The amyloid precursor protein intracellular domain induces sleep disruptions and its nuclear localization fluctuates in circadian pacemaker neurons in Drosophila and mice.

The most prominent symptom of Alzheimer's disease (AD) is cognitive decline; however, sleep and other circadian disruptions are also common in AD patients. Sleep disruptions have been connected with memory problems and therefore the changes in sleep patterns observed in AD patients may also actively contribute to cognitive decline. However, the underlying molecular mechanisms that connect sleep disruptions and AD are unclear. A characteristic feature of AD is the formation of plaques consisting of Amyloid-ß (Aß) peptides generated by cleavage of the Amyloid Precursor Protein (APP). Besides Aß, APP cleavage generates several other fragments, including the APP intracellular domain (AICD) that has been linked to transcriptional regulation and neuronal homeostasis. Here we show that overexpression of the AICD reduces the early evening expression of two core clock genes and disrupts the sleep pattern in flies. Analyzing the subcellular localization of the AICD in pacemaker neurons, we found that the AICD levels in the nucleus are low during daytime but increase at night. While this pattern of nuclear AICD persisted with age, the nighttime levels were higher in aged flies. Increasing the cleavage of the fly APP protein also disrupted AICD nuclear localization. Lastly, we show that the day/nighttime nuclear pattern of the AICD is also detectable in neurons in the suprachiasmatic nucleus of mice and that it also changes with age. Together, these data suggest that AD-associated changes in APP processing and the subsequent changes in AICD levels may cause sleep disruptions in AD.

Cognitive aging is associated with redistribution of synaptic weights in the hippocampus.

Behaviors that rely on the hippocampus are particularly susceptible to chronological aging, with many aged animals (including humans) maintaining cognition at a young adult-like level, but many others the same age showing marked impairments. It is unclear whether the ability to maintain cognition over time is attributable to brain maintenance, sufficient cognitive reserve, compensatory changes in network function, or some combination thereof. While network dysfunction within the hippocampal circuit of aged, learning-impaired animals is well-documented, its neurobiological substrates remain elusive. Here we show that the synaptic architecture of hippocampal regions CA1 and CA3 is maintained in a young adult-like state in aged rats that performed comparably to their young adult counterparts in both trace eyeblink conditioning and Morris water maze learning. In contrast, among learning-impaired, but equally aged rats, we found that a redistribution of synaptic weights amplifies the influence of autoassociational connections among CA3 pyramidal neurons, yet reduces the synaptic input onto these same neurons from the dentate gyrus. Notably, synapses within hippocampal region CA1 showed no group differences regardless of cognitive ability. Taking the data together, we find the imbalanced synaptic weights within hippocampal CA3 provide a substrate that can explain the abnormal firing characteristics of both CA3 and CA1 pyramidal neurons in aged, learning-impaired rats. Furthermore, our work provides some clarity with regard to how some animals cognitively age successfully, while others' lifespans outlast their "mindspans."

Hypersensitivity to metals in metal-on-metal hip arthroplasty: a prospective study of one hundred and thirty five lymphocyte transformation tests.

BACKGROUND: Metal allergy remains a controversial topic in the orthopaedic community. It is not known if or to what degree metal sensitivity contributes to inflammatory soft tissue failures, unexplained residual pain, or clinical complications after total joint replacement with metal prostheses. METHODS: We investigated the efficacy of the lymphocyte transformation test (LTT) in predicting adverse outcomes in patients after receiving a metal joint replacement. Our study cohort consists of 135 metal-on-metal hip resurfacing arthroplasty cases performed between 2013 and 2015. All study patients had an LTT preoperatively. We retrospectively analyzed clinical outcomes and failures for our cohort. RESULTS: There was no difference in LTT reactivity between men and women. Of the 135 patients tested, 46 (34.1% of cohort) tested positive to at least one of the materials comprising their implant, and 78 patients (57.8%) had at least one reactive score to any component of the LTT. After a minimum follow-up of two years, we did not observe an allergic response to the implant in any patients. There were no failures requiring revision. We observed a 2.2% rate of moderate residual pain; no patients with residual pain tested positive for metal sensitivity. When patients with moderate-high LTT reactivity (30.4% of cohort) were compared to the remainder of the study group, there was no difference in HHS or UCLA activity score. There was no correlation between blood metal ion levels and LTT reactivity. CONCLUSION: We were unable to prove any predictive value of the LTT. We failed to identify hypersensitivity to metals in patients with metal-on-metal hip resurfacing arthroplasty.

FTD-associated mutations in Tau result in a combination of dominant and recessive phenotypes.

Although mutations in the microtubules-associated protein Tau have long been connected with several neurodegenerative diseases, the underlying molecular mechanisms causing these tauopathies are still not fully understood. Studies in various models suggested that dominant gain-of-function effects underlie the pathogenicity of these mutants; however, there is also evidence that the loss of normal physiological functions of Tau plays a role in tauopathies. Previous studies on Tau in Drosophila involved expressing the human Tau protein in the background of the endogenous Tau gene in addition to inducing high expression levels. To study Tau pathology in more physiological conditions, we recently created Drosophila knock-in models that express either wildtype human Tau (hTauWT) or disease-associated mutant hTau (hTauV337M and hTauK369I) in place of the endogenous Drosophila Tau (dTau). Analyzing these flies as homozygotes, we could therefore detect recessive effects of the mutations while identifying dominant effects in heterozygotes. Using memory, locomotion and sleep assays, we found that homozygous mutant hTau flies showed deficits already when quite young whereas in heterozygous flies, disease phenotypes developed with aging. Homozygotes also revealed an increase in microtubule diameter, suggesting that changes in the cytoskeleton underlie the axonal degeneration we observed in these flies. In contrast, heterozygous mutant hTau flies showed abnormal axonal targeting and no detectable changes in microtubules. However, we previously showed that heterozygosity for hTauV337M interfered with synaptic homeostasis in central pacemaker neurons and we now show that heterozygous hTauK369I flies have decreased levels of proteins involved in the release of synaptic vesicles. Taken together, our results demonstrate that both mutations induce a combination of dominant and recessive disease-related phenotypes that provide behavioral and molecular insights into the etiology of Tauopathies.

Limited Evidence for Accumulation of Latent Infections of Canker-Causing Pathogens in Shoots of Stone Fruit and Nut Crops in California.

Prevalence of latent infections of the canker-causing fungi Botryosphaeria dothidea and species of Cytospora, Diplodia, Lasiodiplodia, Neofusicoccum, and Phomopsis in young shoots of almond, prune, and walnut trees in California was studied to test the hypotheses that latent infections accumulate from current-season shoots to 1-year-old shoots in the orchard and there are distinct associations among pathogen taxa present as latent infections in the same shoot. Samples of newly emerged and 1-year-old shoots were periodically collected in each almond, prune, and walnut orchard for two growing seasons. A real-time quantitative PCR assay was used to quantify latent infection with three parameters: incidence, molecular severity, and latent infection index. Diplodia spp. were absent from most samples. For almond, Lasiodiplodia spp. and Cytospora spp. were detected with a maximum incidence >90%, while B. dothidea and Neofusicoccum spp. incidence was <20% in most cases. In prune orchards, the incidence levels of B. dothidea were >50% in most cases, while those of Cytospora spp. and Lasiodiplodia spp. were 30 to 60% and 30 to 100%, respectively. For walnut, many samplings showed higher incidence in 1-year-old (30 to 80%) than in newly emerged shoots (10 to 50%). Accumulation of latent infection between the two shoot age classes was detected in only a few cases. The percentages of samples showing coexistence of two, three, and four pathogen taxa in the same shoot were 20 to 25, <10, and <5%, respectively. Pairwise associations among pathogen taxa in the same shoot were significant in many cases.

Prevalence, Predictors, and Treatment of Impostor Syndrome: a Systematic Review.

BACKGROUND: Impostor syndrome is increasingly presented in the media and lay literature as a key behavioral health condition impairing professional performance and contributing to burnout. However, there is no published review of the evidence to guide the diagnosis or treatment of patients presenting with impostor syndrome. PURPOSE: To evaluate the evidence on the prevalence, predictors, comorbidities, and treatment of impostor syndrome. DATA SOURCES: Medline, Embase, and PsycINFO (January 1966 to May 2018) and bibliographies of retrieved articles. STUDY SELECTION: English-language reports of evaluations of the prevalence, predictors, comorbidities, or treatment of impostor syndrome. DATA EXTRACTION: Two independent investigators extracted data on study variables (e.g., study methodology, treatments provided); participant variables (e.g., demographics, professional setting); diagnostic tools used, outcome variables (e.g., workplace performance, reductions in comorbid conditions); and pre-defined quality variables (e.g., human subjects approval, response rates reported). DATA SYNTHESIS: In total, 62 studies of 14,161 participants met the inclusion criteria (half were published in the past 6 years). Prevalence rates of impostor syndrome varied widely from 9 to 82% largely depending on the screening tool and cutoff used to assess symptoms and were particularly high among ethnic minority groups. Impostor syndrome was common among both men and women and across a range of age groups (adolescents to late-stage professionals). Impostor syndrome is often comorbid with depression and anxiety and is associated with impaired job performance, job satisfaction, and burnout among various employee populations including clinicians. No published studies evaluated treatments for this condition. LIMITATIONS: Studies were heterogeneous; publication bias may be present. CONCLUSIONS: Clinicians and employers should be mindful of the prevalence of impostor syndrome among professional populations and take steps to assess for impostor feelings and common comorbidities. Future research should include evaluations of treatments to mitigate impostor symptoms and its common comorbidities.

Perdeuterated Conjugated Polymers for Ultralow-Frequency Magnetic Resonance of OLEDs.

The formation of excitons in OLEDs is spin dependent and can be controlled by electron-paramagnetic resonance, affecting device resistance and electroluminescence yield. We explore electrically detected magnetic resonance in the regime of very low magnetic fields (<1 mT). A pronounced feature emerges at zero field in addition to the conventional spin- 1 / 2 Zeeman resonance for which the Larmor frequency matches that of the incident radiation. By comparing a conventional π-conjugated polymer as the active material to a perdeuterated analogue, we demonstrate the interplay between the zero-field feature and local hyperfine fields. The zero-field peak results from a quasistatic magnetic-field effect of the RF radiation for periods comparable to the carrier-pair lifetime. Zeeman resonances are resolved down to 3.2 MHz, approximately twice the Larmor frequency of an electron in Earth's field. However, since reducing hyperfine fields sharpens the Zeeman peak at the cost of an increased zero-field peak, we suggest that this result may constitute a fundamental low-field limit of magnetic resonance in carrier-pair-based systems. OLEDs offer an alternative solid-state platform to investigate the radical-pair mechanism of magnetic-field effects in photochemical reactions, allowing models of biological magnetoreception to be tested by measuring spin decoherence directly in the time domain by pulsed experiments.

Digit ratios and motor and health-related fitness in pre-adolescent females.

Background: Assessing different aspects of physical fitness in children whose abilities are undeveloped and their associations with second-to-fourth digit ratio (2D:4D) may better determine the potential athleticism of an individual.Aim: The purpose of the study was to examine relationships between the digit ratios and selected motor and health-related fitness parameters in a large sample of pre-adolescent females.Subjects and methods: Participants included 8-12 year old Iranian and Afghan girls. The length of the left and right second and fourth digits was measured by scanning and computer-assisted image analysis. Motor- and health-related fitness tests were evaluated.Results: No significant correlations were noted between right 2D:4D ratio and physical fitness components. Left 2D:4D and physical fitness components were not correlated, with the exception of handgrip strength (r = -0.193). However, right and left second digit lengths were negatively correlated with predicted VO2max (p ≤ 0.01). In addition, right-left 2D:4D was significantly negatively correlated with flexibility, and significantly positively correlated with height and body fat percentage.Conclusion: In contrast to previous investigations, it seems that left 2D:4D is a predictor of strength, but not aerobic exercise. It is suggested there may be a potential relationship between prenatal androgen exposure and high flexibility, low body fat percentage and the generation of muscular strength in pre-adolescent females.

Femoral Fixation Methods in Hip Resurfacing Arthroplasty: An 11-Year Retrospective Comparison of 4013 Cases.

BACKGROUND: The optimal femoral fixation method remains unclear. To evaluate the role of femoral fixation techniques in hip resurfacing, we present a comparison of 2 consecutive groups: group 1 (739 hips) with cemented femoral components; group 2 (3274 hips) with uncemented femoral components. METHODS: We retrospectively analyzed our clinical database to compare failures, reoperations, complications, clinical results, and radiographic measurements. Groups were consecutive, so cemented cases had longer follow-up. However, all patients from both groups were at least 2 years out from surgery. Two-year clinical and radiographic data were compared. Longer-term comparison data as well as Kaplan-Meier implant survivorship curves specifically focusing on femoral failure modes were analyzed. RESULTS: Kaplan-Meier 10-year implant survivorship using nontraumatic femoral failure as an end point was 98.9% for the cemented and 100% for the uncemented femoral component. The uncemented, group 2 cases showed a significantly lower raw failure rate (1.1% vs 4.6%), 2-year failure rate (0.8% vs 2.8%), 2-year femoral failure rate (0.4% vs 0.9%), and a lower combined rate of femoral complications and failures (0.6% vs 1.8%). In cases that did not fail, patient mean clinical scores, pain scores, and combined range of motion were all significantly better for group 2. CONCLUSION: We have demonstrated that in the fully porous-coated ReCap device, uncemented femoral fixation is superior to cemented fixation at 11 years follow-up (0.0% vs 1.1% late femoral loosening) in this single-surgeon cohort. Early femoral fractures also reduced from 0.8% to 0.3%, but this may be partially or completely due to a new bone density management program. This study demonstrates better femoral implant survivorship for the uncemented device compared to the cemented femoral resurfacing component for this implant design.

Charge Generation Pathways in Organic Solar Cells: Assessing the Contribution from the Electron Acceptor.

Photocurrent generation in organic bulk heterojunction (BHJ) solar cells is most commonly understood as a process which predominantly involves photoexcitation of the lower ionization potential species (donor) followed by electron transfer to the higher electron affinity material (acceptor) [i.e., photoinduced electron transfer (PET), which we term Channel I]. A mirror process also occurs in which photocurrent is generated through photoexcitation of the acceptor followed by hole transfer to the nonexcited donor or photoinduced hole transfer (PHT), which we term Channel II. The role of Channel II photocurrent generation has often been neglected due to overlap of the individual absorption spectra of the donor and acceptor materials that are commonly used. More recently Channel II charge generation has been explored for several reasons. First, many of the new high-efficiency polymeric donors are used as the minority component in bulk heterojunction blends, and therefore, the acceptor absorption is a significant fraction of the total; second, nonfullerene acceptors have been prepared, which through careful design, allow for spectral separation from the donor material, facilitating fundamental studies on charge generation. In this article, we review the methodologies for investigating the two charge generation channels. We also discuss the factors that affect charge generation via Channel I and II pathways, including energy levels of the materials involved, exciton diffusion, and other considerations. Finally, we take a comprehensive look at the nonfullerene acceptor literature and discuss what information about Channel I and Channel II can be obtained from the experiments conducted and what other experiments could be undertaken to provide further information about the operational efficiencies of Channels I and II.

Tau imaging in neurodegenerative diseases.

Aggregated tau protein is a major neuropathological substrate central to the pathophysiology of neurodegenerative diseases such as Alzheimer's disease (AD), frontotemporal dementia, progressive supranuclear palsy, corticobasal degeneration and chronic traumatic encephalopathy. In AD, it has been shown that the density of hyperphosphorylated tau tangles correlates closely with neuronal dysfunction and cell death, unlike ß-amyloid. Until now, diagnostic and pathologic information about tau deposition has only been available from invasive techniques such as brain biopsy or autopsy. The recent development of selective in-vivo tau PET imaging ligands including [(18)F]THK523, [(18)F]THK5117, [(18)F]THK5105 and [(18)F]THK5351, [(18)F]AV1451(T807) and [(11)C]PBB3 has provided information about the role of tau in the early phases of neurodegenerative diseases, and provided support for diagnosis, prognosis, and imaging biomarkers to track disease progression. Moreover, the spatial and longitudinal relationship of tau distribution compared with ß - amyloid and other pathologies in these diseases can be mapped. In this review, we discuss the role of aggregated tau in tauopathies, the challenges posed in developing selective tau ligands as biomarkers, the state of development in tau tracers, and the new clinical information that has been uncovered, as well as the opportunities for improving diagnosis and designing clinical trials in the future.

Tuning the optoelectronic properties of nonfullerene electron acceptors.

Broad spectral coverage over the solar spectrum is necessary for photovoltaic technologies and is a focus for organic solar cells. We report a series of small-molecule, nonfullerene electron acceptors containing the [(benzo[c][1,2,5]thiadiazol-4-yl)methylene]malononitrile unit as a high electron affinity component. The optoelectronic properties of these molecules were fine-tuned with the objective of attaining strong absorption at longer wavelengths by changing the low-ionization-potential moiety. The electron-accepting function of these materials was investigated with poly(3-n-hexylthiophene) (P3HT) as a standard electron donor. Significant photocurrent generation in the near infrared region, with an external quantum yield reaching as high as 22 % at 700 nm and an onset >800 nm was achieved. The results support efficient hole transfer to P3HT taking place after light absorption by the acceptor molecules. A Channel II-dominated power conversion efficiency of up to 1.5 % was, thus, achieved.

Marching Band Camp Injury Rates at the Collegiate Level.

AIMS: Marching band camp injuries were recorded over the course of 1 week (10 field practices) to determine injury rate for preseason. METHODS: Members were instructed to self-report any type of injury that occurred. The collected data were coded and analyzed for total injuries and injuries per section. The injury counts, along with total practices and band members per section, were used to calculate injury rate per 1,000 exposures for total injury and injury per section. RESULTS: There were a total of 191 injuries reported in 1,540 practice exposures. The overall injury rate was 124.03/1,000 exposures. The instrument with the highest injury rate was the mellophone (220.0/1,000 exposures), followed by the trombone (190.0/1,000 exposures), and percussion (184.62/ 1,000 exposures). The instrument with the lowest injury rate was the clarinet (43.75/1,000 exposures). CONCLUSION: The findings demonstrate that marching band is a strenuous activity and deserves to be considered an area of emerging practice for athletic trainers and other health care professionals.

Spectral dependence of the internal quantum efficiency of organic solar cells: effect of charge generation pathways.

The conventional picture of photocurrent generation in organic solar cells involves photoexcitation of the electron donor, followed by electron transfer to the acceptor via an interfacial charge-transfer state (Channel I). It has been shown that the mirror-image process of acceptor photoexcitation leading to hole transfer to the donor is also an efficient means to generate photocurrent (Channel II). The donor and acceptor components may have overlapping or distinct absorption characteristics. Hence, different excitation wavelengths may preferentially activate one channel or the other, or indeed both. As such, the internal quantum efficiency (IQE) of the solar cell may likewise depend on the excitation wavelength. We show that several model high-efficiency organic solar cell blends, notably PCDTBT:PC70BM and PCPDTBT:PC60/70BM, exhibit flat IQEs across the visible spectrum, suggesting that charge generation is occurring either via a dominant single channel or via both channels but with comparable efficiencies. In contrast, blends of the narrow optical gap copolymer DPP-DTT with PC70BM show two distinct spectrally flat regions in their IQEs, consistent with the two channels operating at different efficiencies. The observed energy dependence of the IQE can be successfully modeled as two parallel photodiodes, each with its own energetics and exciton dynamics but both having the same extraction efficiency. Hence, an excitation-energy dependence of the IQE in this case can be explained as the interplay between two photocurrent-generating channels, without recourse to hot excitons or other exotic processes.

Ion-regulated allosteric binding of fullerenes (C60 and C70) by tetrathiafulvalene-calix[4]pyrroles.

The effect of ionic species on the binding of fullerenes (C60 and C70) by tetrathiafulvalene-calix[4]pyrrole (TTF-C4P) receptors and the nature of the resulting supramolecular complexes (TTF-C4P + fullerene + halide anion + tetraalkylammonium cation) was studied in the solid state through single crystal X-ray diffraction methods and in dichloromethane solution by means of continuous variation plots and UV-vis spectroscopic titrations. These analyses revealed a 1:1 stoichiometry between the anion-bound TTF-C4Ps and the complexed fullerenes. The latter guests are bound within the bowl-like cup of the C4P in a ball-and-socket binding mode. The interactions between the TTF-C4P receptors and the fullerene guests are highly influenced by both the nature of halide anions and their counter tetraalkylammonium cations. Three halides (F(-), Cl(-), and Br(-)) were studied. All three potentiate the binding of the two test fullerenes by inducing a conformational change from the 1,3-alternate to the cone conformer of the TTF-C4Ps, thus acting as positive heterotropic allosteric effectors. For a particular halide anion, the choice of tetraalkylammonium salts serves to modulate the strength of the TTF-C4P-fullerene host-guest binding interactions and, in conjunction with variations in the halide anion, can be exploited to alter the inherent selectivity of the host for a given fullerene. Differences in binding are reflected in the excited state optical properties. Overall, the present four-component system provides an illustration of how host-guest binding events involving appropriately designed artificial receptors can be fine-tuned via the addition of simple ionic species as allosteric modulators.

Athletic Trainers' Beliefs Regarding Professionalism.

CONTEXT: Limited research exists regarding athletic trainers' (ATs') perceptions of professionalism. OBJECTIVE: To explore the lived experiences of ATs and their perceptions of professionalism. DESIGN: Qualitative study. SETTING: Participants were ATs who completed a semistructured interview protocol via audio-only recording conferencing. PATIENTS OR OTHER PARTICIPANTS: Seventeen participants (age = 33 ± 8 years; range = 25-56 years) who were certified ATs with an average of 10 years of experience (SD = ±8; range = 1-33 years) were interviewed. DATA COLLECTION AND ANALYSIS: Individuals self-identified their interest in participating in a follow-up interview recruitment located within a survey. Interviews occurred until saturation was met and included a variety of participants. Demographic information was gathered from the survey for each person. All transcripts were audio recorded, transcribed verbatim, and coded using a 3-person coding team following the consensual qualitative research protocol. Member checking, auditing, and triangulation established trustworthiness and credibility in the data-analysis process. RESULTS: A total of 4 domains with supporting categories were identified. Athletic trainers spoke of the employee environment that affected perceptions of what was determined to be professional, specifically in various settings or situations. They shared their personal determination of outward appearance and expression when differentiating what was deemed professional, including references to cleanliness, judgment of self-expression, and implicit bias. Whether intentional or unintentional, participants made comments that demonstrated a bias toward sex or race and ethnicity when determining outward appearance appropriateness. They noted various cultural awareness situations, including progression of perceptions over time, external pressure, and internal dialog. Respondents shared discourse regarding an internal struggle of what was right and wrong in their responses. They discussed professionalism based on the provider's conduct, mainly in terms of communication and patient care. Participants shared that communication occurring through both verbal and nonverbal means is vital to the perceptions of professionalism for ATs. CONCLUSIONS: Current views of professionalism in athletic training were shaped by various lived experiences. With the movement toward athletic training becoming more diverse, equitable, and inclusive, antiquated professionalism ideals need to shift to provide a better work environment for all.

Rehabilitative Health Care Professionals' Perceptions of Appearance-Based Professionalism.

CONTEXT: Professionalism has been discussed and defined in a variety of ways, including attire and other forms of self-expression. OBJECTIVES: To determine athletic trainer (AT), physical therapist (PT), and athletic training or PT students' perceptions of appearance-based professionalism in the workplace and, secondly, to ascertain how perceptions differed across professions. DESIGN: Cross-sectional study. SETTING: Web-based survey. PATIENTS OR OTHER PARTICIPANTS: Athletic trainers, PTs, and athletic training and PT students who were predominantly White, non-Hispanic, female, aged 30 ± 9 years, and recruited via listservs and social media. DATA COLLECTION AND ANALYSIS: The independent variables were participant demographics. The dependent variables were self-reported perceptions of professionalism for each photo. The survey consisted of 3 sections: demographics, 8 photos of ATs or PTs with depictions of patient-provider interactions, and open-ended responses. For each photo, participants selected yes, no, or unsure regarding the photo. An open-ended response was prompted with a no or unsure selection. The participant further described the reason for that choice. RESULTS: Most participants determined the health care provider depicted in 7 photos appeared professional. Only 1 photo was deemed unprofessional by the professional majority. Significant differences existed between students and professionals for 5 photos. The proportion of participants who reported the photos were unprofessional differed among professions for 2 photos. From our qualitative analysis, we found 6 domains: (1) unprofessional attire and hair, (2) situation-dependent attire, (3) role confusion and health care employer or employee identification, (4) nonappearance related, (5) tattoo-related bias, and (6) rethinking after question is displayed. CONCLUSION: What is considered appropriate and professional is not concrete. Differing concepts of professionalism generated biased judgments and criticisms. CLINICAL RELEVANCE: Our findings should lead providers to reexamine the definition of professionalism. The past should not dictate the future, and today's social mores can help shape the definition as it should be considered in today's settings.

Chlorogenic Acids, Acting via Calcineurin, Are the Main Compounds in Centella asiatica Extracts That Mediate Resilience to Chronic Stress in Drosophila melanogaster.

Common symptoms of depressive disorders include anhedonia, sleep problems, and reduced physical activity. Drugs used to treat depression mostly aim to increase serotonin signaling but these can have unwanted side effects. Depression has also been treated by traditional medicine using plants like Centella asiatica (CA) and this has been found to be well tolerated. However, very few controlled studies have addressed CA's protective role in depression, nor have the active compounds or mechanisms that mediate this function been identified. To address this issue, we used Drosophila melanogaster to investigate whether CA can improve depression-associated symptoms like anhedonia and decreased climbing activity. We found that a water extract of CA provides resilience to stress induced phenotypes and that this effect is primarily due to mono-caffeoylquinic acids found in CA. Furthermore, we describe that the protective function of CA is due to a synergy between chlorogenic acid and one of its isomers also present in CA. However, increasing the concentration of chlorogenic acid can overcome the requirement for the second isomer. Lastly, we found that chlorogenic acid acts via calcineurin, a multifunctional phosphatase that can regulate synaptic transmission and plasticity and is also involved in neuronal maintenance.

Synergistic and threshold effects of GH1 and GHR promoter size variation on body growth and fat accrual in young Nelore (Bos indicus) bulls.

A synergistic effect in the somatotropic axis (GH1-GHR-IGF1) was observed in 736 young Nelore (Bos indicus) bulls under ad libitum grass feeding conditions on irrigated pasture in central Brazil. Stepwise substitution of shorter alleles of the promoter region of the growth hormone gene (GH1) and the P1 promoter of the GH1 receptor gene (GHR) with longer alleles was associated with significantly increased body weight gain (W550, weight at age 550 days; ADG, average daily gain) and fat accrual (FAT, rib eye fat thickness). A threshold effect on ADG was associated with allele size variation at the GH1. A best fit model indicated a 3- to 6-fold effect of GH1 variation on ADG, when compared to the variation at the GHR and a known microsatellite at the somatomedin gene (IGF1, insulin-like growth factor 1). A threshold effect on FAT was associated with substitution of the short GHR allele by the longer GHR alleles; the effect of the GHR variation on FAT was 10-fold that of the variation at the GH1 and IGF1 loci. Among the 10 GH1-GHR-IGF1 multi-genotypes identified, the predominant genotype was homozygous for the large GH1 promoter (long/long, G2/G2 or domestic type), short GHR promoter (short/short or wild type), and short IGF1 microsatellite (short/short or wild type). This predominant multi-genotype suggests that selection pressure in the Nelore breed has been directed towards high ADG and W550, and low FAT. Our results mirror previous findings in the oMtla-oGH transgenic mouse model, in which the level of somatotropic gene expression acts through a threshold mechanism, and low expression results in adipogenesis, while high expression increases body growth.