Shared evolutionary origin of major histocompatibility complex polymorphism in sympatric lemurs.

Genes of the major histocompatibility complex (MHC) play a central role in adaptive immune responses of vertebrates. They exhibit remarkable polymorphism, often crossing species boundaries with similar alleles or allelic motifs shared across species. This pattern may reflect parallel parasite-mediated selective pressures, either favouring the long maintenance of ancestral MHC allelic lineages across successive speciation events by balancing selection ("trans-species polymorphism"), or alternatively favouring the independent emergence of functionally similar alleles post-speciation via convergent evolution. Here, we investigate the origins of MHC similarity across several species of dwarf and mouse lemurs (Cheirogaleidae). We examined MHC class II variation in two highly polymorphic loci (DRB, DQB) and evaluated the overlap of gut-parasite communities in four sympatric lemurs. We tested for parasite-MHC associations across species to determine whether similar parasite pressures may select for similar MHC alleles in different species. Next, we integrated our MHC data with those previously obtained from other Cheirogaleidae to investigate the relative contribution of convergent evolution and co-ancestry to shared MHC polymorphism by contrasting patterns of codon usage at functional vs. neutral sites. Our results indicate that parasites shared across species may select for functionally similar MHC alleles, implying that the dynamics of MHC-parasite co-evolution should be envisaged at the community level. We further show that balancing selection maintaining trans-species polymorphism, rather than convergent evolution, is the primary mechanism explaining shared MHC sequence motifs between species that diverged up to 30 million years ago.

Hair cortisol concentrations correlate negatively with survival in a wild primate population.

BACKGROUND: Glucocorticoid hormones are known to play a key role in mediating a cascade of physiological responses to social and ecological stressors and can therefore influence animals' behaviour and ultimately fitness. Yet, how glucocorticoid levels are associated with reproductive success or survival in a natural setting has received little empirical attention so far. Here, we examined links between survival and levels of glucocorticoid in a small, short-lived primate, the grey mouse lemur (Microcebus murinus), using for the first time an indicator of long-term stress load (hair cortisol concentration). Using a capture-mark-recapture modelling approach, we assessed the effect of stress on survival in a broad context (semi-annual rates), but also under a specific period of high energetic demands during the reproductive season. We further assessed the power of other commonly used health indicators (body condition and parasitism) in predicting survival outcomes relative to the effect of long-term stress. RESULTS: We found that high levels of hair cortisol were associated with reduced survival probabilities both at the semi-annual scale and over the reproductive season. Additionally, very good body condition (measured as scaled mass index) was related to increased survival at the semi-annual scale, but not during the breeding season. In contrast, variation in parasitism failed to predict survival. CONCLUSION: Altogether, our results indicate that long-term increased glucocorticoid levels can be related to survival and hence population dynamics, and suggest differential strength of selection acting on glucocorticoids, body condition, and parasite infection.

The Minor Capsid Protein VP11 of Thermophilic Bacteriophage P23-77 Facilitates Virus Assembly by Using Lipid-Protein Interactions.

UNLABELLED: Thermus thermophilus bacteriophage P23-77 is the type member of a new virus family of icosahedral, tailless, inner-membrane-containing double-stranded DNA (dsDNA) viruses infecting thermophilic bacteria and halophilic archaea. The viruses have a unique capsid architecture consisting of two major capsid proteins assembled in various building blocks. We analyzed the function of the minor capsid protein VP11, which is the third known capsid component in bacteriophage P23-77. Our findings show that VP11 is a dynamically elongated dimer with a predominantly α-helical secondary structure and high thermal stability. The high proportion of basic amino acids in the protein enables electrostatic interaction with negatively charged molecules, including nucleic acid and large unilamellar lipid vesicles (LUVs). The plausible biological function of VP11 is elucidated by demonstrating the interactions of VP11 with Thermus-derived LUVs and with the major capsid proteins by means of the dynamic-light-scattering technique. In particular, the major capsid protein VP17 was able to link VP11-complexed LUVs into larger particles, whereas the other P23-77 major capsid protein, VP16, was unable to link VP11-comlexed LUVs. Our results rule out a previously suggested penton function for VP11. Instead, the electrostatic membrane association of VP11 triggers the binding of the major capsid protein VP17, thus facilitating a controlled incorporation of the two different major protein species into the assembling capsid. IMPORTANCE: The study of thermophilic viruses with inner membranes provides valuable insights into the mechanisms used for stabilization and assembly of protein-lipid systems at high temperatures. Our results reveal a novel way by which an internal membrane and outer capsid shell are linked in a virus that uses two different major protein species for capsid assembly. We show that a positive protein charge is important in order to form electrostatic interactions with the lipid surface, thereby facilitating the incorporation of other capsid proteins on the membrane surface. This implies an alternative function for basic proteins present in the virions of other lipid-containing thermophilic viruses, whose proposed role in genome packaging is based on their capability to bind DNA. The unique minor capsid protein of bacteriophage P23-77 resembles in its characteristics the scaffolding proteins of tailed phages, though it constitutes a substantial part of the mature virion.

MYC regulates the unfolded protein response and glucose and glutamine uptake in endocrine resistant breast cancer.

BACKGROUND: About 70% of all breast cancers are estrogen receptor alpha positive (ER+) and are treated with antiestrogens. However, 50% of ER + tumors develop resistance to these drugs (endocrine resistance). In endocrine resistant cells, an adaptive pathway called the unfolded protein response (UPR) is elevated that allows cells to tolerate stress more efficiently than in sensitive cells. While the precise mechanism remains unclear, the UPR can trigger both pro-survival and pro-death outcomes that depend on the nature and magnitude of the stress. In this study, we identified MYC, an oncoprotein that is upregulated in endocrine resistant breast cancer, as a regulator of the UPR in glucose-deprived conditions. METHODS: ER+ human breast cancer cell lines (LCC1, LCC1, LY2 and LCC9) and rat mammary tumors were used to confirm upregulation of MYC in endocrine resistance. To evaluate functional relevance of proteins, siRNA-mediated inhibition or small molecule inhibitors were used. Cell density/number was evaluated with crystal violet assay; cell cycle and apoptosis were measured by flow cytometry. Relative quantification of glutamine metabolites were determined by mass spectrometry. Signaling molecules of the UPR, apoptosis or autophagy pathways were investigated by western blotting. RESULTS: Increased MYC function in resistant cells correlated with increased dependency on glutamine and glucose for survival. Inhibition of MYC reduced cell growth and uptake of both glucose and glutamine in resistant cells. Interestingly, in glucose-deprived conditions, glutamine induced apoptosis and necrosis, arrested autophagy, and triggered the unfolded protein response (UPR) though GRP78-IRE1α with two possible outcomes: (i) inhibition of cell growth by JNK activation in most cells and, (ii) promotion of cell growth by spliced XBP1 in the minority of cells. These disparate effects are regulated, at different signaling junctions, by MYC more robustly in resistant cells. CONCLUSIONS: Endocrine resistant cells overexpress MYC and are better adapted to withstand periods of glucose deprivation and can use glutamine in the short term to maintain adequate metabolism to support cell survival. Our findings reveal a unique role for MYC in regulating cell fate through the UPR, and suggest that targeting glutamine metabolism may be a novel strategy in endocrine resistant breast cancer.

Hyperinsulinemia acts via acinar insulin receptors to initiate pancreatic cancer by increasing digestive enzyme production and inflammation.

The rising pancreatic cancer incidence due to obesity and type 2 diabetes is closely tied to hyperinsulinemia, an independent cancer risk factor. Previous studies demonstrated reducing insulin production suppressed pancreatic intraepithelial neoplasia (PanIN) pre-cancerous lesions in Kras-mutant mice. However, the pathophysiological and molecular mechanisms remained unknown, and in particular it was unclear whether hyperinsulinemia affected PanIN precursor cells directly or indirectly. Here, we demonstrate that insulin receptors (Insr) in KrasG12D-expressing pancreatic acinar cells are dispensable for glucose homeostasis but necessary for hyperinsulinemia-driven PanIN formation in the context of diet-induced hyperinsulinemia and obesity. Mechanistically, this was attributed to amplified digestive enzyme protein translation, triggering of local inflammation, and PanIN metaplasia in vivo. In vitro, insulin dose-dependently increased acinar-to-ductal metaplasia formation in a trypsin- and Insr-dependent manner. Collectively, our data shed light on the mechanisms connecting obesity-driven hyperinsulinemia and pancreatic cancer development.

An Examination of the RDoC Negative Valence Systems Domain Constructs and the Self-Reports Unit of Analysis.

In response to shortcomings with the current diagnostic classification system for mental health disorders, such as poor validity and reliability of categorical diagnoses, the National Institute of Mental Health proposed the Research Domain Criteria (RDoC) initiative to move towards a dimensional approach using translational research. The current study examined associations between measures of behaviors, cognitions, and mental health symptoms and how they overlap in the Negative Valence Systems (NVS) domain. Specifically, we examined how the Self-Reports unit of analysis reflects the RDoC NVS constructs of acute threat, potential threat, sustained threat, frustrative nonreward, and loss. The overall goal was to identify additional self-report measures that reflect these constructs. Participants, two student samples and two community samples (total N = 1,509), completed online self-reported measures. Questionnaire total and subscale scores were submitted to a principal-axis factor analysis with Promax rotation separately for each sample. For both student samples and one community sample six-factor solutions emerged reflecting major aspects of the RDoC NVS and positive valence systems, particularly acute threat (i.e., fear/panic), potential threat (i.e., inhibition/worry), sustained threat (i.e., chronic stress), loss (i.e., low well-being), frustrative nonreward (i.e., reactive aggression), and reduced behavioral activation. The second community sample differed in that fear/panic and frustration/anger was combined in a general distress factor. Recommendations for additional NVS self-report markers are discussed.

Effects of hyperinsulinemia on pancreatic cancer development and the immune microenvironment revealed through single-cell transcriptomics.

BACKGROUND: Hyperinsulinemia is independently associated with increased risk and mortality of pancreatic cancer. We recently reported that genetically reduced insulin production resulted in ~ 50% suppression of pancreatic intraepithelial neoplasia (PanIN) precancerous lesions in mice. However, only female mice remained normoglycemic, and only the gene dosage of the rodent-specific Ins1 alleles was tested in our previous model. Moreover, we did not delve into the molecular and cellular mechanisms associated with modulating hyperinsulinemia. METHODS: We studied how reduced Ins2 gene dosage affects PanIN lesion development in both male and female Ptf1aCreER;KrasLSL-G12D mice lacking the rodent-specific Ins1 gene (Ins1-/-). We generated control mice having two alleles of the wild-type Ins2 gene (Ptf1aCreER;KrasLSL-G12D;Ins1-/-;Ins2+/+) and experimental mice having one allele of Ins2 gene (Ptf1aCreER;KrasLSL-G12D;Ins1-/-;Ins2+/-). We then performed thorough histopathological analyses and single-cell transcriptomics for both genotypes and sexes. RESULTS: High-fat diet-induced hyperinsulinemia was transiently or modestly reduced in female and male mice, respectively, with only one allele of Ins2. This occurred without dramatically affecting glucose tolerance. Genetic reduction of insulin production resulted in mice with a tendency for less PanIN and acinar-to-ductal metaplasia (ADM) lesions. Using single-cell transcriptomics, we found hyperinsulinemia affected multiple cell types in the pancreas, with the most statistically significant effects on local immune cell types that were highly represented in our sampled cell population. Specifically, hyperinsulinemia modulated pathways associated with protein translation, MAPK-ERK signaling, and PI3K-AKT signaling, which were changed in epithelial cells and subsets of immune cells. CONCLUSIONS: These data suggest a potential role for the immune microenvironment in hyperinsulinemia-driven PanIN development. Together with our previous work, we propose that mild suppression of insulin levels may be useful in preventing pancreatic cancer by acting on multiple cell types.

Factors related to the use of a head-mounted display for individuals with low vision.

AIM: The decision-making process around the (non-)use of assistive technologies is multifactorial. The goal of the present study was to identify which factors predict or correlate with the use of a head-mounted magnification device for low vision (LV) (eSight Eyewear), by applying this multifactorial paradigm in order to tailor LV rehabilitation interventions to reduce device abandonment. METHODS: Using a cross-sectional design, participants were recruited from 567 eSight Eyewear owners to complete a 45-min survey online including questions from standardized questionnaires classified into four families: personal, device-related, environmental, and interventional. Using current device use/nonuse as a binary outcome, logistic regression analyses were performed to identify the variables that predicted the highest percentage of variance in eSight use. RESULTS: The 109 (19.2%) respondents with complete data had a mean age of 47.7 years (SD = 25.4, range: 9-96), 51% self-reported a central visual impairment. The final regression model alternatives accounted for 84.7%, 68.7%, 83.7%, and 64.7% (Nagelkerke's pseudo R2) of the variance in eSight use. The most consistently predictive variables of sustained device use across models were: higher scores on the Psychological Impact of Assistive Devices Scale (PIADS) and the Quebec User Evaluation of Satisfaction with assistive Technology (QUEST) scale, and participants' lack of experiencing headaches while using the device. CONCLUSIONS: None of the traditional clinical variables (demographics, ocular, or general health), or LV rehabilitation experience was predictive of sustained use of a head-mounted LV display. However, the administration of standardized device-impact questionnaires may be able to identify device users that could benefit from individualized attention during LV rehabilitation provision to reduce the probability of device abandonment.Implications for rehabilitationInvestigating the factors predicting (non-)use of head-mounted magnification devices for low vision (LV) is important to identify patients with a higher risk of device nonuse and to provide evidence for interventions designed to improve use.The optimal combinations of our statistical analysis models highlighted the importance of individualized attention focusing on the user during LV rehabilitation provision of, and training with, head-mounted devices.Standardized device-related quality of life measures were robust predictors of device use and may be able to identify individuals that could benefit from individualized attention during LV rehabilitation.The absence of headaches while using a head-mounted magnification device was a robust predictor of continued use.User follow-up service satisfaction strongly predicted continued devices use, indicating that manufacturers and rehabilitation service organizations need to maintain a high level of service.

Fear and Coping in Students during the Early Stages of the COVID-19 Pandemic: A Combined Cross-Sectional and Longitudinal Study.

The overwhelming impacts of the COVID-19 pandemic have been experienced by individuals across the world. Additional circumstances unique to students affected their studies during the early stages of the pandemic, with changes in living and studying mid-semester. The current study aimed to investigate predictors of fear of COVID-19 in college students during this acute phase using cross-sectional and longitudinal samples. In total, 175 undergraduate students completed an online questionnaire in the spring 2020 semester following lockdown. A subset of 58 students completed a separate survey in fall 2019, which served as a baseline. For the cross-sectional sample, pre-COVID-19 and current living situations did not predict COVID-19 fears. However, a propensity to experience panic was significantly associated with greater COVID-19 fears. How students coped with the pandemic was not associated with COVID-19 fears, although a greater propensity to use denial as a coping style tended to be related to greater COVID-19 fears. In the longitudinal subsample, students showed decreased positive mood and social stress load while depressive mood increased after lockdown. Their preferred coping styles changed, utilizing more self-distraction and acceptance, and less self-blame and substance use. Findings reflect both positive and negative consequences of the pandemic. The unique changes in students' lifestyles will need to be met by tailored interventions.

Self-Perceived Mental Health Status, Digital Activity, and Physical Distancing in the Context of Lockdown Versus Not-in-Lockdown Measures in Italy and Croatia: Cross-Sectional Study in the Early Ascending Phase of the COVID-19 Pandemic in March 2020.

The novelty of the coronavirus disease 2019 (COVID-19) pandemic is that it is occurring in a globalized society enhanced by digital capabilities. Our aim was to analyze the psychological and emotional states of participants in different pandemic-related contexts, with a focus on their digital and physical distancing behaviors. The online survey was applied during the ascending phase of the pandemic in March 2020 in two neighboring EU countries: Italy and Croatia. The study subjects involved four groups, two directly affected by epidemiological measures and two serving as controls-(1) participants from Italy who were in lockdown (Italy group), (2) participants from Croatia who were not in lockdown but who were in direct contact with an infected person and underwent epidemiological measures (CRO-contact group), (3) participants from Croatia who were in an analogous situation but not near the same infected person (CRO-no contact group), and (4) participants from Croatia who were not aware of any infected person (CRO-unrelated group). The survey consisted of validated scales of psychological and emotional states, and custom-made questionnaires on the digital (online) and physical (off-line) behavior of the participants. The Italy group in lockdown had higher self-perceived scores for depression, stress, post-traumatic intrusion, and avoidance, as well as the highest digital activity and physical distancing than the not-in-lockdown Croatian groups. The insight into the extent of online activities and off-line isolation allowed for the introduction of Digital Activity and Physical Distancing Scores. Self-perceived post-traumatic avoidance was higher in both the Italy and CRO-contact groups than the control CRO-no contact and CRO-unrelated groups, and higher avoidance correlated with higher Digital Activity and Physical Distancing Scores. Being in direct contact with the infected person, the CRO-contact group had no other alterations than unexpectedly lower post-traumatic hyperarousal when compared with the Italy group. The Italy group in lockdown demonstrated higher self-perceived psychological toll together with higher digital activity and physical distancing than Croatian groups not in lockdown, even when compared with the affected CRO-contact group. The study outcomes suggest that the general emergency measures influenced citizens in lockdown more than exposure to the virus through direct contact with an infected person.

Hyperinsulinemia in Obesity, Inflammation, and Cancer.

The relative insufficiency of insulin secretion and/or insulin action causes diabetes. However, obesity and type 2 diabetes mellitus can be associated with an absolute increase in circulating insulin, a state known as hyperinsulinemia. Studies are beginning to elucidate the cause-effect relationships between hyperinsulinemia and numerous consequences of metabolic dysfunctions. Here, we review recent evidence demonstrating that hyperinsulinemia may play a role in inflammation, aging and development of cancers. In this review, we will focus on the consequences and mechanisms of excess insulin production and action, placing recent findings that have challenged dogma in the context of the existing body of literature. Where relevant, we elaborate on the role of specific signal transduction components in the actions of insulin and consequences of chronic hyperinsulinemia. By discussing the involvement of hyperinsulinemia in various metabolic and other chronic diseases, we may identify more effective therapeutics or lifestyle interventions for preventing or treating obesity, diabetes and cancer. We also seek to identify pertinent questions that are ripe for future investigation.

Breast Cancer Endocrine Therapy Promotes Weight Gain With Distinct Adipose Tissue Effects in Lean and Obese Female Mice.

Breast cancer survivors treated with tamoxifen and aromatase inhibitors report weight gain and have an elevated risk of type 2 diabetes, especially if they have obesity. These patient experiences are inconsistent with, preclinical studies using high doses of tamoxifen which reported acute weight loss. We investigated the impact of breast cancer endocrine therapies in a preclinical model of obesity and in a small group of breast adipose tissue samples from women taking tamoxifen to understand the clinical findings. Mature female mice were housed at thermoneutrality and fed either a low-fat/low-sucrose (LFLS) or a high-fat/high-sucrose (HFHS) diet. Consistent with the high expression of Esr1 observed in mesenchymal stem cells from adipose tissue, endocrine therapy was associated with adipose accumulation and more preadipocytes compared with estrogen-treated control mice but resulted in fewer adipocyte progenitors only in the context of HFHS. Analysis of subcutaneous adipose stromal cells revealed diet- and treatment-dependent effects of endocrine therapies on various cell types and genes, illustrating the complexity of adipose tissue estrogen receptor signaling. Breast cancer therapies supported adipocyte hypertrophy and associated with hepatic steatosis, hyperinsulinemia, and glucose intolerance, particularly in obese females. Current tamoxifen use associated with larger breast adipocyte diameter only in women with obesity. Our translational studies suggest that endocrine therapies may disrupt adipocyte progenitors and support adipocyte hypertrophy, potentially leading to ectopic lipid deposition that may be linked to a greater type 2 diabetes risk. Monitoring glucose tolerance and potential interventions that target insulin action should be considered for some women receiving life-saving endocrine therapies for breast cancer.

Interplay between amplified spontaneous emission, Forster resonant energy transfer, and self-absorption in hybrid poly(9,9-dioctylfluorene)-CdSe/ZnS nanocrystal thin films.

We investigated the excitation density dependence of the photoluminescence spectra of hybrid poly(9,9-dioctylfluorene)-CdSe/ZnS nanocrystals (PF8-NCs) thin films. We demonstrate that this experiment allows the determination of the efficiency of all the CdSe/ZnS NCs excitation processes and that the presence of amplified spontaneous emission (ASE) from the PF8 leads to a strong dependence of the NC excitation processes from the laser excitation density. Below the PF8 ASE threshold only about 6% of the excitons in the NCs are due to pump laser absorption, while about 94% of the NC excitation is due to the interaction with the PF8, and it is due for about 58% to PF8-->NC Forster resonant energy transfer (FRET) and for about 37% to reabsorption by the NCs of the PF8 luminescence. The presence of PF8 ASE significantly modifies this scenario by strongly decreasing the FRET importance and strongly increasing the reabsorption one. The interplay between reduced FRET and increased reabsorption overall decreases the NC excitation due to PF8 indicating that ASE from the donors should be avoided if efficient NCs excitation under strong pumping is wished.

Positive social feedback alters emotional ratings and reward valuation of neutral faces.

Evaluation of facial and vocal emotional cues is vital in social interactions but can be highly influenced by characteristics of the observer, such as sex, age, and symptoms of affective disorders. Our evaluations of others' emotional expressions are likely to change as we get to know them and anticipate how they are likely to behave. However, the role of associative learning in the evaluation of social cues remains poorly understood. In this study, we investigated whether emotional ratings (valence and arousal) and reward valuation ("liking" and "wanting" measures) of neutral facial expressions can be altered through associative learning. We also examined whether emotional ratings and reward valuation varied with symptoms of anxiety and depression, disorders known to impair socio-affective functioning. Participants (N = 324) were young adults, ranging in scores across dimensions of depression and anxiety symptoms: "general distress" (common to depression and anxiety), "anhedonia-apprehension" (more specific to depression), and "fears" (more specific to anxiety). They rated neutral faces and completed a probabilistic learning task that paired images of neutral faces with positive or negative social feedback. Results demonstrated that pairing neutral faces with positive social feedback increased ratings of arousal, valence, and reward valuation (both "liking" and "wanting"). Pairing neutral faces with negative feedback reduced valence ratings and reduced "wanting," but did not impact arousal ratings or "liking." Symptoms of general distress were associated with negative bias in valence ratings, symptoms of anhedonia-apprehension were associated with reduced "wanting," and symptoms of fears were associated with altered accuracy over trials. Notably, the association between general distress and negative bias was reduced following the associative learning task. This suggests that disrupted evaluation of social cues can be improved through brief training.

PRDM3 attenuates pancreatitis and pancreatic tumorigenesis by regulating inflammatory response.

Pancreatic ductal adenocarcinoma (PDAC) is associated with metaplastic changes in the pancreas but the transcriptional program underlying these changes is incompletely understood. The zinc finger transcription factor, PRDM3, is lowly expressed in normal pancreatic acini and its expression increases during tumorigenesis. Although PRDM3 promotes proliferation and migration of PDAC cell lines, the role of PRDM3 during tumor initiation from pancreatic acinar cells in vivo is unclear. In this study, we showed that high levels of PRDM3 expression in human pancreas was associated with pancreatitis, and well-differentiated but not poorly differentiated carcinoma. We examined PRDM3 function in pancreatic acinar cells during tumor formation and pancreatitis by inactivating Prdm3 using a conditional allele (Ptf1aCreER;Prdm3flox/flox mice) in the context of oncogenic Kras expression and supraphysiological cerulein injections, respectively. In Prdm3-deficient mice, KrasG12D-driven preneoplastic lesions were more abundant and progressed to high-grade precancerous lesions more rapidly. This is consistent with our observations that low levels of PRDM3 in human PDAC was correlated significantly with poorer survival in patient. Moreover, loss of Prdm3 in acinar cells elevated exocrine injury, enhanced immune cell activation and infiltration, and greatly increased acinar-to-ductal cell reprogramming upon cerulein-induced pancreatitis. Whole transcriptome analyses of Prdm3 knockout acini revealed that pathways involved in inflammatory response and Hif-1 signaling were significantly upregulated in Prdm3-depleted acinar cells. Taken together, our results suggest that Prdm3 favors the maintenance of acinar cell homeostasis through modulation of their response to inflammation and oncogenic Kras activation, and thus plays a previously unexpected suppressive role during PDAC initiation.

Wounding response in xylem of Scots pine seedlings shows wide genetic variation and connection with the constitutive defence of heartwood.

In this greenhouse experiment, 3-year-old Scots pine (Pinus sylvestris L.) seedlings were wounded by drilling holes through the stem. In the xylem next to the wound, the concentration of resin acids (RAC) increased, and the production of extractives typical for heartwood (stilbenes) and knotwood (stilbenes and lignans) of mature trees was induced. The induced stilbenes were pinosylvin (PS) and pinosylvin monomethyl ether (PSM), and the lignans nortrachelogenin (NTG) and matairesinol (MR). There was positive phenotypic correlation between concentrations of the different extractives. Except for the RAC, the extractive concentrations showed no correlation with the size of the seedlings. The treated seedlings belonged to half-sib families, which enabled the estimation of the genetic parameters for the response variables. The proportion of heritable variation (heritability, h(2)) in the concentration of PS, NTG and MR varied between 0.71 and 1.03, whereas for PSM and RAC the heritability was lower (0.35 and 0.31). Genetic correlation was significant between PS and PSM (r = 0.55, P = 0.018), and between NTG and MR (r = 0.50, P = 0.033). Heritabilities were also estimated on the basis of the regression of the offspring on their mothers h(2)(0P). These estimates were assessed for the concentration of PS, PSM and RAC in the wound response area of the seedlings and correspondingly in the heartwood of their mothers. The heritability was highest for the concentration of PS h(2)(0P). The findings of this study support the suggestion that the wounding of Scots pine seedlings may facilitate the development of an early testing method for breeding heartwood durability.

Study protocol: A multisite trial of Work-Related Cognitive behavioral therapy for unemployed persons with social anxiety.

This paper provides a methodological description of a multi-site, randomized controlled trial (RCT) of a cognitive-behavioral intervention for enhancing employment success among unemployed persons whose employment efforts have been undermined by social anxiety disorder (SAD). SAD is a common and impairing condition, with negative impacts on occupational functioning. In response to these documented employment-related impairments, in a previous project, we produced and tested an eight-session work-related group cognitive-behavioral therapy provided alongside vocational services as usual (WCBT + VSAU). WCBT is delivered by vocational service professionals and is designed in a context and style that overcomes accessibility and stigma-related obstacles with special focus on employment-related targets. Our previous project found that WCBT + VSAU significantly improved social anxiety, depression, and a range of employment-related outcomes compared to a control group of socially anxious job-seekers who received vocational services as usual without WCBT (VSAU-alone). Participants in this study were all homeless, primarily African American job-seekers with high levels of psychiatric comorbidity and limited education and employment histories. The present, two-region study addresses whether WCBT + VSAU enhances job placement, job retention and mental health outcomes in a larger sample assessed over an extended follow-up period. In addition, this trial evaluates whether the effects of WCBT + VSAU generalize to a new population of urban-based, racially diverse job-seekers with vocational and educational histories that differ from our original sample. This study also investigates the system-effects of WCBT + VSAU in a new site that will be informative for broad implementation of WCBT + VSAU. Finally, this project involves a refined, technology-assisted form of WCBT + VSAU designed to be delivered more easily by vocational services professionals.

Can modulation of mammary gland development by dietary factors support breast cancer prevention?

Breast cancer continues to be a major challenge for public health, since it is the most common cancer of women in the Western world, and its prevalence is still increasing. In order to achieve better results in the prevention and treatment of breast cancer it is crucial to identify the mechanisms behind its initiation, i.e. the changes and deviations that have occurred in the mammary gland growth. It has long been known that a woman's reproductive history is the strongest breast cancer risk factor if genetic background and age are excluded. The reproductive hormones, and the timing of events leading to changes in these hormones, and consequently, in the mammary gland, are the most important players. However, it has become obvious that dietary components may also contribute to breast cancer risk through their effects on the mammary gland. The past few years have added important information to our knowledge of the mechanisms behind breast cancer initiation at the level of target cells (mammary stem cells) and gene expression (genetic 'fingerprint' associated with persistent pregnancy-induced protection against breast cancer), as well as of the effects of certain dietary factors (steroid action modulators). These results and their links to breast cancer initiation and progression will be discussed.

Optical properties of N-succinimidyl bithiophene and the effects of the binding to biomolecules: comparison between coupled-cluster and time-dependent density functional theory calculations and experiments.

We report a joint theoretical-experimental study on the optical properties of 5-N-succinimidyl-2,2'-bithiophene (NS-2T), a prototype system for a new class of biomarkers. Time-dependent density functional theory (TD-DFT) and approximate coupled-cluster single and doubles (CC2) calculations are performed in the ground and excited states. Theoretical results are compared with absorption, photoluminescence (PL), time-resolved PL, and PL quantum efficiency measurements. The excited state of NS-2T has a larger dipole moment as compared to that of the ground state, explaining the experimental shift of the PL peak in solvents of different polarity, and a smaller intersystem crossing (ISC) rate as compared to that of isolated bithiophene (2T), explaining the increased PL quantum efficiency. We also studied two model systems to describe the effects of the covalent binding of NS-2T to biomolecules and proteins with the epsilon-NH(2) lysine groups. These model systems show optical properties closer to 2T, as the PL quantum efficiency is reduced due to the increased ISC rate. Theoretical calculations and experimental results show that covalent binding of NS-2T to a biomolecule will blue-shift the absorption but not the photoluminescence. CC2 and TD-DFT can very well describe the absorption and photoluminescence energies of all three systems, but the presence of several charge-transfer transitions in the TD-DFT spectrum of NS-2T required the use of a correlated method to validate the TD-DFT results.

Hyperinsulinemia in Obesity, Inflammation, and Cancer

The relative insufficiency of insulin secretion and/or insulin action causes diabetes. However, obesity and type 2 diabetes mellitus can be associated with an absolute increase in circulating insulin, a state known as hyperinsulinemia. Studies are beginning to elucidate the cause-effect relationships between hyperinsulinemia and numerous consequences of metabolic dysfunctions. Here, we review recent evidence demonstrating that hyperinsulinemia may play a role in inflammation, aging and development of cancers. In this review, we will focus on the consequences and mechanisms of excess insulin production and action, placing recent findings that have challenged dogma in the context of the existing body of literature. Where relevant, we elaborate on the role of specific signal transduction components in the actions of insulin and consequences of chronic hyperinsulinemia. By discussing the involvement of hyperinsulinemia in various metabolic and other chronic diseases, we may identify more effective therapeutics or lifestyle interventions for preventing or treating obesity, diabetes and cancer. We also seek to identify pertinent questions that are ripe for future investigation.