Community established best practice recommendations for tephra studies-from collection through analysis.

Tephra is a unique volcanic product with an unparalleled role in understanding past eruptions, long-term behavior of volcanoes, and the effects of volcanism on climate and the environment. Tephra deposits also provide spatially widespread, high-resolution time-stratigraphic markers across a range of sedimentary settings and thus are used in numerous disciplines (e.g., volcanology, climate science, archaeology). Nonetheless, the study of tephra deposits is challenged by a lack of standardization that inhibits data integration across geographic regions and disciplines. We present comprehensive recommendations for tephra data gathering and reporting that were developed by the tephra science community to guide future investigators and to ensure that sufficient data are gathered for interoperability. Recommendations include standardized field and laboratory data collection, reporting and correlation guidance. These are organized as tabulated lists of key metadata with their definition and purpose. They are system independent and usable for template, tool, and database development. This standardized framework promotes consistent documentation and archiving, fosters interdisciplinary communication, and improves effectiveness of data sharing among diverse communities of researchers.

Knock-in models related to Alzheimer's disease: synaptic transmission, plaques and the role of microglia.

BACKGROUND: Microglia are active modulators of Alzheimer's disease but their role in relation to amyloid plaques and synaptic changes due to rising amyloid beta is unclear. We add novel findings concerning these relationships and investigate which of our previously reported results from transgenic mice can be validated in knock-in mice, in which overexpression and other artefacts of transgenic technology are avoided. METHODS: AppNL-F and AppNL-G-F knock-in mice expressing humanised amyloid beta with mutations in App that cause familial Alzheimer's disease were compared to wild type mice throughout life. In vitro approaches were used to understand microglial alterations at the genetic and protein levels and synaptic function and plasticity in CA1 hippocampal neurones, each in relationship to both age and stage of amyloid beta pathology. The contribution of microglia to neuronal function was further investigated by ablating microglia with CSF1R inhibitor PLX5622. RESULTS: Both App knock-in lines showed increased glutamate release probability prior to detection of plaques. Consistent with results in transgenic mice, this persisted throughout life in AppNL-F mice but was not evident in AppNL-G-F with sparse plaques. Unlike transgenic mice, loss of spontaneous excitatory activity only occurred at the latest stages, while no change could be detected in spontaneous inhibitory synaptic transmission or magnitude of long-term potentiation. Also, in contrast to transgenic mice, the microglial response in both App knock-in lines was delayed until a moderate plaque load developed. Surviving PLX5266-depleted microglia tended to be CD68-positive. Partial microglial ablation led to aged but not young wild type animals mimicking the increased glutamate release probability in App knock-ins and exacerbated the App knock-in phenotype. Complete ablation was less effective in altering synaptic function, while neither treatment altered plaque load. CONCLUSIONS: Increased glutamate release probability is similar across knock-in and transgenic mouse models of Alzheimer's disease, likely reflecting acute physiological effects of soluble amyloid beta. Microglia respond later to increased amyloid beta levels by proliferating and upregulating Cd68 and Trem2. Partial depletion of microglia suggests that, in wild type mice, alteration of surviving phagocytic microglia, rather than microglial loss, drives age-dependent effects on glutamate release that become exacerbated in Alzheimer's disease.

A revised AMS and tephra chronology for the Late Middle to Early Upper Paleolithic occupations of Ortvale Klde, Republic of Georgia.

The nature and timing of the shift from the Late Middle Paleolithic (LMP) to the Early Upper Paleolithic (EUP) varied geographically, temporally, and substantively across the Near East and Eurasia; however, the result of this process was the archaeological disappearance of Middle Paleolithic technologies across the length and breadth of their geographic distribution. Ortvale Klde rockshelter (Republic of Georgia) contains the most detailed LMP-EUP archaeological sequence in the Caucasus, an environmentally and topographically diverse region situated between southwest Asia and Europe. Tephrochronological investigations at the site reveal volcanic ash (tephra) from various volcanic sources and provide a tephrostratigraphy for the site that will facilitate future correlations in the region. We correlate one of the cryptotephra layers to the large, caldera-forming Nemrut Formation eruption (30,000 years ago) from Nemrut volcano in Turkey. We integrate this tephrochronological constraint with new radiocarbon dates and published ages in an OxCal Bayesian age model to produce a revised chronology for the site. This model increases the ages for the end of the LMP (∼47.5-44.2 ka cal BP) and appearance of the EUP (∼46.7-43.6 ka cal BP) at Ortvale Klde, which are earlier than those currently reported for other sites in the Caucasus but similar to estimates for specific sites in southwest Asia and eastern Europe. These data, coupled with archaeological, stratigraphic, and taphonomic observations, suggest that at Ortvale Klde, (1) the appearance of EUP technologies of bone and stone has no technological roots in the preceding LMP, (2) a LMP population vacuum likely preceded the appearance of these EUP technologies, and (3) the systematic combination of tephra correlations and absolute dating chronologies promises to substantially improve our inter-regional understanding of this critical time interval of human evolution and the potential interconnectedness of hominins at different sites.

The magnitude and impact of the 431 CE Tierra Blanca Joven eruption of Ilopango, El Salvador.

The Tierra Blanca Joven (TBJ) eruption from Ilopango volcano deposited thick ash over much of El Salvador when it was inhabited by the Maya, and rendered all areas within at least 80 km of the volcano uninhabitable for years to decades after the eruption. Nonetheless, the more widespread environmental and climatic impacts of this large eruption are not well known because the eruption magnitude and date are not well constrained. In this multifaceted study we have resolved the date of the eruption to 431 ± 2 CE by identifying the ash layer in a well-dated, high-resolution Greenland ice-core record that is >7,000 km from Ilopango; and calculated that between 37 and 82 km3 of magma was dispersed from an eruption coignimbrite column that rose to ∼45 km by modeling the deposit thickness using state-of-the-art tephra dispersal methods. Sulfate records from an array of ice cores suggest stratospheric injection of 14 ± 2 Tg S associated with the TBJ eruption, exceeding those of the historic eruption of Pinatubo in 1991. Based on these estimates it is likely that the TBJ eruption produced a cooling of around 0.5 °C for a few years after the eruption. The modeled dispersal and higher sulfate concentrations recorded in Antarctic ice cores imply that the cooling would have been more pronounced in the Southern Hemisphere. The new date confirms the eruption occurred within the Early Classic phase when Maya expanded across Central America.

Identification of GSK3186899/DDD853651 as a Preclinical Development Candidate for the Treatment of Visceral Leishmaniasis.

The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (1) for VL.

Insights Into the Different Effects of Food on Intestinal Secretion Using Magnetic Resonance Imaging.

BACKGROUND: Plant foods may stimulate intestinal secretion through chemicals designed to deter herbivores, including lactucins in lettuce and rhein in rhubarb. This may increase ileostomy output and induce diarrhoea in people with intact bowels. OBJECTIVE: We aimed to determine the effect of food on intestinal water content using Magnetic Resonance Imaging (MRI). DESIGN: A three period crossover trial of isocaloric meals in adults without bowel disorders. Meals: 2 slices white bread with 10 g butter; 300 g rhubarb with 60 mL lactose free cream; 300 g lettuce with 30 mL mayonnaise. PRIMARY OUTCOME: Area under curve (AUC) small bowel water content (SBWC) using MRI. SECONDARY OUTCOMES: ascending colon water content; T1 relaxation time of ascending colon (T1AC); gastric volume; visual analogue scales of bloating and satiety (0-100). MRI analysts were blinded. Scanned fasting and hourly to 180 min postprandial. Symptoms scored half-hourly. RESULTS: 9 female and 6 male subjects completed the study. AUC SBWC fell after bread but rose after lettuce and even more after rhubarb, difference from baseline being (Bread AUC -5662 (1209) ml.min vs Lettuce 3194 (1574) ml.min and Rhubarb 10586 (1629) ml.min (P < 0.01). Rhubarb induced a rise in T1AC but differences at 3 hours were not significant (P = 0.06). Gastric volume at T = 0 significantly was higher for both lettuce and rhubarb (571 ± 92 and 558 ± 89 mls) respectively compared to bread (314 ± 108 mls) (p < 0.0001). Symptom scores were higher for lettuce > rhubarb > bread. CONCLUSION: Lettuce and rhubarb meals increased intestinal water content, demonstrating how different foods can alter ileal flow and stool consistency.

Outcomes of early parent-child adrenocortical attunement in the high-risk offspring of depressed parents.

This study examined the impact of parent-child attunement of morning cortisol on parenting and child outcomes in dyads with and without parental depression. Participants included 142 parent-child dyads (3-5 years-old) who provided morning cortisol samples at Wave 1, and 98 dyads returned for the 3-year follow-up at Wave 2. Results indicated that for parents with a history of depression and for female children, stronger attunement predicted increases in parental hostility from Wave 1 to Wave 2. For females only, stronger attunement was related to children's depressive symptoms at Wave 1 and Wave 2. Stronger attunement was also associated with increases in children's depressive symptoms from Wave 1 to Wave 2, poorer psychosocial functioning at Wave 1, and ADHD symptoms at Wave 2. Findings highlight attunement as an important biological process related to parenting and child outcomes and suggest it may play a role in the intergenerational transmission of depression risk.

Stability and Predictive Validity of the Parent-Child Sleep Interactions Scale: A Longitudinal Study Among Preschoolers.

Little research has examined the processes underlying children's persistent sleep problems and links with later psychopathology. The current study examined the stability of parent-child sleep interactions as assessed with the parent-reported Parent-Child Sleep Interactions Scale (PSIS) and examined whether sleep interactions in preschool-age children predict sleep problems and psychiatric symptoms later in childhood. Participants included 108 preschool-age children (50% female) and their parents. Parents completed the PSIS when children were 3-5 years (T1) and again when they were 6-9 years (T2). The PSIS includes three subscales-Sleep Reinforcement (reassurance of child sleep behaviors), Sleep Conflict (parent-child conflict at bedtime), Sleep Dependence (difficulty going to sleep without parent)-and a total score. Higher scores indicate more problematic bedtime interactions. Children's sleep problems and psychiatric symptoms at T1 and T2 were assessed with a clinical interview. PSIS scores were moderately stable from T1 to T2, and the factor structure of the PSIS remained relatively consistent over time. Higher total PSIS scores at T1 predicted increases in children's sleep problems at T2. Higher PSIS Sleep Conflict scores at T1 predicted increases in oppositional defiant disorder symptoms at T2. Children with more sleep problems and higher PSIS Sleep Reinforcement scores at T1 showed increases in attention deficit/hyperactivity disorder, depressive, and anxiety symptoms at T2. These findings provide evidence for the predictive validity of the PSIS and highlight the importance of early parent-child sleep interactions in the development of sleep and psychiatric symptoms in childhood. Parent-child sleep interactions may serve as a useful target for interventions.

Design and Synthesis of Brain Penetrant Trypanocidal N-Myristoyltransferase Inhibitors.

N-Myristoyltransferase (NMT) represents a promising drug target within the parasitic protozoa Trypanosoma brucei (T. brucei), the causative agent for human African trypanosomiasis (HAT) or sleeping sickness. We have previously validated T. brucei NMT as a promising druggable target for the treatment of HAT in both stages 1 and 2 of the disease. We report on the use of the previously reported DDD85646 (1) as a starting point for the design of a class of potent, brain penetrant inhibitors of T. brucei NMT.

Listeria monocytogenes Replicate in Bone Marrow-Derived CD11c+ Cells but Not in Dendritic Cells Isolated from the Murine Gastrointestinal Tract.

Recent fate-mapping studies and gene-expression profiles suggest that commonly used protocols to generate bone marrow-derived cultured dendritic cells yield a heterogeneous mixture, including some CD11chi cells that may not have a bona fide counterpart in vivo. In this study, we provide further evidence of the discordance between ex vivo-isolated and in vitro-cultured CD11c+ cells by analyzing an additional phenotype, the ability to support cytosolic growth of the facultative intracellular bacterial pathogen Listeria monocytogenes Two days after foodborne infection of mice with GFP-expressing L. monocytogenes, a small percentage of CD103neg and CD103+ conventional dendritic cells (cDC) in the intestinal lamina propria and mesenteric lymph nodes were GFP+ However, in vitro infection of the same subsets of cells harvested from naive mice resulted in inefficient invasion by the bacteria (<0.1% of the inoculum). The few intracellular bacteria detected survived for only a few hours. In contrast, cultured CD103negCD11c+ cells induced by GM-CSF readily supported exponential growth of L. monocytogenes Flt3 ligand-induced cultures yielded CD103+CD11c+ cells that more closely resembled cDC, with only a modest level of L. monocytogenes replication. For both culture protocols, the longer the cells were maintained in vitro, the more readily they supported intracellular growth. The results of this study suggest that cDC are not a niche for intracellular growth of L. monocytogenes during intestinal infection of mice.

Parental depression and parent and child stress physiology: Moderation by parental hostility.

This study examined the moderating role of parental hostility on the associations between parental depression and the cortisol awakening response (CAR) and morning cortisol levels of both parents and children. 148 parents and 148 preschool-aged children provided salivary cortisol samples at waking, 30 and 45 min post-waking on two consecutive days. Parental depression was assessed using a clinical interview, and parental hostility was assessed using an observational parent-child interaction task. Results indicated that the combination of parental lifetime depression and high parental hostility was associated with lower morning cortisol levels in both parents and children. This interactive effect was present in children regardless of their exposure to parental depression. In addition, the combination of higher levels of parents' current depressive symptoms and parental hostility was associated with lower parent CAR. Lastly, parents' and children's lower morning cortisol levels were associated with parent-reported child externalizing symptoms. Findings demonstrate that parents and children have similar stress system functioning related to parental depression and the parenting context, as well as children's behavioral problems, which may play a role in the intergenerational transmission of risk for psychopathology.

Discovery and Optimization of 5-Amino-1,2,3-triazole-4-carboxamide Series against Trypanosoma cruzi.

Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is the most common cause of cardiac-related deaths in endemic regions of Latin America. There is an urgent need for new safer treatments because current standard therapeutic options, benznidazole and nifurtimox, have significant side effects and are only effective in the acute phase of the infection with limited efficacy in the chronic phase. Phenotypic high content screening against the intracellular parasite in infected VERO cells was used to identify a novel hit series of 5-amino-1,2,3-triazole-4-carboxamides (ATC). Optimization of the ATC series gave improvements in potency, aqueous solubility, and metabolic stability, which combined to give significant improvements in oral exposure. Mitigation of a potential Ames and hERG liability ultimately led to two promising compounds, one of which demonstrated significant suppression of parasite burden in a mouse model of Chagas' disease.

Exacerbation of alopecia areata: A possible complication of sodium tetradecyl sulphate foam sclerotherapy treatment for varicose veins.

A 40-year-old woman with a history of alopecia areata related to stress or hormonal changes was treated for bilateral primary symptomatic varicose veins (CEAP clinical score C2S) of pelvic origin, using a staged procedure. Her first procedure entailed pelvic vein embolisation of three pelvic veins using 14 coils and including foam sclerotherapy of the tributaries, using 3% sodium tetradecyl sulphate. Following this procedure, she had an exacerbation of alopecia areata with some moderate shedding of hair. Subsequently, she underwent endovenous laser ablation under local anaesthetic without incident. Seven months after the pelvic vein embolisation, she underwent foam sclerotherapy of leg and labial varicose veins using sodium tetradecyl sulphate. Two days following this procedure, she had a severe exacerbation of alopecia areata with gross shedding of hair. These two episodes of exacerbation of alopecia areata appear to be associated with sodium tetradecyl sulphate foam sclerotherapy of veins.

Parent-child adrenocortical concordance in early childhood: The moderating role of parental depression and child temperament.

This study examined biological concordance between parent and child morning cortisol and whether parent and child-level risk factors for depression moderated this association. Participants included 136 parents and their preschool-aged children. Parents and children obtained salivary cortisol samples at waking, and 30 and 45min post-waking across two days to assess the cortisol awakening response. Parental lifetime depression was assessed using a clinical interview and child temperamental negative emotionality (NE) and positive emotionality (PE) were assessed using an observational laboratory-based assessment. Results indicated significant parent-child concordance between both average cortisol levels and cortisol fluctuations across waking. Greater concordance was observed for dyads with parents with a lifetime history of depression and with children high in NE and PE. These parent- and child-level moderators were associated with different indices of concordance. Findings highlight the need to examine the role of parent and child risk factors for depression on parent-child adrenocortical concordance.

Magma reservoir dynamics at Toba caldera, Indonesia, recorded by oxygen isotope zoning in quartz.

Quartz is a common phase in high-silica igneous rocks and is resistant to post-eruptive alteration, thus offering a reliable record of magmatic processes in silicic magma systems. Here we employ the 75 ka Toba super-eruption as a case study to show that quartz can resolve late-stage temporal changes in magmatic δ18O values. Overall, Toba quartz crystals exhibit comparatively high δ18O values, up to 10.2‰, due to magma residence within, and assimilation of, local granite basement. However, some 40% of the analysed quartz crystals display a decrease in δ18O values in outermost growth zones compared to their cores, with values as low as 6.7‰ (maximum ∆core-rim = 1.8‰). These lower values are consistent with the limited zircon record available for Toba, and the crystallisation history of Toba quartz traces an influx of a low-δ18O component into the magma reservoir just prior to eruption. Here we argue that this late-stage low-δ18O component is derived from hydrothermally-altered roof material. Our study demonstrates that quartz isotope stratigraphy can resolve magmatic events that may remain undetected by whole-rock or zircon isotope studies, and that assimilation of altered roof material may represent a viable eruption trigger in large Toba-style magmatic systems.

Children's cortisol responses to a social evaluative laboratory stressor from early to middle childhood.

This study examined the stability of children's cortisol responses to a social evaluative laboratory stressor from early to middle childhood. Ninety-six children (51 males) completed stress-inducing laboratory tasks and provided five salivary cortisol samples in early (W1) and middle (W2) childhood. Although W1 cortisol responses did not predict W2 cortisol responses, children's cortisol responses demonstrated change: compared to their W1 cortisol responses, children's W2 cortisol responses demonstrated an increased slope and more negative quadratic curvature. Furthermore, child psychiatric symptoms at W1 moderated the stability of children's cortisol responses. Children with fewer preschool psychiatric symptoms demonstrated greater inter-individual and intra-individual stability, whereas children with higher preschool psychiatric symptoms and comorbidity demonstrated systematic inter-individual and intra-individual instability in cortisol responses over time. Findings suggest a developmental shift toward increasing cortisol stress responses from early to middle childhood and highlight preschool psychopathology as a moderator of stability in children's cortisol responses over time.

Physiological and Behavioral Vulnerability Markers Increase Risk to Early Life Stress in Preschool-Aged Children.

The study examined whether child physiological (cortisol reactivity) and behavioral (negative emotionality) risk factors moderate associations between the early rearing environment, as measured by child exposure to maternal depression and stressful life events, and preschool psychopathology and psychosocial functioning. A sample of 156 preschool-aged children (77 boys, 79 girls; age M = 49.80 months, SD = 9.57, range: 36-71) participated in an observational assessment of temperament and was exposed to a stress-inducing laboratory task, during which we obtained five salivary cortisol samples. Parents completed clinical interviews to assess child and parent psychopathology and stressful life events. Results indicated that the combination of a blunted pattern of cortisol reactivity and recent stressful life events was associated with higher levels of preschoolers' externalizing symptoms and lower psychosocial functioning. In addition, greater life stress was associated with higher levels of preschoolers' internalizing symptoms. Lastly, children with high levels of negative emotionality and who were exposed to maternal depression had the lowest social competence. Our findings highlight the critical role of the early environment, particularly for children with identified risk factors, and add to our understanding of pathways involved in early emerging psychopathology and impairment.

Preschool irritability predicts child psychopathology, functional impairment, and service use at age nine.

BACKGROUND: Little is known about the predictive validity and clinical significance of chronic irritability during early childhood. This prospective, longitudinal study examined associations of preschool chronic irritability with psychiatric disorders, functional impairment, and service use at age nine in a large community sample. METHODS: Four hundred and forty-six children were assessed at age three and again at age nine. Child psychopathology and functional impairment were assessed at age three with the Preschool Age Psychiatric Assessment (PAPA) with parents and at age nine with the Kiddie-Schedule of Affective Disorders and Schizophrenia (K-SADS) with parents and children. Items from the PAPA were used to create a dimensional measure of chronic irritability at age three. At age nine, mothers, fathers, and youth completed the Child Depression Inventory (CDI) and the Screen for Anxiety Related Disorders (SCARED). RESULTS: Chronic irritability at age three predicted any current and lifetime anxiety disorders at age nine, current and lifetime generalized anxiety disorder, and current separation anxiety, after controlling for baseline anxiety disorders. In addition, preschool irritability predicted increases in anxiety and disruptive behavior disorder symptoms on the K-SADS, and maternal and paternal reports of depressive and anxiety symptoms on the CDI and SCARED. Lastly, preschool irritability predicted greater functional impairment and outpatient treatment use, even after controlling for all psychiatric disorders at baseline. CONCLUSIONS: Findings underscore the central role of irritability in developmental psychopathology and support the importance of early detection and interventions targeting preschool irritability.

"It takes two": the interaction between parenting and child temperament on parents' stress physiology.

The biological basis of parenting has received recent attention given the profound effects of parenting on both child and parent health outcomes. This study examined the moderating role of child temperamental effortful control on the association between observed parental hostility and parents' cortisol awakening response (CAR), a critical index of stress system functioning. Participants included 149 parents and their preschool-aged children. Parents obtained salivary cortisol samples at waking, and 30 and 45 min post-waking across two consecutive days. Parental hostility was assessed during an observational parent-child interaction task, and child effortful control was assessed using parent report. Parental hostility was associated with parents' lower cortisol levels at 30 and 45 min post-waking and lower CAR. Moreover, results demonstrated an interaction between parenting and child temperament on parent CAR. The findings highlight the need to examine the interplay between parenting and child temperament on parents' stress physiology.