Expression and distribution of EPHA4 and Ephrin A3 in Aohan fine-wool sheep skin

The objective of this study was to identify the expression and distribution of EPHA4 and Ephrin A3 genes in the development and morphogenesis of hair follicles in fine-wool sheep. The results could lay a theoretical basis for understanding the molecular mechanism that regulates hair follicle development. The skin of Aohan fine-wool sheep at different developmental stages (embryonic day 90, E90d, and 120, E120d, and postnatal day 1, B1d, and 30, B30d) were selected. Real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry were used to study the levels of mRNA and proteins, respectively. The RT-qPCR results showed that the mRNA expression level of EPHA4 at B1d was significantly lower than at E120d (p<0.01). The expression of Ephrin A3 at E120d was significantly higher than that at E90d and B1d (p<0.01). Immunohistochemical detection results showed that the level and localisation of EPHA4 and Ephrin A3 proteins had spatial and temporal specificity. EPHA4 expression in dermal papilla cells might be important for inducing Aohan fine-hair follicle regeneration and for controlling the properties of the hair. Ephrin A3 might play an important role in the redifferentiation of secondary hair follicles and might also be involved in the inhibition of apoptosis-related gene expression in hair follicles. The Ephrin A3 signalling pathway might accelerate the growth of fine-hair follicles and increase the density of hair follicles.

Measuring Human Rights Abuse from Access to Information Requests

Existing measures of human rights abuses are often only available at the country-year level. Several more fine-grained measures exhibit spatio-temporal inaccuracies or reporting biases due to the primary sources upon which they rely. To address these challenges, and to increase the diversity of available human rights measures more generally, this study provides the first quantitative effort to measure human rights abuses from textual records of citizen-government interactions. Using a dataset encompassing over 1.5 million access-to-information (ATI) requests made to the Mexican federal government from June 2003 onward, supervised classification is used to identify the subset of these requests that pertain to human rights abuses of various types. The results from this supervised machine learning exercise are validated against (i) gold standard ATI requests pertaining to past human rights abuses in Mexico and (ii) several accepted external measures of sub-national and sub-annual human rights abuses. In doing so, we demonstrate that the measurement of human rights abuses from citizen-submitted ATI request texts can provide measures of human rights abuse that exhibit both high validity and notable spatio-temporal specificity, relative to existent human rights datasets and variables.

Improving spatial data in health geographics: a practical approach for testing data to measure children’s physical activity and food environments using Google Street View

Background Geographic information systems (GIS) are often used to examine the association between both physical activity and nutrition environments, and children’s health. It is often assumed that geospatial datasets are accurate and complete. Furthermore, GIS datasets regularly lack metadata on the temporal specificity. Data is usually provided ‘as is’, and therefore may be unsuitable for retrospective or longitudinal studies of health outcomes. In this paper we outline a practical approach to both fill gaps in geospatial datasets, and to test their temporal validity. This approach is applied to both district council and open-source datasets in the Taranaki region of Aotearoa New Zealand. Methods We used the ‘streetview’ python script to download historic Google Street View (GSV) images taken between 2012 and 2016 across specific locations in the Taranaki region. Images were reviewed and relevant features were incorporated into GIS datasets. Results A total of 5166 coordinates with environmental features missing from council datasets were identified. The temporal validity of 402 (49%) environmental features was able to be confirmed from council dataset considered to be ‘complete’. A total of 664 (55%) food outlets were identified and temporally validated. Conclusions Our research indicates that geospatial datasets are not always complete or temporally valid. We have outlined an approach to test the sensitivity and specificity of GIS datasets using GSV images. A substantial number of features were identified, highlighting the limitations of many GIS datasets.

Shifts in growth, but not differentiation, foreshadow the formation of exaggerated forms under chicken domestication

Domestication provides an outstanding opportunity for biologists to explore the underpinnings of organismal diversification. In domesticated animals, selective breeding for exaggerated traits is expected to override genetic correlations that normally modulate phenotypic variation in nature. Whether this strong directional selection affects the sequence of tightly synchronized events by which organisms arise (ontogeny) is often overlooked. To address this concern, we compared the ontogeny of the red junglefowl (RJF) ( Gallus gallus ) to four conspecific lineages that underwent selection for traits of economic or ornamental value to humans. Trait differentiation sequences in embryos of these chicken breeds generally resembled the representative ancestral condition in the RJF, thus revealing that early ontogeny remains highly canalized even during evolution under domestication. This key finding substantiates that the genetic cost of domestication does not necessarily compromise early ontogenetic steps that ensure the production of viable offspring. Instead, disproportionate beak and limb growth (allometry) towards the end of ontogeny better explained phenotypes linked to intense selection for industrial-scale production over the last 100 years. Illuminating the spatial and temporal specificity of development is foundational to the enhancement of chicken breeds, as well as to ongoing research on the origins of phenotypic variation in wild avian species.

“Ready for What?”: Timing and Speculation in Alzheimer’s Disease Drug Development

“Readiness cohorts” are an innovation in clinical trial design to tackle the scarcity of time and people in drug studies. This has emerged in response to the challenges of recruiting the “right” research participants at the “right time” in the context of precision medicine. In this paper, we consider how the achievement of “readiness” aligns temporalities, biologies, and market processes of pharmaceutical innovation: how the promise of “willing bodies” in research emerges in relation to intertwined economic and biological time imperatives. Drawing on long-term engagement with the field of Alzheimer’s disease prevention and interviews with researchers from academia and the pharmaceutical industry, we describe the discursive construction and practical arrangement of readiness. This paper contributes to understandings of temporal specificity, or “timing,” within prevention research and casts critical light on the way this specificity—the threshold for “trial readiness”—relates to an opaque and highly speculative drug development pipeline. Extending the study of biomedical potential, as that which holds promise but may not yet exist, we consider how absences operate in adaptive trials. By highlighting these absences (“ready for what?”), we outline an opportunity for socio-ethical research to intervene in the speculative gaps of drug development.

Temporal specificity of abnormal neural oscillations during phonatory events in Laryngeal Dystonia

Laryngeal Dystonia is a debilitating disorder of voicing in which the laryngeal muscles are intermittently in spasm resulting in involuntary interruptions during speech. The central pathophysiology of laryngeal dystonia, underlying computational impairments in vocal motor control, remains poorly understood. Although prior imaging studies have found aberrant activity in the central nervous system during phonation in patients with laryngeal dystonia, it is not known at what timepoints during phonation these abnormalities emerge and what function may be impaired. To investigate this question, we recruited 22 adductor laryngeal dystonia patients (15 female, age range = 28.83-72.46 years) and 18 controls (8 female, age range = 27.40-71.34 years). We leveraged the fine temporal resolution of magnetoencephalography to monitor neural activity around glottal movement onset, subsequent voice onset and after the onset of pitch feedback perturbations. We examined event-related beta-band (12-30 Hz) and high-gamma band (65-150 Hz) neural oscillations. Prior to glottal movement onset, we observed abnormal frontoparietal motor preparatory activity. After glottal movement onset, we observed abnormal activity in somatosensory cortex persisting through voice onset. Prior to voice onset and continuing after, we also observed abnormal activity in the auditory cortex and the cerebellum. After pitch feedback perturbation onset, we observed no differences between controls and patients in their behavioural responses to the perturbation. But in patients, we did find abnormal activity in brain regions thought to be involved in the auditory feedback control of vocal pitch (premotor, motor, somatosensory and auditory cortices). Our study results confirm the abnormal processing of somatosensory feedback that has been seen in other studies. However, there were several remarkable findings in our study. First, patients have impaired vocal motor activity even before glottal movement onset, suggesting abnormal movement preparation. These results are significant because: (i) they occur before movement onset, abnormalities in patients cannot be ascribed to deficits in vocal performance, and (ii) they show that neural abnormalities in laryngeal dystonia are more than just abnormal responses to sensory feedback during phonation as has been hypothesised in some previous studies. Second, abnormal auditory cortical activity in patients begins even before voice onset, suggesting abnormalities in setting up auditory predictions before the arrival of auditory feedback at voice onset. Generally, activation abnormalities identified in key brain regions within the speech motor network around various phonation events not only provide temporal specificity to neuroimaging phenotypes in laryngeal dystonia but also may serve as potential therapeutic targets for neuromodulation.

Tissue culture and biological time: Alexis Carrel, Henri Bergson and the plasticity of living matter

Taking the early tissue culture experiments of Alexis Carrel in the 1910s–1930s as its example, the article explores the relationship between advances in biotechnological control over living matter and a holistic ontology of life, which stresses the temporal specificity of living things. With reference to Henri Bergson, Carrel argued that physiological time depends on an organism’s relationship to its milieu. By developing a laboratory apparatus and culture media, new objects of investigation could be made to live outside the organism and be brought to behave in novel temporal ways. In difference to recent biotechnological advances, like for example genome editing, which seek to ‘engineer’ living organisms by rebuilding them from their DNA up, then, early twentieth century interventionist laboratory practices were often linked to an understanding that biological plasticity results from organismic complexity and interactions between organism and milieu. These notions contributed to shaping laboratory apparatuses and techniques; they also helped to establish an understanding of environmental control that would allow for the production of novel ‘living things’.

MEYE: Web-app for translational and real-time pupillometry

Pupil dynamics alterations have been found in patients affected by a variety of neuropsychiatric conditions, including autism. Studies in mouse models have used pupillometry for phenotypic assessment and as a proxy for arousal. Both in mice and humans, pupillometry is non-invasive and allows for longitudinal experiments supporting temporal specificity, however its measure requires dedicated setups. Here, we introduce a Convolutional Neural Network that performs on-line pupillometry in both mice and humans in a web app format. This solution dramatically simplifies the usage of the tool for non-specialist and non-technical operators. Because a modern web browser is the only software requirement, this choice is of great interest given its easy deployment and set-up time reduction. The tested model performances indicate that the tool is sensitive enough to detect both spontaneous and evoked pupillary changes, and its output is comparable with state-of-the-art commercial devices.

The Kinase Specificity of Protein Kinase Inhibitor Peptide

G-protein-coupled-receptor (GPCR) signaling is exquisitely controlled to achieve spatial and temporal specificity. The endogenous protein kinase inhibitor peptide (PKI) confines the spatial and temporal spread of the activity of protein kinase A (PKA), which integrates inputs from three major types of GPCRs. Despite its wide usage as a pharmaceutical inhibitor of PKA, it was unclear whether PKI only inhibits PKA activity. Here, the effects of PKI on 55 mouse kinases were tested in in vitro assays. We found that in addition to inhibiting PKA activity, both PKI (6–22) amide and full-length PKIα facilitated the activation of multiple isoforms of protein kinase C (PKC), albeit at much higher concentrations than necessary to inhibit PKA. Thus, our results call for appropriate interpretation of experimental results using PKI as a pharmaceutical agent. Furthermore, our study lays the foundation to explore the potential functions of PKI in regulating PKC activity and in coordinating PKC and PKA activities.

The kinase specificity of protein kinase inhibitor peptide (PKI)

G-protein-coupled-receptor (GPCR) signaling is exquisitely controlled to achieve spatial and temporal specificity. The endogenous protein kinase inhibitor peptide (PKI) confines the spatial and temporal spread of the activity of protein kinase A (PKA), which integrates inputs from three major types of GPCRs. Despite its wide usage as a pharmaceutical inhibitor of PKA, it was unclear whether PKI only inhibits PKA activity. Here, the effects of PKI on 55 mouse kinases were tested in in vitro assays. We found that in addition to inhibiting PKA activity, both PKI (6-22) amide and full-length PKIα facilitated the activation of multiple isoforms of protein kinase C (PKC), albeit at much higher concentrations than necessary to inhibit PKA. Thus, our results call for appropriate interpretation of experimental results using PKI as a pharmaceutical agent. Furthermore, our study lays the foundation to explore the potential functions of PKI in regulating PKC activity and in coordinating PKC and PKA activities.