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This article presents new archaeological observations and multidisciplinary research from Dor, Israel to establish a more reliable relative sea level for the Carmel Coast and Southern Levant between the Middle Bronze Age and the Roman period (ca. 3500-1800 y BP). Our record indicates a period of low relative sea level, around -2.5 m below present, from the Middle Bronze Age to the Hellenistic period (ca. 3500-2200 y BP). This was followed by a rapid rise to present levels, starting in the Hellenistic period and concluding during the Roman period (ca. 2200-1800 y BP). These Roman levels agree with other relative sea-level indications from Israel and other tectonically stable areas in the Mediterranean. Several relative sea-level reconstruction models carried out in the current study provide different predictions due to their parameters and do not model the changes observed from field data which points to a non-isostatic origin for the changes. Long-term low stable Iron Age relative sea level can be seen in Dor, where Iron Age harbor structures remain around the same elevation between ca. 3100-2700 y BP. A similar pattern occurs at Atlit, the Iron Age harbor to the north used continuously from ca. 2900 y BP to the beginning of the Hellenistic period (ca. 2200 y BP). An examination of historical and archaeological sources reveals decline and occasional disappearance of Hellenistic sites along the coast of Israel at ca. 2200 y BP (2nd century BCE), as in the case of Yavneh Yam, Ashdod Yam, Straton's Tower, and tel Taninim. In Akko-Ptolemais, the large harbor installations built in the Hellenistic period were never replaced by a substantial Roman harbor. The conclusions of this research are thus relevant for the sea-level research community and for the historical analyses of the Israeli and South Levantine coastline.

Tsunami events in antiquity had a profound influence on coastal societies. Six thousand years of historical records and geological data show that tsunamis are a common phenomenon affecting the eastern Mediterranean coastline. However, the possible impact of older tsunamis on prehistoric societies has not been investigated. Here we report, based on optically stimulated luminescence chronology, the earliest documented Holocene tsunami event, between 9.91 to 9.29 ka (kilo-annum), from the eastern Mediterranean at Dor, Israel. Tsunami debris from the early Neolithic is composed of marine sand embedded within fresh-brackish wetland deposits. Global and local sea-level curves for the period, 9.91-9.29 ka, as well as surface elevation reconstructions, show that the tsunami had a run-up of at least ~16 m and traveled between 3.5 to 1.5 km inland from the palaeo-coastline. Submerged slump scars on the continental slope, 16 km west of Dor, point to the nearby "Dor-complex" as a likely cause. The near absence of Pre-Pottery Neolithic A-B archaeological sites (11.70-9.80 cal. ka) suggest these sites were removed by the tsunami, whereas younger, late Pre-Pottery Neolithic B-C (9.25-8.35 cal. ka) and later Pottery-Neolithic sites (8.25-7.80 cal. ka) indicate resettlement following the event. The large run-up of this event highlights the disruptive impact of tsunamis on past societies along the Levantine coast.

The article presents results of residue analysis, based on Gas Chromatograph Mass Spectrometer (GC-MS) measurements, conducted on 13 ceramic storage jars unearthed in the Babylonian destruction layer (586 BCE) in Jerusalem. Five of the jars bear rosette stamp impressions on their handles, indicating that their content was related to the kingdom of Judah's royal economy. The identification of the original contents remains is significant for the understanding of many aspects related to the nutrition, economy and international trade in the ancient Levant. The study shed light on the contents of the jars and the destruction process of the buildings in which they were found. The jars were used alternatively for storing wine and olive oil. The wine was flavored with vanilla. These results attest to the wine consumption habits of the Judahite elite and echo Jerusalem's involvement in the trans-regional South Arabian trade of spices and other lucrative commodities on the eve of its destruction by Nebuchadnezzar.

Telomere length (TL) is widely studied as a possible biomarker for stress-related cellular aging and decreased longevity. There have been conflicting findings about the relationship between family caregiving stress and TL. Several initial cross-sectional studies have found associations between longer duration of caregiving or perceived stressfulness of caregiving and shortened TL, suggesting that caregiving poses grave risks to health. Previous reviews have suggested the need for longitudinal methods to investigate this topic. This study examined the association between the transition to family caregiving and change in TL across ~9 years. Data was utilized from the Caregiving Transitions Study, an ancillary study to the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study. TL was assayed using qPCR and analyzed as the telomere-to-single copy gene ratio for each participant at baseline and follow-up. General linear models examined the association between caregiving status and the change in TL for 208 incident caregivers and 205 controls, as well as associations between perceived stress and TL among caregivers. No association was found between TL change and caregiving (p = 0.494), and fully adjusted models controlling for health and socioeconomic factors did not change the null relationship (p = 0.305). Among caregivers, no association was found between perceived caregiving stress and change in TL (p = 0.336). In contrast to earlier cross-sectional studies, this longitudinal, population-based study did not detect a significant relationship between the transition into a family caregiving role and changes in TL over time. Given the widespread citation of previous findings suggesting that caregiving shortens telomeres and places caregivers at risk of early mortality, these results demonstrate the potential need of a more balanced narrative about caregiving.

OBJECTIVE:The American College of Gynecology (ACOG) recommendation does not limit air travel during pregnancy, yet the evidence for air travel effect on adverse pregnancy outcomes is limited and debatable. Study objectives were to examine the association between air travel during pregnancy and preterm birth together with decreased birth weight. STUDY DESIGN:A retrospective cohort study. METHODS:The study evaluated 628,292 women who gave birth to singleton infants from 9/2000 to 9/2016 and classified them into "air travel during pregnancy" or not, based on flight insurance as proxy. Multiple linear regression models were utilized to examine the relationship between air travel during pregnancy and newborn's gestational age and birth weight, while accounting for socioeconomic status, diabetes, high-risk pregnancies, and smoking. RESULTS:A total of 41,677 (6.6%) births of women who air traveled during pregnancy was included, and 586,615 (93.4%) births of women who did not. Air travel during pregnancy was associated with a statistically significant (p

[This corrects the article DOI: 10.1371/journal.pone.0243619.].

This article presents new archaeological observations and multidisciplinary research from Dor, Israel to establish a more reliable relative sea level for the Carmel Coast and Southern Levant between the Middle Bronze Age and the Roman period (ca. 3500-1800 y BP). Our record indicates a period of low relative sea level, around -2.5 m below present, from the Middle Bronze Age to the Hellenistic period (ca. 3500-2200 y BP). This was followed by a rapid rise to present levels, starting in the Hellenistic period and concluding during the Roman period (ca. 2200-1800 y BP). These Roman levels agree with other relative sea-level indications from Israel and other tectonically stable areas in the Mediterranean. Several relative sea-level reconstruction models carried out in the current study provide different predictions due to their parameters and do not model the changes observed from field data which points to a non-isostatic origin for the changes. Long-term low stable Iron Age relative sea level can be seen in Dor, where Iron Age harbor structures remain around the same elevation between ca. 3100-2700 y BP. A similar pattern occurs at Atlit, the Iron Age harbor to the north used continuously from ca. 2900 y BP to the beginning of the Hellenistic period (ca. 2200 y BP). An examination of historical and archaeological sources reveals decline and occasional disappearance of Hellenistic sites along the coast of Israel at ca. 2200 y BP (2nd century BCE), as in the case of Yavneh Yam, Ashdod Yam, Straton's Tower, and tel Taninim. In Akko-Ptolemais, the large harbor installations built in the Hellenistic period were never replaced by a substantial Roman harbor. The conclusions of this research are thus relevant for the sea-level research community and for the historical analyses of the Israeli and South Levantine coastline.

Paleomagnetic analysis of archaeological materials is crucial for understanding the behavior of the geomagnetic field in the past. As it is often difficult to accurately date the acquisition of magnetic information recorded in archaeological materials, large age uncertainties and discrepancies are common in archaeomagnetic datasets, limiting the ability to use these data for geomagnetic modeling and archaeomagnetic dating. Here we present an accurately dated reconstruction of the intensity and direction of the field in Jerusalem in August, 586 BCE, the date of the city's destruction by fire by the Babylonian army, which marks the end of the Iron Age in the Levant. We analyzed 54 floor segments, of unprecedented construction quality, unearthed within a large monumental structure that had served as an elite or public building and collapsed during the conflagration. From the reconstructed paleomagnetic directions, we conclude that the tilted floor segments had originally been part of the floor of the second story of the building and cooled after they had collapsed. This firmly connects the time of the magnetic acquisition to the date of the destruction. The relatively high field intensity, corresponding to virtual axial dipole moment (VADM) of 148.9 ± 3.9 ZAm2, accompanied by a geocentric axial dipole (GAD) inclination and a positive declination of 8.3°, suggests instability of the field during the 6th century BCE and redefines the duration of the Levantine Iron Age Anomaly. The narrow dating of the geomagnetic reconstruction enabled us to constrain the age of other Iron Age finds and resolve a long archaeological and historical discussion regarding the role and dating of royal Judean stamped jar handles. This demonstrates how archaeomagnetic data derived from historically-dated destructions can serve as an anchor for archaeomagnetic dating and its particular potency for periods in which radiocarbon is not adequate for high resolution dating.

Tsunami events in antiquity had a profound influence on coastal societies. Six thousand years of historical records and geological data show that tsunamis are a common phenomenon affecting the eastern Mediterranean coastline. However, the possible impact of older tsunamis on prehistoric societies has not been investigated. Here we report, based on optically stimulated luminescence chronology, the earliest documented Holocene tsunami event, between 9.91 to 9.29 ka (kilo-annum), from the eastern Mediterranean at Dor, Israel. Tsunami debris from the early Neolithic is composed of marine sand embedded within fresh-brackish wetland deposits. Global and local sea-level curves for the period, 9.91-9.29 ka, as well as surface elevation reconstructions, show that the tsunami had a run-up of at least ~16 m and traveled between 3.5 to 1.5 km inland from the palaeo-coastline. Submerged slump scars on the continental slope, 16 km west of Dor, point to the nearby "Dor-complex" as a likely cause. The near absence of Pre-Pottery Neolithic A-B archaeological sites (11.70-9.80 cal. ka) suggest these sites were removed by the tsunami, whereas younger, late Pre-Pottery Neolithic B-C (9.25-8.35 cal. ka) and later Pottery-Neolithic sites (8.25-7.80 cal. ka) indicate resettlement following the event. The large run-up of this event highlights the disruptive impact of tsunamis on past societies along the Levantine coast.

ObjectiveExposure to early-life adversity (ELA) can result in long-term changes to physiological systems, which predispose individuals to negative health outcomes. This biological embedding of stress-responsive systems may operate via dysregulation of physiological resources in response to common stressors. The present pilot study outlines a novel experimental design to test how young adults' exposure to ELA influences neuroendocrine and inflammatory responses to acute stress.Materials and methodsParticipants were 12 males (mean age = 21.25), half of whom endorsed at least three significant adverse events up to age 18 years ('ELA group'), and half who confirmed zero ('controls'). Using a randomized within-subjects, between-groups experimental design, we induced acute psychosocial stress (Trier Social Stress Test, TSST), and included a no-stress control condition one week apart. During these sessions, we obtained repeated measurements of physiological reactivity, gene expression of the glucocorticoid receptor (NR3C1), and plasma levels of pro-inflammatory cytokines (IL-1β, IL-6, IL-8 and TNFα) over a 4-hour window post-test.ResultsIn this pilot study, the ELA group evinced higher cortisol response and blunted NR3C1 gene expression in response to the TSST compared with controls, while no differences were observed in the no-stress condition. For pro-inflammatory cytokines, only IL-6 increased significantly in response to the TSST, with no differences between the two groups.ConclusionOverall, this pilot feasibility study provides a framework to investigate the biological embedding of early-adversity via dysregulation across physiological and genomic systems in response to acute psychosocial stress. ELA may program such systems in a maladaptive manner more likely to manifest during times of duress, predisposing individuals to the negative health consequences of everyday stressors. Future studies with larger sample size including both males and females are needed to replicate and expand upon these preliminary findings.

OBJECTIVES:Affective disorders are among the most prevalent disorders in the elderly. The present study aims to examine the sociodemographic and clinical correlates of major depressive disorder (MDD) and dysthymia in different European and Associated countries using standardized interview techniques. Furthermore, service utilization for the elderly with depression is assessed. METHODS:The MentDis_ICF65+ study is a cross-sectional survey (N = 3,142) that was conducted in six different European and Associated countries (Germany, Italy, Spain, Switzerland, England and Israel) with a subsample of n = 463 elderly with any depressive disorder. RESULTS:Sociodemographic and clinical correlates, such as gender, age and symptom severity, were significantly associated with MDD and dysthymia in the elderly. Only 50% of elderly with any depressive disorder were treated with psycho- or pharmacotherapy. CONCLUSION:Our findings identified sociodemographic and clinical characteristics for depression risk in the elderly and highlight the need to improve service delivery to older adults who suffer from depression.

ObjectiveTo investigate whether binge-eating in patients with eating disorders (EDs) is associated with attentional deficits.MethodsWe studied ED patients with binge-eating (n = 51), no binge-eating (n = 59) and controls (n = 58). ED patients were assessed following the stabilization of weight and ED pathology. Attention assessment included evaluation of attention deficit hyperactivity disorder (ADHD) diagnosis, the Adult ADHD Self-Report (ASRS) and ADHD Rating Scale-IV-Home Version (ADHD-RS) questionnaires, and attention functioning assessed with neuropsychological tools. The severity of eating-related pathology, depression, anxiety and obsessionality was also monitored.ResultsPatients with binge-eating showed more ADHD symptomatology on the ADHD-RS compared with non-binge-eating patients. No differences were found between binge-eating and non-binge-eating patients in ADHD diagnosis and neuropsychological functioning. Among the specific ED subtypes, patients with anorexia nervosa binge/purge type (AN-B/P) showed the highest rates of ADHD symptomatology on the ADHD-RS, and were characterized with sustained attention deficits.ConclusionBinge-eating is not associated with attention deficits as measured by objective neuropsychological tools. Nonetheless, it is associated with attentional difficulties as measured with the self-reported ADHD-RS. AN-B/P patients are the only ED category showing objective sustained attention deficits.

Desert communities world-wide are used as natural laboratories for the study of convergent evolution, yet inferences drawn from such studies are necessarily indirect. Here, we brought desert organisms together (rodents and vipers) from two deserts (Mojave and Negev). Both predators and prey in the Mojave have adaptations that give them competitive advantage compared to their middle-eastern counterparts. Heteromyid rodents of the Mojave, kangaroo rats and pocket mice, have fur-lined cheek pouches that allow them to carry larger loads of seeds under predation risk compared to gerbilline rodents of the Negev Deserts. Sidewinder rattlesnakes have heat-sensing pits, allowing them to hunt better on moonless nights when their Negev sidewinding counterpart, the Saharan horned vipers, are visually impaired. In behavioral-assays, we used giving-up density (GUD) to gauge how each species of rodent perceived risk posed by known and novel snakes. We repeated this for the same set of rodents at first encounter and again two months later following intensive "natural" exposure to both snake species. Pre-exposure, all rodents identified their evolutionarily familiar snake as a greater risk than the novel one. However, post-exposure all identified the heat-sensing sidewinder rattlesnake as a greater risk. The heteromyids were more likely to avoid encounters with, and discern the behavioral difference among, snakes than their gerbilline counterparts.

Alcohol use disorders (AUD) in older people have been the subject of increasing interest in Europe and worldwide. However, thus far, no reliable data exist regarding the prevalence of AUD in people over the age of 65 years in Europe.To assess the current (past month), 12-month and lifetime prevalence of alcohol use, abuse and dependence in people aged 65-84 years.The MentDis_ICF65+ study was a representative stepwise cross-sectional survey that was conducted in six European and associated cities (Hamburg, Germany; Ferrara, Italy; London/Canterbury, England; Madrid, Spain; Geneva, Switzerland and Jerusalem, Israel).In total, 3,142 community-dwelling people aged between 65 and 84 years who lived in participating cities were assessed with an age-sensitive diagnostic interview (CIDI65+).The prevalence of lifetime alcohol use was 81% for the overall sample. The observed AUD (DSM-IV-TR) prevalence was as follows: current, 1.1%; 12-month, 5.3% and lifetime, 8.8%. Alcohol consumption and AUD were more prevalent in males, and a significant interaction between gender and city was observed; greater gender differences in the prevalence of these disorders were observed in Hamburg, London/Canterbury and Geneva in comparison to the other cities. The prevalence of lifetime alcohol consumption and 12-month AUD tended to be lower in older persons.The results highlight the appropriateness of using age-adjusted diagnostic tools (CIDI65+) to identify alcohol use and AUD in older people. Different alcohol use patterns were observed in males and females. The results seem to indicate the presence of different alcohol use patterns between northern and southern European countries. Specialized services are proposed, including brief and/or more intensive interventions framed intensive and more simple interventions framed in stepped care strategies, to improve the social and health resources available for older people across Europe.

Food entrainment is the internal mechanism whereby the phase and period of circadian clock genes comes under the control of daily scheduled food availability. Food entrainment allows the body to efficiently realign the internal timing of behavioral and physiological functions such that they anticipate food intake. Food entrainment can occur with or without caloric restriction, as seen with daily schedules of restricted feeding (RF) or restricted treat (RT) that restrict food or treat intake to a single feeding time. However, the extent of clock gene control is more pronounced with caloric restriction, highlighting the role of energy balance in regulating clock genes. Recent studies have implicated dopamine (DA) to be involved in food entrainment and caloric restriction is known to affect dopaminergic pathways to enhance locomotor activity. Since food entrainment results in the development of a distinct behavioral component, called food anticipatory activity (FAA), we examined the role of locomotor sensitization (LS) in food entrainment by 1) observing whether amphetamine (AMPH) sensitization results in enhanced locomotor output of FAA and 2) measuring LS of circadian and non-circadian feeding paradigms to an acute injection of AMPH (AMPH cross-sensitization). Unexpectedly, AMPH sensitization did not show enhancement of FAA. On the contrary, LS did develop with sufficient exposure to RF. LS was present after 2 weeks of RF, but not after 1, 3 or 7 days into RF. When food was returned and rats regain their original body weight at 10-15 days post-RF, LS remained present. LS did not develop to RT, nor to feedings of a non-circadian schedule, e.g. variable restricted feeding (VRF) or variable RT (VRT). Further, when RF was timed to the dark period, LS was observed only when tested at night; RF timed to the light period resulted in LS that was present during day and night. Taken together our results show that LS develops with food entrainment to RF, an effect that is dependent on the chronicity and circadian phase of RF but independent of body weight. Given that LS involves reorganization of DA-regulated motor circuitry, our work provides indirect support for the role of DA in the food entrainment pathway of RF. The findings also suggest differences in neuronal pathways involved in LS from AMPH sensitization and LS from RF.

Individuals with colorectal cancer (CRC) have a tendency to intestinal bleeding which may result in mild to severe iron deficiency anemia, but for many colon cancer patients hematological abnormalities are subtle. The fecal occult blood test (FOBT) is used as a pre-screening test whereby those with a positive FOBT are referred to colonscopy. We sought to determine if information contained in the complete blood count (CBC) report coud be processed automatically and used to predict the presence of occult colorectal cancer (CRC) in the setting of a large health services plan. Using the health records of the Maccabi Health Services (MHS) we reviewed CBC reports for 112,584 study subjects of whom 133 were diagnosed with CRC in 2008 and analysed these with the MeScore tool. The odds ratio for being diagnosed with CRC in 2008 was calculated with regards to the MeScore, using cutoff levels of 97% and 99% percentiles. For individuals in the highest one percentile, the odds ratio for CRC was 21.8 (95% CI 13.8 to 34.2). For the majority of the individuals with cancer, CRC was not suspected at the time of the blood draw. Frequent use of anticoagulants, the presence of other gastrointestinal pathologies and non-GI malignancies were assocaitged with false positive MeScores. The MeScore can help identify individuals in the population who would benefit most from CRC screening, including those with no clinical signs or symptoms of CRC.

Evidence is conflicting regarding the association between Helicobacter pylori infection and diabetes mellitus. The study objective was to examine associations of H. pylori infection, gastric ulcers and duodenal ulcers, with diabetes mellitus.This cross-sectional study was undertaken using coded data from the computerized database of Maccabi Health Services in Israel, on 147,936 individuals aged 25-95 years who underwent the urea breath test during 2002-2012. Multiple logistic regression models were conducted, while adjusting for known risk factors for diabetes mellitus.A H. pylori positive test was recorded for 76,992 (52.0%) individuals and diabetes for 12,207 (8.3%). The prevalence of diabetes was similar in individuals with and without H. pylori infection, but this association was modified (P for heterogeneity 0.049) by body mass index (BMI): adjusted odds ratio (aOR) 1.16 (95% confidence intervals (CI) 1.04-1.29) in persons with BMI

Altered brain anatomy in specific gray-matter regions has been shown in patients with posttraumatic stress disorder (PTSD). Recently, white-matter tracts have become a focus of research in PTSD. The corpus callosum (CC) is the principal white-matter fiber bundle, crucial in relaying sensory, motor and cognitive information between hemispheres. Alterations in CC fibers have been reported in PTSD and might be assumed to underlie substantial behavioral and cognitive sequelae; however most diffusion tensor imaging (DTI) studies in adult-onset PTSD failed to address the clinical correlates between imaging and PTSD symptoms severity, behavioral manifestation and cognitive functions. In the current study we examined (a) to what extent microstructural integrity of the CC is associated with memory performance and (b) whether imaging and cognitive parameters are associated with PTSD symptom severity. DTI data were obtained and fractional anisotropy (FA) values were computed for 16 patients and 14 controls. PTSD symptom severity was assessed by employing the clinician administered PTSD scale (CAPS) and memory was tested using a task probing item and associative memory for words and pictures. Significant correlations were found between PTSD symptoms severity, memory accuracy and reaction-time to CC FA values in the PTSD group. This study demonstrates meaningful clinical and cognitive correlates of microstructural connectivity. These results have implications for diagnostic tools and future studies aimed at identifying individuals at risk for PTSD.

Uncovering heterogeneities in the progression of early PTSD symptoms can improve our understanding of the disorder's pathogenesis and prophylaxis.To describe discrete symptom trajectories and examine their relevance for preventive interventions.Latent Growth Mixture Modeling (LGMM) of data from a randomized controlled study of early treatment. LGMM identifies latent longitudinal trajectories by exploring discrete mixture distributions underlying observable data.Hadassah Hospital unselectively receives trauma survivors from Jerusalem and vicinity.Adult survivors of potentially traumatic events consecutively admitted to the hospital's emergency department (ED) were assessed ten days and one-, five-, nine- and fifteen months after ED admission. Participants with data at ten days and at least two additional assessments (n = 957) were included; 125 received cognitive behavioral therapy (CBT) between one and nine months.We used LGMM to identify latent parameters of symptom progression and tested the effect of CBT on these parameters. CBT consisted of 12 weekly sessions of either cognitive therapy (n = 41) or prolonged exposure (PE, n = 49), starting 29.8±5.7 days after ED admission, or delayed PE (n = 35) starting at 151.8±42.4 days. CBT effectively reduced PTSD symptoms in the entire sample.Latent trajectories of PTSD symptoms; effects of CBT on these trajectories.THREE TRAJECTORIES WERE IDENTIFIED: Rapid Remitting (rapid decrease in symptoms from 1- to 5-months; 56% of the sample), Slow Remitting (progressive decrease in symptoms over 15 months; 27%) and Non-Remitting (persistently elevated symptoms; 17%). CBT accelerated the recovery of the Slow Remitting class but did not affect the other classes.The early course of PTSD symptoms is characterized by distinct and diverging response patterns that are centrally relevant to understanding the disorder and preventing its occurrence. Studies of the pathogenesis of PTSD may benefit from using clustered symptom trajectories as their dependent variables.

The beginning of metallurgy in the ancient Near East attracts much attention. The southern Levant, with the rich assemblage of copper artifacts from the Nahal Mishmar cave and the unique gold rings of the Nahal Qanah cave, is regarded as a main center of early metallurgy during the second half of the 5th millennium CalBC. However, a recently discovered copper awl from a Middle Chalcolithic burial at Tel Tsaf, Jordan Valley, Israel, suggests that cast metal technology was introduced to the region as early as the late 6th millennium CalBC. This paper examines the chemical composition of this item and reviews its context. The results indicate that it was exported from a distant source, probably in the Caucasus, and that the location where it was found is indicative of the social status of the buried individual. This rare finding indicates that metallurgy was first diffused [corrected] to the southern Levant through exchange networks and only centuries later involved local productionThis copper awl, the earliest metal artifact found in the southern Levant, indicates that the elaborate Late Chalcolithic metallurgy developed from a more ancient tradition.

Mounting effective innate and adaptive immune responses are critical for viral clearance and the generation of long lasting immunity. It is known that production of inhibitory factors may result in the inability of the host to clear viruses, resulting in chronic viral persistence. Fibrinogen-like protein 2 (FGL2) has been identified as a novel effector molecule of CD4(+)CD25(+) Foxp3(+) regulatory T (Treg) cells that inhibits immune activity by binding to FCγRIIB expressed primarily on antigen presenting cells (APC). In this study, we show that infection of mice with Lymphocytic Choriomeningitis Virus WE (LCMV WE) leads to increased plasma levels of FGL2, which were detected as early as 2 days post-infection (pi) and persisted until day 50 pi. Mice deficient in FGL2 (fgl2(-/-)) had increased viral titers of LCMV WE in the liver early p.i but cleared the virus by day 12 similar to wild type mice. Dendritic cells (DC) isolated from the spleens of LCMV WE infected fgl2(-/-) had increased expression of the DC maturation markers CD80 and MHC Class II compared to wild type (fgl2(+/+)). Frequencies of CD8(+) and CD4(+) T cells producing IFNγ in response to ex vivo peptide re-stimulation isolated from the spleen and lymph nodes were also increased in LCMV WE infected fgl2(-/-) mice. Increased frequencies of CD8(+) T cells specific for LCMV tetramers GP33 and NP396 were detected within the liver of fgl2(-/-) mice. Plasma from fgl2(-/-) mice contained higher titers of total and neutralizing anti-LCMV antibody. Enhanced anti-viral immunity in fgl2(-/-) mice was associated with increased levels of serum alanine transaminase (ALT), hepatic necrosis and inflammation following LCMV WE infection. These data demonstrate that targeting FGL2 leads to early increased viral replication but enhanced anti-viral adaptive T & B cell responses. Targeting FGL2 may enhance the efficacy of current anti-viral therapies for hepatotropic viruses.

BACKGROUND: Necdin, a MAGE family protein expressed primarily in the nervous system, has been shown to interact with both nuclear and cytoplasmic proteins, but the mechanism of its nucleocytoplasmic transport are unknown. METHODOLOGY/PRINCIPAL FINDINGS: We carried out a large-scale interaction screen using necdin as a bait in the yeast RRS system, and found a wide range of potential interactors with different subcellular localizations, including over 60 new candidates for direct binding to necdin. Integration of these interactions into a comprehensive network revealed a number of coherent interaction modules, including a cytoplasmic module connecting to necdin through huntingtin-associated protein 1 (Hap1), dynactin and hip-1 protein interactor (Hippi); a nuclear P53 and Creb-binding-protein (Crebbp) module, connecting through Crebbp and WW domain-containing transcription regulator protein 1 (Wwtr1); and a nucleocytoplasmic transport module, connecting through transportins 1 and 2. We validated the necdin-transportin1 interaction and characterized a sequence motif in necdin that modulates karyopherin interaction. Surprisingly, a D234P necdin mutant showed enhanced binding to both transportin1 and importin β1. Finally, exclusion of necdin from the nucleus triggered extensive cell death. CONCLUSIONS/SIGNIFICANCE: These data suggest that necdin has multiple roles within protein complexes in different subcellular compartments, and indicate that it can utilize multiple karyopherin-dependent pathways to modulate its localization.

Oligomerization plays a major role in regulating the activity of many proteins, and in modulating their interactions. p53 is a homotetrameric transcription factor that has a pivotal role in tumor suppression. Its tetramerization domain is contained within its C-terminal domain, which is a site for numerous protein-protein interactions. Those can either depend on or regulate p53 oligomerization. Here we screened an array of peptides derived from proteins known to bind the tetrameric p53 C-terminal domain (p53CTD) and identified ten binding peptides. We quantitatively characterized their binding to p53CTD using fluorescence anisotropy. The peptides bound tetrameric p53CTD with micromolar affinities. Despite the high charge of the binding peptides, electrostatics contributed only mildly to the interactions. NMR studies indicated that the peptides bound p53CTD at defined sites. The most significant chemical shift deviations were observed for the peptides WS100B(81-92), which bound directly to the p53 tetramerization domain, and PKCα(281-295), which stabilized p53CTD in circular dichroism thermal denaturation studies. Using analytical ultracentrifugation, we found that several of the peptides bound preferentially to p53 tetramers. Our results indicate that the protein-protein interactions of p53 are dependent on the oligomerization state of p53. We conclude that peptides may be used to regulate the oligomerization of p53.

Evidence suggests that the reactivity of the Hypothalamus-Pituitary-Adrenal axis (HPAA) is modulated by both genetic and environmental variables. Of special interest are the underlying molecular mechanisms driving gender differences to psychosocial stressors. Epigenetic mechanisms that sculpt the genome are ideal candidates for mediating the effects of signals on the HPAA. In the current study, we analyzed by pyrosequencing, bisulfite-treated buccal DNA from male and female university students who participated in the Trier Social Stress Test (TSST). A linear regression model was used to ascertain the effects of sex, CpG methylation and genes on stress response. Total cortisol output (area under the curve, AUC) was significantly predicted by glucocorticoid receptor (NR3C1) exon 1F methylation (averaged across 39 CpG sites) solely in female subjects. A single CpG site located in the exon 1F noncanonical nerve growth factor-inducible protein A (NGFI-A) transcription factor was a highly significant predictor of AUC in female subjects. Additionally, variations in the estrogen receptor alpha (ESR1) and the serotonin transporter promoter (5-HTTLPR) genes were independent additive predictors of AUC. The full model accounted for half of the variance (50.06%) in total cortisol output. Notably, this is the first demonstration that epigenetic changes at the GR exon 1F correlate with HPAA reactivity. These findings have important implications for understanding the molecular mechanisms underlying gender differences in stress-related disorders and underscore the unique value of modeling both epigenetic and genetic information in conferring vulnerability to stress.

The genetic origins of altruism, defined here as a costly act aimed to benefit non-kin individuals, have not been examined in young children. However, previous findings concerning adults pointed at the arginine vasopressin receptor 1A (AVPR1A) gene as a possible candidate. AVPR1A has been associated with a range of behaviors including aggressive, affiliative and altruistic phenotypes, and recently a specific allele (327 bp) of one of its promoter region polymorphisms (RS3) has been singled out in particular. We modeled altruistic behavior in preschoolers using a laboratory-based economic paradigm, a modified dictator game (DG), and tested for association between DG allocations and the RS3 "target allele." Using both population and family-based analyses we show a significant link between lower allocations and the RS3 "target allele," associating it, for the first time, with a lower proclivity toward altruistic behavior in children. This finding helps further the understanding of the intricate mechanisms underlying early altruistic behavior.

Polyploidy is a pivotal process in plant evolution as it increase gene redundancy and morphological intricacy but due to the complexity of polysomic inheritance we have only few genetic maps of autopolyploid organisms. A robust mapping framework is particularly important in polyploid crop species, rose included (2n = 4x = 28), where the objective is to study multiallelic interactions that control traits of value for plant breeding. From a cross between the garden, peach red and fragrant cultivar Fragrant Cloud (FC) and a cut-rose yellow cultivar Golden Gate (GG), we generated an autotetraploid GGFC mapping population consisting of 132 individuals. For the map we used 128 sequence-based markers, 141 AFLP, 86 SSR and three morphological markers. Seven linkage groups were resolved for FC (Total 632 cM) and GG (616 cM) which were validated by markers that segregated in both parents as well as the diploid integrated consensus map.The release of the Fragaria vesca genome, which also belongs to the Rosoideae, allowed us to place 70 rose sequenced markers on the seven strawberry pseudo-chromosomes. Synteny between Rosa and Fragaria was high with an estimated four major translocations and six inversions required to place the 17 non-collinear markers in the same order. Based on a verified linear order of the rose markers, we could further partition each of the parents into its four homologous groups, thus providing an essential framework to aid the sequencing of an autotetraploid genome.

Myofiber cultures give rise to myogenic as well as to non-myogenic cells. Whether these myofiber-associated non-myogenic cells develop from resident stem cells that possess mesenchymal plasticity or from other stem cells such as mesenchymal stem cells (MSCs) remain unsolved. To address this question, we applied a method for reconstructing cell lineage trees from somatic mutations to MSCs and myogenic and non-myogenic cells from individual myofibers that were cultured at clonal density.Our analyses show that (i) in addition to myogenic progenitors, myofibers also harbor non-myogenic progenitors of a distinct, yet close, lineage; (ii) myofiber-associated non-myogenic and myogenic cells share the same muscle-bound primordial stem cells of a lineage distinct from bone marrow MSCs; (iii) these muscle-bound primordial stem-cells first part to individual muscles and then differentiate into myogenic and non-myogenic stem cells.

ARTS (Sept4_i2) is a mitochondrial pro-apoptotic protein that functions as a tumor suppressor. Its expression is significantly reduced in leukemia and lymphoma patients. ARTS binds and inhibits XIAP (X-linked Inhibitor of Apoptosis protein) by interacting with its Bir3 domain. ARTS promotes degradation of XIAP through the proteasome pathway. By doing so, ARTS removes XIAP inhibition of caspases and enables apoptosis to proceed. ARTS contains 27 unique residues in its C-terminal domain (CTD, residues 248-274) which are important for XIAP binding. Here we characterized the molecular details of this interaction. Biophysical and computational methods were used to show that the ARTS CTD is intrinsically disordered under physiological conditions. Direct binding of ARTS CTD to Bir3 was demonstrated using NMR and fluorescence spectroscopy. The Bir3 interacting region in ARTS CTD was mapped to ARTS residues 266-274, which are the nine C-terminal residues in the protein. Alanine scan of ARTS 266-274 showed the importance of several residues for Bir3 binding, with His268 and Cys273 contributing the most. Adding a reducing agent prevented binding to Bir3. A dimer of ARTS 266-274 formed by oxidation of the Cys residues into a disulfide bond bound with similar affinity and was probably required for the interaction with Bir3. The detailed analysis of the ARTS - Bir3 interaction provides the basis for setting it as a target for anti cancer drug design: It will enable the development of compounds that mimic ARTS CTD, remove IAPs inhibition of caspases, and thereby induce apoptosis.

The rational design of amyloid oligomer inhibitors is yet an unmet drug development need. Previous studies have identified the role of tryptophan in amyloid recognition, association and inhibition. Furthermore, tryptophan was ranked as the residue with highest amyloidogenic propensity. Other studies have demonstrated that quinones, specifically anthraquinones, can serve as aggregation inhibitors probably due to the dipole interaction of the quinonic ring with aromatic recognition sites within the amyloidogenic proteins. Here, using in vitro, in vivo and in silico tools we describe the synthesis and functional characterization of a rationally designed inhibitor of the Alzheimer's disease-associated beta-amyloid. This compound, 1,4-naphthoquinon-2-yl-L-tryptophan (NQTrp), combines the recognition capacities of both quinone and tryptophan moieties and completely inhibited Abeta oligomerization and fibrillization, as well as the cytotoxic effect of Abeta oligomers towards cultured neuronal cell line. Furthermore, when fed to transgenic Alzheimer's disease Drosophila model it prolonged their life span and completely abolished their defective locomotion. Analysis of the brains of these flies showed a significant reduction in oligomeric species of Abeta while immuno-staining of the 3(rd) instar larval brains showed a significant reduction in Abeta accumulation. Computational studies, as well as NMR and CD spectroscopy provide mechanistic insight into the activity of the compound which is most likely mediated by clamping of the aromatic recognition interface in the central segment of Abeta. Our results demonstrate that interfering with the aromatic core of amyloidogenic peptides is a promising approach for inhibiting various pathogenic species associated with amyloidogenic diseases. The compound NQTrp can serve as a lead for developing a new class of disease modifying drugs for Alzheimer's disease.

The intracellular oligomerization of α-synuclein is associated with Parkinson's disease and appears to be an important target for disease-modifying treatment. Yet, to date, there is no specific inhibitor for this aggregation process. Using unbiased systematic peptide array analysis, we identified molecular interaction domains within the β-synuclein polypeptide that specifically binds α-synuclein. Adding such peptide fragments to α-synuclein significantly reduced both amyloid fibrils and soluble oligomer formation in vitro. A retro-inverso analogue of the best peptide inhibitor was designed to develop the identified molecular recognition module into a drug candidate. While this peptide shows indistinguishable activity as compared to the native peptide, it is stable in mouse serum and penetrates α-synuclein over-expressing cells. The interaction interface between the D-amino acid peptide and α-synuclein was mapped by Nuclear Magnetic Resonance spectroscopy. Finally, administering the retro-inverso peptide to a Drosophila model expressing mutant A53T α-synuclein in the nervous system, resulted in a significant recovery of the behavioral abnormalities of the treated flies and in a significant reduction in α-synuclein accumulation in the brains of the flies. The engineered retro-inverso peptide can serve as a lead for developing a novel class of therapeutic agents to treat Parkinson's disease.

In experimental economics, the preference for reciprocal fairness has been observed in the controlled and incentivized laboratory setting of the ultimatum game, in which two individuals decide on how to divide a sum of money, with one proposing the share while the second deciding whether to accept. Should the proposal be accepted, the amount is divided accordingly. Otherwise, both would receive no money. A recent twin study has shown that fairness preference inferred from responder behavior is heritable, yet its neurogenetic basis remains unknown. The D4 receptor (DRD4) exon3 is a well-characterized functional polymorphism, which is known to be associated with attention deficit hyperactivity disorder and personality traits including novelty seeking and self-report altruism. Applying a neurogenetic approach, we find that DRD4 is significantly associated with fairness preference. Additionally, the interaction among this gene, season of birth, and gender is highly significant. This is the first result to link preference for reciprocal fairness to a specific gene and suggests that gene × environment interactions contribute to economic decision making.

1% of the genes of the human malaria causing agent Plasmodium falciparum belong to the heterogeneous var gene family which encodes P. falciparum erythrocyte membrane protein 1 (PFEMP1). This protein mediates part of the pathogenesis of the disease by causing adherence of infected erythrocytes (IE) to the host endothelium. At any given time, only one copy of the family is expressed on the IE surface. The cues which regulate the allelic exclusion of these genes are not known. We show the existence of a differential expression pattern of these genes upon exposure to biological stress in relation to their positional placement on the chromosome - expression of centrally located var genes is induced while sub-telomeric copies of the family are repressed - this phenomenon orchestrated by the histone deacetylase pfsir2. Moreover, stress was found to cause a switch in the pattern of the expressed var genes thus acting as a regulatory cue. By using pharmacological compounds which putatively affect pfsir2 activity, distinct changes of var gene expression patterns were achieved which may have therapeutic ramifications. As disease severity is partly associated with expression of particular var gene subtypes, manipulation of the IE environment may serve as a mechanism to direct transcription towards less virulent genes.

BACKGROUND:Economic games observe social decision making in the laboratory that involves real money payoffs. Previously we have shown that allocation of funds in the Dictator Game (DG), a paradigm that illustrates costly altruistic behavior, is partially determined by promoter-region repeat region variants in the arginine vasopressin 1a receptor gene (AVPR1a). In the current investigation, the gene encoding the related oxytocin receptor (OXTR) was tested for association with the DG and a related paradigm, the Social Values Orientation (SVO) task. METHODOLOGY/PRINCIPAL FINDINGS:Association (101 male and 102 female students) using a robust-family based test between 15 single tagging SNPs (htSNPs) across the OXTR was demonstrated with both the DG and SVO. Three htSNPs across the gene region showed significant association with both of the two games. The most significant association was observed with rs1042778 (p = 0.001). Haplotype analysis also showed significant associations for both DG and SVO. Following permutation test adjustment, significance was observed for 2-5 locus haplotypes (p

BackgroundPhylogenetic mitochondrial DNA haplogroups are highly partitioned across global geographic regions. A unique exception is the X haplogroup, which has a widespread global distribution without major regions of distinct localization.Principal findingsWe have examined mitochondrial DNA sequence variation together with Y-chromosome-based haplogroup structure among the Druze, a religious minority with a unique socio-demographic history residing in the Near East. We observed a striking overall pattern of heterogeneous parental origins, consistent with Druze oral tradition, together with both a high frequency and a high diversity of the mitochondrial DNA (mtDNA) X haplogroup within a confined regional subpopulation. Furthermore demographic modeling indicated low migration rates with nearby populations.ConclusionsThese findings were enabled through the use of a paternal kindred based sampling approach, and suggest that the Galilee Druze represent a population isolate, and that the combination of a high frequency and diversity of the mtDNA X haplogroup signifies a phylogenetic refugium, providing a sample snapshot of the genetic landscape of the Near East prior to the modern age.

The cell lineage tree of a multicellular organism represents its history of cell divisions from the very first cell, the zygote. A new method for high-resolution reconstruction of parts of such cell lineage trees was recently developed based on phylogenetic analysis of somatic mutations accumulated during normal development of an organism. In this study we apply this method in mice to reconstruct the lineage trees of distinct cell types. We address for the first time basic questions in developmental biology of higher organisms, namely what is the correlation between the lineage relation among cells and their (1) function, (2) physical proximity and (3) anatomical proximity. We analyzed B-cells, kidney-, mesenchymal- and hematopoietic-stem cells, as well as satellite cells, which are adult skeletal muscle stem cells isolated from their niche on the muscle fibers (myofibers) from various skeletal muscles. Our results demonstrate that all analyzed cell types are intermingled in the lineage tree, indicating that none of these cell types are single exclusive clones. We also show a significant correlation between the physical proximity of satellite cells within muscles and their lineage. Furthermore, we show that satellite cells obtained from a single myofiber are significantly clustered in the lineage tree, reflecting their common developmental origin. Lineage analysis based on somatic mutations enables performing high resolution reconstruction of lineage trees in mice and humans, which can provide fundamental insights to many aspects of their development and tissue maintenance.