The anti-epileptic drug Valproic Acid (VPA) inhibits steroidogenesis in bovine theca and granulosa cells in vitro

Valproic acid (VPA) is used widely to treat epilepsy and bipolar disorder. Women undergoing VPA treatment reportedly have an increased incidence of polycystic ovarian syndrome (PCOS)-like symptoms including hyperandrogenism and oligo- or amenorrhoea. To investigate potential direct effects of VPA on ovarian steroidogenesis we used primary bovine theca (TC) and granulosa (GC) cells maintained under conditions that preserve their 'follicular' phenotype. Effects of VPA (7.8-500 µg/ml) on TC were tested with/without LH. Effects of VPA on GC were tested with/without FSH or IGF analogue. VPA reduced (P<0.0001) both basal (70% suppression; IC(50) 67±10 µg/ml) and LH-induced (93% suppression; IC(50) 58±10 µg/ml) androstenedione secretion by TC. VPA reduced CYP17A1 mRNA abundance (>99% decrease; P<0.0001) with lesser effects on LHR, STAR, CYP11A1 and HSD3B1 mRNA (<90% decrease; P<0.05). VPA only reduced TC progesterone secretion induced by the highest (luteinizing) LH dose tested; TC number was unaffected by VPA. At higher concentrations (125-500 µg/ml) VPA inhibited basal, FSH- and IGF-stimulated estradiol secretion (P<0.0001) by GC without affecting progesterone secretion or cell number. VPA reversed FSH-induced upregulation of CYP19A1 and HSD17B1 mRNA abundance (P<0.001). The potent histone deacetylase (HDAC) inhibitors trichostatin A and scriptaid also suppressed TC androstenedione secretion and granulosal cell oestrogen secretion suggesting that the action of VPA reflects its HDAC inhibitory properties. In conclusion, these findings refute the hypothesis that VPA has a direct stimulatory action on TC androgen output. On the contrary, VPA inhibits both LH-dependent androgen production and FSH/IGF-dependent estradiol production in this in vitro bovine model, likely by inhibition of HDAC.

Technical note: Organics-induced fluorescence in Raman studies of sulfuric acid aerosols

Fluorescence is a troublesome side effect in laboratory Raman studies on sulfuric acid solutions and aerosol particles. We performed experiments showing that organic matter induces fluorescence in H2SO4/H2O solutions. The intensity of the fluorescence signal appears to be almost independent of the concentration of the organic substances, but depends strongly on the sulfuric acid concentration. The ubiquity of organic substances in the atmosphere, their relatively high abundance, and the insensitivity of the fluorescence with respect to their concentrations will render most acidic natural aerosols subject to absorption and fluorescence, possibly influencing climate forcing. We show that, while fluorescence may in the future become a valuable tool of aerosol diagnostics, the concurrent absorption is too small to significantly affect the atmosphere's radiative balance.

Effect of Rht alleles on the tolerance of wheat grain set to high temperature and drought stress during booting and anthesis

Factorial pot experiments were conducted to compare the responses of GA-sensitive and GA-insensitive reduced height (Rht) alleles in wheat for susceptibility to heat and drought stress during booting and anthesis. Grain set (grains/spikelet) of near isogenic lines (NILs) was assessed following three day transfers to controlled environments imposing day temperatures (t) from 20 to 40°C. Transfers were during booting and/or anthesis and pots maintained at field capacity (FC) or had water withheld. Logistic responses (y = c/1+e-b(t -m)) described declining grain set with increasing t, and t5 was that fitted to give a 5% reduction in grain set. Averaged over NIL, t5 for anthesis at FC was 31.7±0.47°C (S.E.M, 26 d.f.). Drought at anthesis reduced t5 by <2°C. Maintaining FC at booting conferred considerable resistance to high temperatures (t5=33.9°C) but booting was particularly heat susceptible without water (t5 =26.5°C). In one background (cv. Mercia), for NILs varying at the Rht-D1 locus, there was progressive reduction in t5 with dwarfing and reduced gibberellic acid (GA) sensitivity (Rht-D1a, tall, 32.7±0.72; Rht-D1b, semi-dwarf, 29.5±0.85; Rht-D1c, severe dwarf, 24.2±0.72). This trend was not evident for the Rht-B1 locus, or for Rht-D1b in an alternative background (Maris Widgeon). The GA-sensitive severe dwarf Rht12 was more heat tolerant (t5=29.4±0.72) than the similarly statured GA-insensitive Rht-D1c. The GA-sensitive, semi-dwarfing Rht8 conferred greater drought tolerance in one experiment. Despite the effects of Rht-D1 alleles in Mercia on stress tolerance, the inconsistency of the effects over background and locus led to the conclusion that semi-dwarfing with GA-insensitivity did not necessarily increase sensitivity to stress at booting and flowering. In comparison to effects of semi-dwarfing alleles, responses to heat stress are much more dramatically affected by water availability and the precise growth stage at which the stress is experienced by the plants.

Parenting difficulties and postnatal depression: implications for primary healthcare assessment and intervention

Postnatal depression (PND) is associated with impairments in the mother–child relationship, and these impairments are themselves associated with adverse child outcomes. Thus, compared to the children of non-depressed mothers, children of mothers with PND are more likely to be insecurely attached, and to have externalising behaviour problems and poor cognitive development. Each of these three child outcomes is predicted by a particular pattern of difficulty in parenting: insecure attachment is related to maternal insensitivity, particularly in relation to infant distress and emotional vulnerability; externalising problems are particularly common in the context of hostile parenting; and poor cognitive development is related to parental difficulties in noticing infant signs of interest and supporting their engagement with the environment. This article sets out procedures for how parenting could be assessed in ways that are sensitive to the domain-specific associations between parenting and child outcome, while remaining sensitive to the child's developmental stage. This set of assessments requires field testing.

Pragmatic solutions for syntactic problems: Understanding some L2 syntactic errors in terms of discourse-pragmatic deficits

Contemporary research in generative second language (L2) acquisition has attempted to address observable target-deviant aspects of L2 grammars within a UG-continuity framework (e.g. Lardiere 2000; Schwartz 2003; Sprouse 2004; Prévost & White 1999, 2000). With the aforementioned in mind, the independence of pragmatic and syntactic development, independently observed elsewhere (e.g. Grodzinsky & Reinhart 1993; Lust et al. 1986; Pacheco & Flynn 2005; Serratrice, Sorace & Paoli 2004), becomes particularly interesting. In what follows, I examine the resetting of the Null-Subject Parameter (NSP) for English learners of L2 Spanish. I argue that insensitivity to associated discoursepragmatic constraints on the discursive distribution of overt/null subjects accounts for what appear to be particular errors as a result of syntactic deficits. It is demonstrated that despite target-deviant performance, the majority must have native-like syntactic competence given their knowledge of the Overt Pronoun Constraint (Montalbetti 1984), a principle associated with the Spanish-type setting of the NSP.

Start-up rheometry of highly polydisperse magnetorheological fluids: experiments and simulations

An extensive experimental and simulation study is carried out in conventional magnetorheological fluids formulated by dispersion of mixtures of carbonyl iron particles having different sizes in Newtonian carriers. Apparent yield stress data are reported for a wide range of polydispersity indexes (PDI) from PDI = 1.63 to PDI = 3.31, which for a log-normal distribution corresponds to the standard deviation ranging from to . These results demonstrate that the effect of polydispersity is negligible in this range in spite of exhibiting very different microstructures. Experimental data in the magnetic saturation regime are in quantitative good agreement with particle-level simulations under the assumption of dipolar magnetostatic forces. The insensitivity of the yield stresses to the polydispersity can be understood from the interplay between the particle cluster size distribution and the packing density of particles inside the clusters.

Photoperiod sensitivity affects flowering duration in wheat

Flowering and successful pollination in wheat are key determinants of both quantity and quality of grain. Bread wheat line ‘Paragon’, introgressed with single or multiple day length insensitivity alleles was used to dissect the effects on the timing and duration of flowering within a hierarchical plant architecture. Flowering of wheat plants was observed in a series of pot-based and field experiments. Ppd-D1a was the most potent known allele affecting the timing of flowering, requiring the least thermal time to flowering across all experiments. The duration of flowering for individual lines was dominated by the shift in the start of flowering in later tillers and the number of tillers per plant, rather than variation in flowering duration of individual spikes. There was a strong relationship between flowering duration and the start of flowering with the earliest lines flowering for the longest. The greatest flowering overlap between tillers was recorded for the Ppd-1b. Across all lines, a warmer environment significantly reduced the duration of flowering and the influence of Ppd-1a alleles on the start of flowering. These findings provide evidence of pleiotropic effects of the Ppd-1a alleles, and have direct implications for breeding for increased stress resilient wheat varieties.

The “pain matrix” in pain-free individuals

Human functional imaging provides a correlative picture of brain activity during pain. A particular set of central nervous system structures (eg, the anterior cingulate cortex, thalamus, and insula) consistently respond to transient nociceptive stimuli causing pain. Activation of this so-called pain matrix or pain signature has been related to perceived pain intensity, both within and between individuals,1,2 and is now considered a candidate biomarker for pain in medicolegal settings and a tool for drug discovery. The pain-specific interpretation of such functional magnetic resonance imaging (fMRI) responses, although logically flawed,3,4 remains pervasive. For example, a 2015 review states that “the most likely interpretation of activity in the pain matrix seems to be pain.”4 Demonstrating the nonspecificity of the pain matrix requires ruling out the presence of pain when highly salient sensory stimuli are presented. In this study, we administered noxious mechanical stimuli to individuals with congenital insensitivity to pain and sampled their brain activity with fMRI. Loss-of-function SCN9A mutations in these individuals abolishes sensory neuron sodium channel Nav1.7 activity, resulting in pain insensitivity through an impaired peripheral drive that leaves tactile percepts fully intact.5 This allows complete experimental disambiguation of sensory responses and painful sensations