Neural Network Interactions Modulate CRY-Dependent Photoresponses in Drosophila

Light is one of the chief environmental cues that reset circadian clocks. In Drosophila, CRYPTOCHROME (CRY) mediates acute photic resetting of circadian clocks by promoting the degradation of TIMELESS in a cell-autonomous manner. Thus, even circadian oscillators in peripheral organs can independently perceive light in Drosophila However, there is substantial evidence for nonautonomous mechanisms of circadian photoreception in the brain. We have previously shown that the morning (M) and evening (E) oscillators are critical light-sensing neurons that cooperate to shift the phase of circadian behavior in response to light input. We show here that light can efficiently phase delay or phase advance circadian locomotor behavior in male Drosophila even when either the M- or the E-oscillators are ablated, suggesting that behavioral phase shifts and their directionality are largely a consequence of the cell-autonomous nature of CRY-dependent photoreception. Our observation that the phase response curves of brain and peripheral oscillators are remarkably similar further supports this idea. Nevertheless, the neural network modulates circadian photoresponses. We show that the M-oscillator neurotransmitter pigment dispersing factor plays a critical role in the coordination between M- and E-oscillators after light exposure, and we uncover a potential role for a subset of dorsal neurons in the control of phase advances. Thus, neural modulation of autonomous light detection might play an important role in the plasticity of circadian behavior.SIGNIFICANCE STATEMENT Input pathways provide circadian rhythms with the flexibility needed to harmonize their phase with environmental cycles. Light is the chief environmental cue that synchronizes circadian clocks. In Drosophila, the photoreceptor CRYPTOCHROME resets circadian clocks cell-autonomously. However, recent studies indicate that, in the brain, interactions between clock neurons are critical to reset circadian locomotor behavior. We present evidence supporting the idea that the ability of flies to advance or delay their rhythmic behavior in response to light input essentially results from cell-autonomous photoreception. However, because of their networked organization, we find that circadian neurons have to cooperate to reset the phase of circadian behavior in response to photic cues. Our work thus helps to reconcile cell-autonomous and non-cell-autonomous models of circadian entrainment

Drosophila PSI controls circadian period and the phase of circadian behavior under temperature cycle via tim splicing

The Drosophila circadian pacemaker consists of transcriptional feedback loops subjected to post-transcriptional and post-translational regulation. While post-translational regulatory mechanisms have been studied in detail, much less is known about circadian post-transcriptional control. Thus, we targeted 364 RNA binding and RNA associated proteins with RNA interference. Among the 43 hits we identified was the alternative splicing regulator P-element somatic inhibitor (PSI). PSI regulates the thermosensitive alternative splicing of timeless (tim), promoting splicing events favored at warm temperature over those increased at cold temperature. Psi downregulation shortens the period of circadian rhythms and advances the phase of circadian behavior under temperature cycle. Interestingly, both phenotypes were suppressed in flies that could produce TIM proteins only from a transgene that cannot form the thermosensitive splicing isoforms. Therefore, we conclude that PSI regulates the period of Drosophila circadian rhythms and circadian behavior phase during temperature cycling through its modulation of the tim splicing pattern

The Role of Glutamate and GABA in Autism Spectrum Disorders: Pilot Results from a Proton Magnetic Resonance Spectroscopy Study

Objectives: To measure the levels of glutamate, a major excitatory neurotransmitter; glutamine, a metabolite of glutamate; and γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter; in a pilot study of proton magnetic resonance spectroscopy (1H-MRS) findings in adolescents with Autism Spectrum Disorders (ASD). Methods: The subjects were assessed with the Autism Diagnostic Observation Schedule (ADOS), the Reading the Mind in the Eyes test (RMET) and the Social Responsiveness Scale (SRS). 1H-MRS measures of the anterior cingulate cortex were conducted using a Philips 3.0 T scanner. Results: To date, we have completed the data analysis on 18 subjects, 8 with ASD and 10 healthy control (HC) subjects. There was no significant difference between the combined glutamate + glutamine concentrations as measured by 1H-MRS (ASD = 12.0 ± 0.9 IU, HC = 11.6 ± 0.8 IU, p = 0.37). However, there was a higher than average glutamine level in the ASD group compared to healthy controls (ASD = 2.4 ± 0.2 IU, HC = 1.9 ± 0.3 IU, p = 0.01). This was accompanied by a trend toward lower GABA/Cr levels in the ASD group (ASD = 0.073 ± 0.010, HC = 0.082 ± 0.010, p = 0.06). Glutamine levels in the ACC were correlated positively with deficits of social cognition across groups (higher SRS, lower RMET scores). Those with higher glutamine levels made more errors when identifying emotions in the RMET task (r(10) = -0.77, p = 0.009), and also had more clinically significant scores on the SRS (r(10) = 0.87, p = 0.001). Conclusions: Our results present evidence that glutamine levels measured within the ACC region are higher for adolescent males with ASD than age-matched HC males, and signal that GABA levels may also be decreased in this region. These changes are correlated with deficits in social cognition

Syntheses, Characterization, Density Functional Theory Calculations, and Activity of Tridentate SNS Zinc Pincer Complexes Based on Bis-Imidazole or Bis-Triazole Precursors

A series of tridentate pincer ligands, each possessing two sulfur- and one nitrogen-donor functionalities (SNS), based on bis-imidazole or bis-triazole salts were metallated with ZnCl2 to give new tridentate SNS pincer zinc(II) complexes [(SNS)ZnCl]+. The zinc complexes serve as models for the zinc active site in liver alcohol dehydrogenase (LADH) and were characterized with single crystal X-ray diffraction, 1H, 13C, and HSQC NMR spectroscopies, electrospray mass spectrometry, and elemental analysis. The zinc complexes feature SNS donor atoms and pseudotetrahedral geometry about the zinc center, as is seen for liver alcohol dehydrogenase. The bond lengths and bond angles of the zinc complexes correlate well to those in horse LADH. The SNS ligand precursors were characterized with 1H, 13C, and HSQC NMR spectroscopies, elemental analysis, and cyclic voltammetry, and were found to be redox active. Gaussian calculations were performed and agree with the experimentally observed oxidation potentials for the pincer ligand precursors. The zinc complexes were screened for the reduction of electron-poor aldehydes in the presence of a hydrogen donor, 1-benzyl-1,4-dihydronicotinamide (BNAH), and it was determined that they enhance the reduction of electron-poor aldehydes. The SNS zinc pincer complexes with bis-triazole ligand precursors exhibit higher activity for the reduction of 4-nitrobenzaldehyde than do SNS zinc pincer complexes with bis-imidazole ligand precursors. Quantitative stoichiometric conversion was seen for the reduction of pyridine-2-carboxaldehyde via SNS zinc pincer complexes with either bis-imidazole or bis-triazole ligand precursors

Syntheses, characterization, density functional theory calculations, and activity of tridentate SNS zinc pincer complexes

A series of tridentate SNS ligand precursors were metallated with ZnCl2 to give new tridentate SNS pincer zinc complexes. The zinc complexes serve as models for the zinc active site in liver alcohol dehydrogenase (LADH) and were characterized with single crystal X-ray diffraction, 1H, 13C, and HSQC NMR spectroscopies and electrospray mass spectrometry. The bond lengths and bond angles of the zinc complexes correlate well to those in horse LADH. The zinc complexes feature SNS donor atoms and pseudotetrahedral geometry about the zinc center, as is seen for liver alcohol dehydrogenase. The SNS ligand precursors were characterized with 1H, 13C, and HSQC NMR spectroscopies and cyclic voltammetry, and were found to be redox active. Gaussian calculations were performed and agree quite well with the experimentally observed oxidation potential for the pincer ligand. The zinc complexes were screened for the reduction of electron poor aldehydes in the presence of a hydrogen donor, 1-benzyl-1,4-dihydronicotinamide (BNAH). The zinc complexes enhance the reduction of electron poor aldehydes. Density functional theory calculations were performed to better understand why the geometry about the zinc center is pseudo-tetrahedral rather than pseudo-square planar, which is seen for most pincer complexes. For the SNS tridentate pincer complexes, the data indicate that the pseudo-tetrahedral geometry was 43.8 kcal/mol more stable than the pseudo-square planar geometry. Density functional theory calculations were also performed on zinc complexes with monodentate ligands and the data indicate that the pseudo-tetrahedral geometry was 30.6 kcal/mol more stable than pseudo-square planar geometry. Overall, the relative stabilities of the pseudo-tetrahedral and pseudo-square planar systems are the same for this coordination environment whether the ligand set is a single tridentate SNS system or is broken into three separate units. The preference of a d10 Zn center to attain a tetrahedral local environment trumps any stabilization gained by removal of constraints within the ligand set

Acute Severe Pain Is a Common Consequence of Sexual Assault

Sexual assault (SA) is common, but the epidemiology of acute pain after SA has not previously been reported. We evaluated the severity and distribution of pain symptoms in the early aftermath of SA among women receiving sexual assault nurse examiner (SANE) care, and the treatment of pain by SANE nurses. Severe pain (≥7 on a 0–10 numeric rating scale) was reported by 53/83 women sexual assault survivors (64% [95% CI, 53%–74%]) at the time of SANE evaluation and 43/83 women (52% [95% CI, 41%–63%]) one week later. Pain in four or more body regions was reported by 44/83 women (53% [95% CI, 42%–64%]) at the time of initial evaluation and 49/83 women (59% [95% CI, 48%–70%]) at one week follow-up. Among survivors with severe pain at the time of initial post-assault evaluation, only 7/53 (13% [95% CI, 6%–26%]) received any pain medication at the time of initial SANE treatment. These findings suggest that pain is common in SA survivors in the early post-assault period, but rarely treated

Is dignity therapy feasible to enhance the end of life experience for people with motor neurone disease and their family carers?

Background: Development of interventions that address psychosocial and existential distress in people with motor neurone disease (MND) or that alleviate caregiver burden in MND family carers have often been suggested in the research literature. Dignity therapy, which was developed to reduce psychosocial and existential distress at the end of life, has been shown to benefit people dying of cancer and their families. These results may not be transferable to people with MND. The objectives of this study are to assess the feasibility, acceptability and potential effectiveness of dignity therapy to enhance the end of life experience for people with motor neurone disease and their family carers. Methods/design: This is a cross-sectional study utilizing a single treatment group and a pre/post test design. The study population will comprise fifty people diagnosed with MND and their nominated family carers. Primarily quantitative outcomes will be gathered through measures assessed at baseline and at approximately one week after the intervention. Outcomes for participants include hopefulness, spirituality and dignity. Outcomes for family carers include perceived caregiver burden, hopefulness and anxiety/depression. Feedback and satisfaction with the intervention will be gathered through a questionnaire. Discussion: This detailed research will explore if dignity therapy has the potential to enhance the end of life experience for people with MND and their family carers, and fill a gap for professionals who are called on to address the spiritual, existential and psychosocial needs of their MND patients and families

Heterozygous frameshift variants in HNRNPA2B1 cause early-onset oculopharyngeal muscular dystrophy

Missense variants in RNA-binding proteins (RBPs) underlie a spectrum of disease phenotypes, including amyotrophic lateral sclerosis, frontotemporal dementia, and inclusion body myopathy. Here, we present ten independent families with a severe, progressive muscular dystrophy, reminiscent of oculopharyngeal muscular dystrophy (OPMD) but of much earlier onset, caused by heterozygous frameshift variants in the RBP hnRNPA2/B1. All disease-causing frameshift mutations abolish the native stop codon and extend the reading frame, creating novel transcripts that escape nonsense-mediated decay and are translated to produce hnRNPA2/B1 protein with the same neomorphic C-terminal sequence. In contrast to previously reported disease-causing missense variants in HNRNPA2B1, these frameshift variants do not increase the propensity of hnRNPA2 protein to fibrillize. Rather, the frameshift variants have reduced affinity for the nuclear import receptor karyopherin β2, resulting in cytoplasmic accumulation of hnRNPA2 protein in cells and in animal models that recapitulate the human pathology. Thus, we expand the phenotypes associated with HNRNPA2B1 to include an early-onset form of OPMD caused by frameshift variants that alter its nucleocytoplasmic transport dynamics

Testing the relative sensitivity of 102 ecological variables as indicators of woodland condition in the New Forest, UK.

Forests globally are facing an increasing number of threats from modified disturbance regimes, novel stressors and changing environmental conditions. This has ultimately resulted in declines in the ecological condition of many forest and woodland ecosystems, leading to widespread tree mortality and stand dieback. Effective indicators of overall woodland ecological condition are therefore needed for environmental monitoring and to support management responses. To test the effectiveness of different variables that could potentially be used as indicators of woodland condition, 102 variables that describe woodland structure, composition, functioning, edaphic conditions and disturbance regimes were assessed along 12 replicate gradients of beech stand dieback. Results indicated that 35 variables differed significantly between at least two stages of the dieback gradient, indicating their sensitivity to stand dieback. Seven of these indicators related to woodland species composition, two to functional processes, 20 to structural features, four to edaphic conditions, and two to disturbance regimes. These results demonstrate that effective indicators can potentially be identified for each of the ecological categories. Effective composition indicators included species richness of ectomycorrhizal fungi, ground flora and epiphytic lichens; functional indicators were soil respiration rate and net nitrification rate; edaphic conditions included soil Na:Ca ratio, exchangeable sodium, total carbon, Ca:Al ratio; structural indicators included canopy openness, litter cover, sward height, and volume of deadwood, and for disturbance the indicator was Equus dung density. Other measures, such as shrub cover and species richness of carabid beetles and spiders, were not found to vary significantly along the dieback gradients, and were therefore not identified as effective indicators. These results demonstrate the value of gradient analysis for evaluating indicators of woodland condition, but also highlight the need for multi-site studies to identify indicators with widescale applicability

Quantifying sources of variability in infancy research using the infant-directed-speech preference

Psychological scientists have become increasingly concerned with issues related to methodology and replicability, and infancy researchers in particular face specific challenges related to replicability: For example, high-powered studies are difficult to conduct, testing conditions vary across labs, and different labs have access to different infant populations. Addressing these concerns, we report on a large-scale, multisite study aimed at (a) assessing the overall replicability of a single theoretically important phenomenon and (b) examining methodological, cultural, and developmental moderators. We focus on infants’ preference for infant-directed speech (IDS) over adult-directed speech (ADS). Stimuli of mothers speaking to their infants and to an adult in North American English were created using seminaturalistic laboratory-based audio recordings. Infants’ relative preference for IDS and ADS was assessed across 67 laboratories in North America, Europe, Australia, and Asia using the three common methods for measuring infants’ discrimination (head-turn preference, central fixation, and eye tracking). The overall meta-analytic effect size (Cohen’s d) was 0.35, 95% confidence interval = [0.29, 0.42], which was reliably above zero but smaller than the meta-analytic mean computed from previous literature (0.67). The IDS preference was significantly stronger in older children, in those children for whom the stimuli matched their native language and dialect, and in data from labs using the head-turn preference procedure. Together, these findings replicate the IDS preference but suggest that its magnitude is modulated by development, native-language experience, and testing procedure. (This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement No 798658.