of the most recent updates in the management of psychotic disorders in epilepsy, taking into account the clinical scenarios where psychotic symptoms occur in epilepsy, interactions with antiepileptic drugs (AEDs) and the risk of seizures with antipsychotics. Psychotic symptoms in epilepsy can arise in a number of different clinical scenarios from peri-ictal symptoms, to chronic interictal psychoses, comorbid schizophrenia and related disorders to the so-called forced normalization phenomenon. Data on the treatment of psychotic disorders in epilepsy are still limited and the management of these problems is still based on individual clinical experience. For this reason, guidelines of treatment outside epilepsy should be adopted taking into account epilepsy-related issues including interactions with AEDs and seizure risk. Second-generation antipsychotics, especially risperidone, can represent a reasonable first-line option because of the low propensity for drug-drug interactions and the low risk of seizures. Quetiapine is burdened by a clinically significant pharmacokinetic interaction with enzyme-inducing drugs leading to undetectable levels of the antipsychotic, even for dosages up to 700 mg per day

The use of routine outcome measures in two child and adolescent mental health services: a completed audit cycle

Background: Routine outcome measurement (ROM) is important for assessing the clinical effectiveness of health services and for monitoring patient outcomes. Within Child and Adolescent Mental Health Services (CAMHS) in the UK the adoption of ROM in CAMHS has been supported by both national and local initiatives (such as government strategies, local commissioning policy, and research). Methods: With the aim of assessing how these policies and initiatives may have influenced the uptake of ROM within two different CAMHS we report the findings of two case-note audits: a baseline audit conducted in January 2011 and a re-audit conducted two years later in December 2012-February 2013. Results: The findings show an increase in both the single and repeated use of outcome measures from the time of the original audit, with repeated use (baseline and follow-up) of the Health of the Nation Outcome Scale for Children and Adolescents (HoNOSCA) scale increasing from 10% to 50% of cases. Re-audited case-notes contained more combined use of different outcome measures, with greater consensus on which measures to use. Outcome measures that were applicable across a wide range of clinical conditions were more likely to be used than symptom-specific measures, and measures that were completed by the clinician were found more often than measures completed by the service user. Conclusions: The findings show a substantial improvement in the use of outcome measures within CAMHS. These increases in use were found across different service organisations which were subject to different types of local service priorities and drivers