Association between hippocampal structure and serum Brain-Derived Neurotrophic Factor (BDNF) in healthy adults: A registered report.

The hippocampus is a highly plastic brain structure supporting functions central to human cognition. Morphological changes in the hippocampus have been implicated in development, aging, as well as in a broad range of neurological and psychiatric disorders. A growing body of research suggests that hippocampal plasticity is closely linked to the actions of brain-derived neurotrophic factor (BDNF). However, evidence on the relationship between hippocampal volume (HCV) and peripheral BDNF levels is scarce and limited to elderly and patient populations. Further, despite evidence that BDNF expression differs throughout the hippocampus and is implicated in adult neurogenesis specifically in the dentate gyrus, no study has so far related peripheral BDNF levels to the volumes of individual hippocampal subfields. Besides its clinical implications, BDNF-facilitated hippocampal plasticity plays an important role in regulating cognitive and affective processes. In the current registered report, we investigated how serum BDNF (sBDNF) levels relate to volumes of the hippocampal formation and its subfields in a large sample of healthy adults (N = 279, 160 f) with a broad age range (20-55 years, mean 40.5) recruited in the context of the ReSource Project. We related HCV to basal sBDNF and, in a subsample (n = 103, 57 f), to acute stress-reactive change in sBDNF. We further tested the role of age as a moderator of both associations. Contrary to our hypotheses, neither basal sBDNF levels nor stress-reactive sBDNF change were associated with total HCV or volume of the dentate gyrus/cornu ammonis 4 (DG/CA4) subfield. We also found no evidence for a moderating effect of age on any of these associations. Our null results provide a first point of reference on the relationship between sBDNF and HCV in healthy mid-age, in contrast to patient or aging populations. We suggest that sBDNF levels have limited predictive value for morphological differences of the hippocampal structure when notable challenge to its neuronal integrity or to neurotrophic capacity is absent.

Crop production in the USA is frequently limited by a lack of pollinators.

Most of the world's crops depend on pollinators, so declines in both managed and wild bees raise concerns about food security. However, the degree to which insect pollination is actually limiting current crop production is poorly understood, as is the role of wild species (as opposed to managed honeybees) in pollinating crops, particularly in intensive production areas. We established a nationwide study to assess the extent of pollinator limitation in seven crops at 131 locations situated across major crop-producing areas of the USA. We found that five out of seven crops showed evidence of pollinator limitation. Wild bees and honeybees provided comparable amounts of pollination for most crops, even in agriculturally intensive regions. We estimated the nationwide annual production value of wild pollinators to the seven crops we studied at over $1.5 billion; the value of wild bee pollination of all pollinator-dependent crops would be much greater. Our findings show that pollinator declines could translate directly into decreased yields or production for most of the crops studied, and that wild species contribute substantially to pollination of most study crops in major crop-producing regions.

The Effect of Nest Box Distribution on Sustainable Propagation of Osmia lignaria (Hymenoptera: Megachilidae) in Commercial Tart Cherry Orchards.

The blue orchard bee, Osmia lignaria (Say), is a solitary bee that is an excellent pollinator of tree fruit orchards. Due to the annual rising costs of honey bee hive rentals, many orchardists are eager to develop management tools and practices to support O. lignaria as an alternative pollinator. Establishing O. lignaria pollination as a sustainable industry requires careful consideration of both bee and orchard management. Here, we test the effect of artificial nest box distribution on in-orchard propagation of O. lignaria in Utah commercial tart cherry orchards. Two nest box distributions were compared across three paired, 1.2-ha plots. One distribution, traditionally employed by O. lignaria consultants, included a centrally located tote for mass-nesting with smaller, surrounding 'satellite' nest boxes at orchard margins. The other distribution was composed of smaller, more equally distributed nest boxes throughout the 1.2-ha plots. Significantly higher propagation of O. lignaria was observed in the latter nest box distribution, although all treatments resulted in bee return exceeding the number of bees initially released. These findings provide support for the use of O. lignaria in tart cherry orchards, and demonstrate how simple changes to bee set-up and management can influence propagation efforts.

Semiautomated quantitative image analysis of glomerular immunohistochemistry markers desmin, vimentin, podocin, synaptopodin and WT-1 in acute and chronic rat kidney disease models.

Five different glomerular immunohistochemistry markers were evaluated and compared in four different acute and chronic rat kidney disease models. Progression of glomerular or podocyte damage was shown in the puromycin aminonucleoside nephrosis (PAN) and Zucker fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rat model. Progression and prevention of glomerular damage was demonstrated in the Zucker diabetic fatty (ZDF) and Dahl salt-sensitive (Dahl SS) rat. Immunohistochemistry was performed for desmin, vimentin, podocin, synaptopodin and Wilms tumor protein-1 (WT-1), and evaluation of glomerular immunohistochemistry markers was done by semiautomated quantitative image analysis. We found desmin and WT-1 as the most sensitive markers for podocyte damage in both acute and chronic glomerular damage followed by vimentin, podocin and synaptopodin. We were able to demonstrate that early podocyte damage as shown by increased desmin and vimentin staining together with either a phenotypic podocyte change or podocyte loss (reduced numbers of WT-1-stained podocytes) drives the progression of glomerular damage. This is followed by a reduction in podocyte-specific proteins such as podocin and synaptopodin. Our report describes the different sensitivity of glomerular or podocyte markers and gives future guidance for the selection of the most sensitive markers for efficacy testing of new drugs as well as for the selection of tissue-based toxicity markers for glomerular or podocyte injury. In addition to functional clinical chemistry markers, desmin and WT-1 immunohistochemistry offers reliable and valuable data on the morphologic state of podocytes.

Global taxonomic, functional, and phylogenetic diversity of bees in apple orchards.

An essential prerequisite to safeguard pollinator species is characterisation of the multifaceted diversity of crop pollinators and identification of the drivers of pollinator community changes across biogeographical gradients. The extent to which intensive agriculture is associated with the homogenisation of biological communities at large spatial scales remains poorly understood. In this study, we investigated diversity drivers for 644 bee species/morphospecies in 177 commercial apple orchards across 33 countries and four global biogeographical biomes. Our findings reveal significant taxonomic dissimilarity among biogeographical zones. Interestingly, despite this dissimilarity, species from different zones share similar higher-level phylogenetic groups and similar ecological and behavioural traits (i.e. functional traits), likely due to habitat filtering caused by perennial monoculture systems managed intensively for crop production. Honey bee species dominated orchard communities, while other managed/manageable and wild species were collected in lower numbers. Moreover, the presence of herbaceous, uncultivated open areas and organic management practices were associated with increased wild bee diversity. Overall, our study sheds light on the importance of large-scale analyses contributing to the emerging fields of functional and phylogenetic diversity, which can be related to ecosystem function to promote biodiversity as a key asset in agroecosystems in the face of global change pressures.

Monitoring Cyp2b10 mRNA expression at cessation of 2-year carcinogenesis bioassay in mouse liver provides evidence for a carcinogenic mechanism devoid of human relevance: the dalcetrapib experience.

INTRODUCTION: Dalcetrapib is a cholesteryl ester transfer protein (CETP) modulator in clinical assessment for cardiovascular outcome benefits. In compliance with regulatory requirements, dalcetrapib was evaluated in rodent 2-year carcinogenesis bioassays. In the mouse bioassay, male mice demonstrated increased liver weight and statistically increased incidences of hepatocellular adenoma/carcinoma. Hepatic cytochrome p450 (Cyp) 2b10 mRNA induction and increased Cyp2b10 enzyme activity signify activation of hepatic nuclear receptor constitutive androstane receptor (CAR), a widely established promoter of rodent-specific hepatic tumors. We therefore monitored hepatic Cyp2b10 mRNA and its enzyme activity in a subset of dalcetrapib-treated male mice from the bioassay. METHODS: Liver samples were obtained from ~1/3 of male mice from each dose group including vehicle-controls (mean and earliest study day of death 678 and 459 respectively). Quantitative real time PCR (qRT-PCR) was performed to determine Cyp2b10 mRNA expression and Cyp1a-, Cyp2b10- and Cyp3a-selective activities were monitored. RESULTS: Cyp2b10 mRNA was strongly induced by dalcetrapib with an expected wide inter-individual variation (5-1421-fold). Group average fold-induction versus vehicle-controls showed a dose-related increase from 48-fold (250mg/kg/day) to 160-fold (750mg/kg/day), which declined slightly at 2000mg/kg/day (97-fold). Cyp enzyme activities showed approximate doubling of total Cyp P450 content per milligram protein and a 9-fold increase in Cyp2b10-selective pentoxyresorufin O-dealkylase activity (750mg/kg/day). DISCUSSION: These data from hepatic Cyp2b10 monitoring are strongly suggestive of CAR activation by dalcetrapib, a mechanism devoid of relevance towards hepatocarcinogenesis in humans; results show feasibility of Cyp2b10 as a surrogate marker for this mechanism at cessation of a carcinogenesis bioassay.

Investigating the impact of distinct contemplative mental trainings on daily life stress, thoughts and affect-Evidence from a nine-month longitudinal ecological momentary assessment study.

Mindfulness-based mental training interventions have become a popular means to alleviate stress and stress-associated health risks. Previous scientific investigations emphasize the importance of exploring the effects of such interventions in naturalistic settings to evaluate their implementation into daily life. Therefore, the current study examined the effects of three distinct mental training modules on a range of measures of daily life experience in the scope of the ReSource Project, a 9-month longitudinal mental training study comparing modules targeting attention and interoception (Presence), socio-affective (Affect) or socio-cognitive abilities (Perspective). We used ecological momentary assessment (EMA) to repeatedly probe levels of stress and stress-coping efficacy combined with stress-reactive cortisol levels, and further explored arousal, affective states, and thought patterns in the daily lives of 289 healthy adults (172 women; 20-55 years). We found increased presence-focused thought and heightened arousal after a training duration of 3-6 months, independent of the type of prior training. Increased coping efficacy emerged specifically after socio-cognitive Perspective training, following 6-9 months of training duration. No training effects were found for subjective stress, stress-reactive cortisol levels, or daily life affect. Our findings corroborate and add ecological validity to previous ReSource findings by showing that they replicate in participants' everyday environment. Regarding endocrine and subjective stress markers, our results suggest caution in generalizing acute laboratory findings to individuals' everyday routines. Overall, the current study provides substantiated insights into how cultivating one's mind through contemplative mental training translates to daily life experience, enhances stress-coping, and may ultimately aide in maintaining health.

An In-Depth Analysis of Brain and Spine Neuroimaging in Children with Abusive Head Trauma: Beyond the Classic Imaging Findings.

BACKGROUND AND PURPOSE: Abusive head trauma is the leading cause of morbidity and mortality in young children. Radiology provides valuable information for this challenging diagnosis, but no single neuroimaging finding is independently diagnostic of abusive head trauma. Our purposes were to describe the prevalence of brain and spine neuroimaging findings and to analyze the association of neuroimaging findings with clinical factors to determine which neuroimaging findings may be used as prognostic indicators. MATERIALS AND METHODS: Children with a confirmed abusive head trauma diagnosis between January 2018 to February 2021 were included in this single-center retrospective study. Patient demographics, survival, Glasgow Coma Scale score on admission, length of hospital stay, and intensive care unit stay were examined. Brain neuroimaging findings were categorized as classic and nonclassic findings. Spine MRIs were also assessed for spinal ligamentous injury, compression fracture, and hemorrhage. The χ2 test or the Wilcoxon rank-sum test was used for the analysis. RESULTS: One hundred two children (male/female ratio: 75:27; average age, 9.49; range, 0.27-53.8 months) were included. Subdural hematoma was the most common (83.3%) classic neuroimaging finding. Bridging vein thrombosis was the most common (30.4%) nonclassic neuroimaging finding. Spinal ligamentous injury was seen in 23/49 patients. Hypoxic-ischemic injury was significantly higher in deceased children (P = .0001). The Glasgow Coma Scale score was lower if hypoxic-ischemic injury (P < .0001) or spinal ligamentous injury were present (P = .017). The length of hospital stay was longer if intraventricular hemorrhage (P = .04), diffuse axonal injury (P = .017), hypoxic-ischemic injury (P = .001), or arterial stroke (P = .0003) was present. The intensive care unit stay was longer if intraventricular hemorrhage (P = .02), diffuse axonal injury (P = .01), hypoxic-ischemic injury (P < .0001), or spinal ligamentous injury (P = .03) was present. CONCLUSIONS: Our results may suggest that a combination of intraventricular hemorrhage, diffuse axonal injury, hypoxic-ischemic injury, arterial stroke, and/or spinal ligamentous injury on neuroimaging at presentation may be used as potential poor prognostic indicators in children with abusive head trauma.

Comprehensive assessment of the photomutagenicity, photogenotoxicity and photo(cyto)toxicity of azulene.

The polycyclic aromatic hydrocarbon azulene and its naturally occurring derivative guaiazulene (1,4-dimethyl-7-isopropylazulene) are known to absorb light in the UV-vis region of the spectrum. Both compounds were reported to be mutagenic in the Salmonella typhimurium bacterial mutagenicity assay (Ames test) in strain TA102, and to cause DNA damage in the comet assay in vitro upon exposure to UVA light. In contrast, another study reported a photoprotective effect in vitro of guaiazulene. We present here a comprehensive assessment of the photo(cyto)toxicity (3T3 fibroblast Neutral Red uptake test), the photomutagenicity (Ames test) and photogenotoxicity (comet assay and micronucleus test in L5178Y cells in vitro) of azulene. In the Ames test, the mutagenicity of azulene was assessed in the presence and absence of UV light by use of the Salmonella strains TA102, TA104, TA2638 and E. coli WP2. Azulene was irradiated before being plated with bacteria (pre-irradiation), or concomitantly with the bacteria either after plating or while in suspension. Guaiazulene was included in some of the experiments. Neither in the photo-Ames test nor in the other photogenotoxicity tests, azulene or guaiazulene showed any photomutagenic or photogenotoxic activity. Weak photo(cyto)toxicity (estimate of PIF≥1.67) was observed with azulene in the 3T3 NRU test, the Alamar Blue test and the relative cell count, which may be due to the generation of reactive oxygen species, as reported recently.

Cooperation across multiple game theoretical paradigms is increased by fear more than anger in selfish individuals.

Cooperative decisions are well predicted by stable individual differences in social values but it remains unclear how they may be modulated by emotions such as fear and anger. Moving beyond specific decision paradigms, we used a suite of economic games and investigated how experimental inductions of fear or anger affect latent factors of decision making in individuals with selfish or prosocial value orientations. We found that, relative to experimentally induced anger, induced fear elicited higher scores on a cooperation factor, and that this effect was entirely driven by selfish participants. In fact, induced fear brought selfish individuals to cooperate similarly to prosocial individuals, possibly as a (selfish) mean to seek protection in others. These results suggest that two basic threat-related emotions, fear and anger, differentially affect a generalized form of cooperation and that this effect is buffered by prosocial value orientation.

Acute psychosocial stress increases serum BDNF levels: an antagonistic relation to cortisol but no group differences after mental training.

Brain-derived neurotrophic factor (BDNF) is an essential facilitator of neuronal plasticity. By counteracting the adverse effects of excessive stress-induced glucocorticoid signaling, BDNF has been implicated as a resilience factor to psychopathology caused by chronic stress. Insights into the effects of acute stress on peripheral BDNF levels in humans are inconclusive. The short-term interplay between BDNF and cortisol in response to acute psychosocial stress remains unexplored. Furthermore, it is unknown whether mental training that is effective at reducing cortisol reactivity can also influence BDNF during acute stress. In the current study, we investigated serum BDNF levels during an acute psychosocial stress paradigm, the Trier Social Stress Test (TSST), in 301 healthy participants (178 women, mean age = 40.65) recruited as part of the ReSource Project, a large-scale mental training study consisting of three distinct 3-month training modules. Using a cross-sectional study design, we first examined the relationship between BDNF and salivary cortisol in a control group with no mental training. Subsequent analyses focused on differences in BDNF stress levels between control and mental training groups. We show that serum BDNF is indeed stress-sensitive, characterized by a significant post-stress increase and subsequent decline to recovery. While respective increases in BDNF and cortisol were not associated, we found two indications for an antagonistic relationship. Higher BDNF peaks after stress were associated with steeper cortisol recovery. On the other hand, the magnitude of the cortisol stress response was linked to steeper BDNF recovery after stress. BDNF levels were not modulated by any of the mental training modules. Providing novel evidence for the dynamics of BDNF and cortisol during acute stress, our findings may further inform research on the physiological mechanisms involved in stress chronification and the associated health risks.

Interactions of momentary thought content and subjective stress predict cortisol fluctuations in a daily life experience sampling study.

Daily life stress is an omnipresent phenomenon in modern society. Research has linked prolonged activation of the hypothalamic-pituitary-adrenal axis to psychiatric and somatic diseases. Everyday stressors substantially contribute to these health risks. Despite the notion that the physiological stress response is highly dependent on concurrent psychological processes, investigations associating diurnal cortisol levels with subjective experience have primarily focused on affective states. The impact of everyday cognitive processes including thought content has been largely neglected. To investigate this link, moment-to-moment associations of psychological experience including subjective stress, thought content and affect, and cortisol levels were assessed throughout the daily routines of 289 healthy adult participants. We found that subjective stress interacted with current thought content and affect in predicting cortisol release: more negative and future-directed thoughts were associated with higher cortisol levels after experiencing subjective stress, suggesting an increase in negative future anticipation. Concurrent cortisol rises might reflect proactive coping to adequately prepare for upcoming demands. In the absence of subjective stress, more past-directed thoughts and negative affect were associated with higher cortisol levels. These findings provide evidence for a fundamental link between thought content and daily cortisol activation, and highlight the significant contribution of thought patterns to physiological stress levels.

Extrapolation of preclinical data into clinical reality translational science.

Human and animal in vitro models are potentially powerful preclinical tools: prediction of pharmacological behaviour of drugs; selection of animal species most closely related to humans based on metabolic patterns; prediction of drug interactions and explanation of metabolic origins of interindividual variabilities in pharmacological activity. Extrapolation of preclinical data into clinical reality is a translational science and remains an ultimate challenge in drug development.

Caring Cooperators and Powerful Punishers: Differential Effects of Induced Care and Power Motivation on Different Types of Economic Decision Making.

Standard economic theory postulates that decisions are driven by stable context-insensitive preferences, while motivation psychology suggests they are driven by distinct context-sensitive motives with distinct evolutionary goals and characteristic psycho-physiological and behavioral patterns. To link these fields and test how distinct motives could differentially predict different types of economic decisions, we experimentally induced participants with either a Care or a Power motive, before having them take part in a suite of classic game theoretical paradigms involving monetary exchange. We show that the Care induction alone raised scores on a latent factor of cooperation-related behaviors, relative to a control condition, while, relative to Care, Power raised scores on a punishment-related factor. These findings argue against context-insensitive stable preferences and theories of strong reciprocity and in favor of a motive-based approach to economic decision making: Care and Power motivation have a dissociable fingerprint in shaping either cooperative or punishment behaviors.

The reaction sites of rotenone and ubiquinone with mitochondrial NADH dehydrogenase.

This article summarizes recent studies in the authors' and other laboratories of selective inhibitors acting at the 'rotenone' site and at the Q binding site in the NADH-Q oxidoreductase segment of the respiratory chain. A wide array of inhibitors act at the rotenone site to block electron flux from the enzyme to the Q pool. Using evidence from studies with rotenone, piericidin A, and analogs of the neurotoxic N-methyl-4-phenylpyridinium, we have proposed two binding sites for these inhibitors, both of which must be occupied for complete inhibition of NADH oxidation.

Cystic fibrosis transmembrane conductance regulator in teleost fish.

The gills and intestinal epithelia of teleost fish express cystic fibrosis transmembrane conductance regulator (CFTR), and utilize this low conductance anion channel in the apical membrane for ion secretion in seawater gill and in the basolateral membrane for ion absorption in freshwater gill. Similarly, in the intestine CFTR is present in the basolateral membrane for intestinal absorption and also in the apical membrane of secreting intestine. The expression of CFTR and the directed trafficking of the protein to the apical or basolateral membrane is salinity-dependent. The CFTR gene has been cloned and sequenced from several teleost species and although all the major elements in the human gene are present, including two nucleotide binding domains that are common to all ATP binding cassette (ABC) transporters, the sequences are divergent compared to shark or human. In euryhaline fish adapting to seawater, CFTR, localized immunocytochemically, redistributes slowly from a basolateral location to the apical membrane while ion secretory capacity increases. The facility with which teleosts regulate CFTR expression and activation during salinity adaptation make this system an appealing model for the expression and trafficking operation of this labile gene product.

Deficiencies of NADH and succinate dehydrogenases in degenerative diseases and myopathies.

This paper examines the experimental foundations of reports in the literature on mitochondrial diseases involving Complexes I and II of the respiratory chain. Many of the reports may be questioned on the basis of the assay conditions used which disregard established knowledge of the precautions required for valid activity measurements. In addition, some findings are open to question because of the experimental material chosen for the study, such as the measurement of NADH oxidase activity in platelets in Parkinson's disease, which affects selectively the dopamine neurons, or the use of autopsy material stored for prolonged periods during which post-mortem changes may have occurred. Deficiencies claimed to involve several components of the respiratory chain may reflect indirect effects, such as defects in the synthesis of iron-sulfur clusters or in the availability of iron, rather than mutations in the genes coding for the deficient enzymes. Nevertheless, there are a few instances reported of Complex II deficiency free from such criticisms. As to Complex I, idiopathic Parkinsonism appears to involve a documentable decline in the activity of this enzyme. Using the model system provided by N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces biochemical, pharmacological, and clinical syndromes closely resembling Parkinsonism, the etiology of the disease is examined.

Studies on the spin-spin interaction between flavin and iron-sulfur cluster in an iron-sulfur flavoprotein.

When the di- or trimethylamine dehydrogenases (trimethylamine:(acceptor) oxidoreductase (demethylating), EC 1.5.99.7) of certain methylotrophic bacteria are reduced by two electrons with substrate unusual EPR signals arise at g = 2 and g = 4 (Steenkamp, D.J. and Beinert, H. (1982) Biochem. J. 207, 233-239; 241-252) indicative of spin-spin interaction between the FMN and iron-sulfur compounds of these enzymes. An attempt is made to understand, describe and simulate these spectra in terms of a triplet state with possible contributions from both dipolar and anisotropic exchange (J) interactions. No direct measurement of J is available, but various approaches to setting limits to J are outlined. According to these, J approximately 0.4 to 3 cm-1 or 15 to 50 cm-1. The spectra show, in the g = 2 region, a pair of rather sharp inner and a pair of broad outer lines; the latter broaden as well as move out from the center with increasing time (after substrate addition) and substrate concentration, while there is little change of g = 4. The best fits to such spectra were obtained by assuming distribution of D and E values, depending on substrate effects and arriving presumably from 'g-strain'. The fact that both shapes and intensities at g = 2 and g = 4 could be reproduced simultaneously at two frequencies indicates that the assumptions underlying our approaches and interpretations are permissible and reasonable, although we cannot claim their uniqueness. The distance between the centers of the spin densities of the flavin radical and the Fe-S cluster is thought to lie between the limits 3 to 5 A if the asymmetries in the spin-spin interaction are magnetic dipole-dipole in origin. Because there is an indication that the interaction is anisotropic exchange, the upper limit is less stringent.

Preliminary X-ray study of p-cresol methylhydroxylase (flavocytochrome c) from Pseudomonas putida N.C.I.B. 9869.

Single crystals of p-cresol methylhydroxylase, a flavocytochrome c from Pseudomonas putida, have been prepared. The crystals are orthorhombic, space group P212121 with unit cell parameters; a = 140.3 A, b = 130.6 A and c = 74.1 A. They contain a single non-symmetric dimer per asymmetric unit and diffract to at least 2.5 A resolution.