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The C4 crop maize (Zea mays) is the most widely grown cereal crop worldwide and is an essential feedstock for food and bioenergy. Improving maize yield is important to achieve food security and agricultural sustainability in the 21st century. One potential means to improve crop productivity is to enhance photosynthesis. ictB, a membrane protein that is highly conserved across cyanobacteria, has been shown to improve photosynthesis, and often biomass, when introduced into diverse C3 plant species. Here, ictB from Synechococcus sp. strain PCC 7942 was inserted into maize using Agrobacterium-mediated transformation. In three controlled-environment experiments, ictB insertion increased leaf starch and sucrose content by up to 25% relative to controls. Experimental field trials in four growing seasons, spanning the Midwestern United States (Summers 2018 & 2019) and Argentina (Winter 2018 & 2019), showed an average of 3.49% grain yield improvement, by as much as 5.4% in a given season and up to 9.4% at certain trial locations. A subset of field trial locations was used to test for modification of ear traits and ФPSII, a proxy for photosynthesis. Results suggested that yield gain in transgenics could be associated with increased ФPSII, and the production of longer, thinner ears with more kernels. ictB localized primarily to the microsome fraction of leaf bundle-sheath cells, but not to chloroplasts. Extramembrane domains of ictB interacted in vitro with proteins involved in photosynthesis and carbohydrate metabolism. To our knowledge, this is the first published evidence of ictB insertion into a species using C4 photosynthesis and the largest-scale demonstration of grain yield enhancement from ictB insertion in planta. Results show that ictB is a valuable yield gene in the economically important crop maize, and are an important proof of concept that transgenic manipulation of photosynthesis can be used to create economically viable crop improvement traits.

Cyanobacteria are valuable organisms for studying the physiology of photosynthesis and carbon fixation, as well as metabolic engineering for the production of fuels and chemicals. This work describes a novel counter selection method for the cyanobacterium Synechococcus sp. PCC 7002 based on organic acid toxicity. The organic acids acrylate, 3-hydroxypropionate, and propionate were shown to be inhibitory towards Synechococcus sp. PCC 7002 and other cyanobacteria at low concentrations. Inhibition was overcome by a loss of function mutation in the gene acsA, which is annotated as an acetyl-CoA ligase. Loss of AcsA function was used as a basis for an acrylate counter selection method. DNA fragments of interest were inserted into the acsA locus and strains harboring the insertion were isolated on selective medium containing acrylate. This methodology was also used to introduce DNA fragments into a pseudogene, glpK. Application of this method will allow for more advanced genetics and engineering studies in Synechococcus sp. PCC 7002 including the construction of markerless gene deletions and insertions. The acrylate counter-selection could be applied to other cyanobacterial species where AcsA activity confers acrylate sensitivity (e.g. Synechocystis sp. PCC 6803).

In poeciliid fish the male anal fin has been transformed into a gonopodium, an intromittent organ required for internal fertilization. Elevated testosterone levels induce metamorphosis of a subset of anal fin rays to grow and form the specialized terminal structures of the gonopodium. The molecular mechanisms underlying these processes are largely unknown. Here, we investigated whether retinoic acid (RA) signaling is involved in gonopodium development in the swordtail Xiphophorus hellerii. We showed that aldh1a2, a RA synthesizing enzyme, and the RA receptors, rar-ga and rar-gb, are expressed in anal fins during metamorphosis. aldh1a2 expression is regulated by testosterone in a concentration-dependent manner and is up-regulated in both hormone-induced and naturally developing gonopodia. Androgen receptor (ar), a putative regulator of gonopodial development, is co-expressed with aldh1a2 and the RA receptors in gonopodial rays. Importantly, experimental increase of RA signaling promoted growth of the gonopodium and increased the number of new segments. Based on gene expression analyses and pharmacological manipulation of gonopodium development, we show that the RA signaling pathway is activated in response to androgen signaling and promotes fin ray growth and development during the metamorphosis of the anal fin into the gonopodium.

In poeciliid fish the male anal fin has been transformed into a gonopodium, an intromittent organ required for internal fertilization. Elevated testosterone levels induce metamorphosis of a subset of anal fin rays to grow and form the specialized terminal structures of the gonopodium. The molecular mechanisms underlying these processes are largely unknown. Here, we investigated whether retinoic acid (RA) signaling is involved in gonopodium development in the swordtail Xiphophorus hellerii. We showed that aldh1a2, a RA synthesizing enzyme, and the RA receptors, rar-ga and rar-gb, are expressed in anal fins during metamorphosis. aldh1a2 expression is regulated by testosterone in a concentration-dependent manner and is up-regulated in both hormone-induced and naturally developing gonopodia. Androgen receptor (ar), a putative regulator of gonopodial development, is co-expressed with aldh1a2 and the RA receptors in gonopodial rays. Importantly, experimental increase of RA signaling promoted growth of the gonopodium and increased the number of new segments. Based on gene expression analyses and pharmacological manipulation of gonopodium development, we show that the RA signaling pathway is activated in response to androgen signaling and promotes fin ray growth and development during the metamorphosis of the anal fin into the gonopodium. [ABSTRACT FROM AUTHOR]

There is convincing evidence that the learning environments digitalization of tools and equipment ultimately results in the speed and depth learning involvement of academia members, by raising attainment of each of the digital learning experiences. The majority of the research that was conducted on the topic of enhancing the digital skills of learners, which would ultimately lead to an increase in their active engagement, was conducted on students in primary and secondary education, leaving members of higher education outside of the scope of the study. Given the uninterrupted search for academic performance and innovation, the current research considers the technological changes that lead to the transformation of the traditional academic learning environments as previously known. The current paper considers the changes in the learners' engagement in the context of the dually digital transformation of the higher academic multi-institutional digitally-learning enhancements. An important factor to be considered regards the leadership evolution (in terms of teaching) that over time, led to a different speed contextual shift, according to its effectiveness, leading to higher or lower students learning (dis)engagement. The current manuscript aims to examine how the higher education digitalization levels could affect the student's learning engagement, under the close monitoring of the academia leadership styles practice. Data collection and analysis implied at first a qualitative approach by issuing an online-distributed survey that resulted in a number of 2272 valid responses. After performing structural equation modelling and proving a valid assessment tool, the analysis resulted into statistically proving the validity of two main hypotheses according to which students learning engagement has a positive effect on the practice of academic leadership. Additionally, results emphasized the fact that higher education digitalization has altogether a negative effect of students learning engagement. Consequently, the current study stresses on the importance of different peers' categories in the context of higher education institutions performance, with an emphasis on the different levels of students' engagement and the leadership styles evolution and practice, aspects uniformly developing within a continuously digitally transformation of the higher education environment. [ABSTRACT FROM AUTHOR]

Patients with chronic kidney disease (CKD) have a high incidence of dyslipidemia comprising high triglyceride (TG) and low high-density lipoprotein (HDL)-cholesterol levels. An abnormal increase of TGs within cells can lead to intracellular lipid accumulation. In addition to dyslipidemia, hyperglycemia in diabetes may elicit ectopic lipid deposition in non-adipose tissues. Hyperglycemia increases intracellular levels of methylglyoxal (MG) leading to cellular dysfunction. A deficit of glyoxalase I (GLO1) contributes to dicarbonyl stress. Whether dicarbonyl stress induced by MG causes renal lipotoxicity through alteration of lipid metabolism signaling is still unknown. In this study, mice with high fat diet-induced diabetes were used to investigate the renal pathology induced by MG. NRK52E cells treated with MG were further used in vitro to delineate the involvement of lipogenic signaling. After treatment with MG for 12 weeks, plasma TG levels, renal fatty changes, and tubular injuries were aggravated in diabetic mice. In NRK52E cells, MG activated the nuclear factor erythroid 2-related factor 2 (Nrf2)/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and sterol regulatory element-binding protein 1 (SREBP1), resulting in stimulation of fatty acid synthase. The intracellular accumulation of lipid droplets was mainly contributed by TGs, which increased the oxidative stress accompanied by high Nrf2 expression. In addition, MG time-dependently activated cyclin D, cyclin-dependent kinase 4 (CDK4), and cleaved caspase-3, evidencing that G0/G1 arrest was associated with apoptosis of NRK52E cells. In conclusion, our studies revealed the mechanism of lipotoxicity caused by MG. The target of such dicarbonyl stress may become a promising therapy for diabetic CKD. [ABSTRACT FROM AUTHOR]

Objectives: This study aims to systematically review the existing literature and critically appraise the evidence of genome-wide association studies (GWAS) on periodontitis. This study also aims to synthesise the findings of genetic risk variants of periodontitis from included GWAS. Methods: A systematic search was conducted on PubMed, GWAS Catalog, MEDLINE, GLOBAL HEALTH and EMBASE via Ovid for GWAS on periodontitis. Only studies exploring single-nucleotide polymorphisms(SNPs) associated with periodontitis were eligible for inclusion. The quality of the GWAS was assessed using the Q-genie tool. Information such as study population, ethnicity, genomic data source, phenotypic characteristics(definition of periodontitis), and GWAS methods(quality control, analysis stages) were extracted. SNPs that reached conventional or suggestive GWAS significance level(5e-8 or 5e-06) were extracted and synthesized. Results: A total of 15 good-quality GWAS on periodontitis were included (Q-genie scores ranged from 38–50). There were huge heterogeneities among studies. There were 11 identified risk SNPs (rs242016, rs242014, rs10491972, rs242002, rs2978951, rs2738058, rs4284742, rs729876, rs149133391, rs1537415, rs12461706) at conventional GWAS significant level (p<5x10-8), and 41 at suggestive level (p<5x10-6), but no common SNPs were found between studies. Three SNPs (rs4284742 [G], rs11084095 [A], rs12461706 [T]) from three large studies were from the same gene region–SIGLEC5. Conclusion: GWAS of periodontitis showed high heterogeneity of methodology used and provided limited SNPs statistics, making identifying reliable risk SNPs challenging. A clear guidance in dental research with requirement of expectation to make GWAS statistics available to other investigators are needed. [ABSTRACT FROM AUTHOR]

Introduction: Auditory-verbal hallucinatory experiences (AVH) have a 12% prevalence in the general pediatric population. Literature reports a higher risk of developing AVH in post-traumatic stress disorder (PTSD). The persistence of AVHs during adolescence represents a risk of evolution into psychotic disorders. Social cognition and emotional markers could be considered prodromes markers of this evolution. The objectives of this prospective observational study are to observe social cognition and emotional markers correlation with the presence and persistence of AVH over two years and with the evolution of PTSD and psychotic diagnosis. Methods and analysis: This prospective case-control study, longitudinal over two years (with an interim reassessment at six months and one year), will include 40 participants aged 8 to 16 years old with a diagnosis of PTSD and without a diagnosis of psychosis according to the criteria of DSM-5 (K-SADS-PL). Subjects included are divided into two groups with AVH and without AVH matched by gender, age and diagnosis. The primary outcome measure will be the correlation between social cognition and emotional makers and the presence of AVH in the PTSD pediatric population without psychotic disorders. The social cognition marker is assessed with the NEPSY II test. The emotional marker is assessed with the Differential Emotion Scale IV and the Revised Beliefs About Voices Questionnaire. The secondary outcome measures are the correlation of these markers with the persistence of AVH and the evolution of the patient's initial diagnosis two years later. Discussion: The originality of our protocol is to explore the potential progression to psychosis from PTSD by cognitive biases. This study supports the hypothesis of connections between PTSD and AVH through sensory, emotional and cognitive biases. It proposes a continuum model from PTSD to psychotic disorder due to impaired perception like AVH. Trial registration: Clinical trial registration: ClinicalTrials.gov Identifier: NCT03356028. [ABSTRACT FROM AUTHOR]

Introduction: There is high evidence that chronic exercise benefits overall depression severity in older adults. However, late-life depression is characterized by considerable heterogeneity in clinical manifestation emphasizing the need for more individualized exercise intervention programs. Therefore, the objective of the proposed review is to investigate the effects of chronic exercise on overall depression severity and on different symptoms of depression in randomized controlled trials (RCTs) including older adults with a mean age of at least 60 years, and by considering the moderating effects of intervention characteristics and individual characteristics. Methods: This protocol is guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols (PRISMA-P). We will use the Population-Intervention-Comparator-Outcomes-Study design (PICOS) criteria for study inclusion and will search the following database sources for relevant RCTs: Web of Science, Academic Search Complete, CINAHL, APA Psycinfo, SPORTDiscuss, Cochrane. Two independent reviewers will conduct the study selection, data extraction, and quality assessment. Disagreement will be solved by a third reviewer. Primary outcome will be changes in overall depression severity and secondary outcomes will encompass changes in symptoms of depression as defined by the DSM-5, such as sleep quality, fatigue, anxiety, mood, apathy, changes in weight, information processing speed, and executive functions, from baseline until the end of the intervention and to any available intermediary measurement or follow up. Meta-analysis will be undertaken to synthesize the effects of chronic exercise on primary and secondary outcomes. Subgroup analysis will investigate the moderating effects of intervention characteristics (frequency, intensity, duration, type of exercise, cognitive demand, social interactions, exercise supervision, behavioral change techniques, compliance, study design, dropout-rate, type of control group) and individual characteristics (age, sex, education, functional capacity, global cognition, population) on primary and secondary outcomes. Additionally, we plan to assess quality of evidence and publication bias, and to carry out sensitivity analysis. Conclusion: The results of the proposed review are anticipated to have a substantial impact on research and clinical practice. On the one hand, the review's conclusions could form the foundation for developing evidence-based recommendations for individualized exercise programs that alleviate depression in older adults. On the other hand, by revealing research gaps, the review results could encourage the formulation of research questions for further RCTs. Protocol registration number: This protocol has been published in the Prospero repository (PROSPERO 2022 CRD42022361418, available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022361418) [ABSTRACT FROM AUTHOR]

Background: VCI is a severe public health problem facing the world today. In addition to pharmacological treatment, non-invasive neuromodulation techniques have also been effective. At this stage, non-invasive neuromodulation techniques combined with pharmacological treatment are the mainstay of clinical treatment, and clinical trials are continuing to be conducted, which is becoming the direction of treatment for VCI. Therefore, we outline this systematic review and network meta-analysis protocol to evaluate and rank clinical data in future studies which can develop optimal protocols for the clinical treatment of VCI with non-invasive neuromodulation techniques in combination with drugs. Methods: The network meta-analysis will search eight databases, including PubMed, Embase, Cochrane Library, Web of Science, China Knowledge Infrastructure Library (CNKI), China Biology Medicine disc (CBM)), Wanfang Data Knowledge Service Platform and Vipshop Journal Service Platform (VIP), for a period of from the establishment of the library to January 30 2022. The quality of the studies will be evaluated using the Cochrane Review's Handbook 5.1 and the PEDro scale to assess the evidence and quality of the included randomised controlled trials. Risk of bias assessment and heterogeneity tests will be performed using the Review Manager 5.4 program, and Bayesian network meta-analysis will be performed using the Stata 16.0 and WinBUGS 1.4.3 program. Results: The results of the network meta-analysis will be published in a peer-reviewed journal. Conclusions: Our study is expected to provide high quality evidence-based medical evidence for the treatment of VCI by clinicians. Trial registration: PROSPERO:CRD42022308580. [ABSTRACT FROM AUTHOR]

Introduction: Executive functions are commonly impaired in individuals with schizophrenia spectrum disorders. Physical exercise has the potential for improving executive functions and can be easily implemented as a therapeutic method. However, there are only few systematic reviews of exercise effects in schizophrenia including cognitive outcomes, and no meta-analytical syntheses of effects on "cool" and "hot" executive functions. The purpose of this systematic review and meta-analysis will be to determine the effects of physical exercise on "cool" and "hot" executive functions of adults with schizophrenia spectrum disorders. Methods and analysis: This protocol was guided by PRISMA-P guidelines. Studies will be searched using combinations of keywords and medical terms in the Web of Science, PubMed, Scopus, and EBSCO databases. Inclusion criteria will be determined as per PICOS approach. The risk of bias will be assessed using the Cochrane RoB2 tool. The certainty of evidence (per outcome) will be assessed using the GRADE method. The meta-analyses will be performed using the DerSimonian and Laird random effects model. Effect sizes (Hedges' g) with 95% confidence intervals will be calculated for each main outcome. Conclusions: The results of this review may be useful for mental health professionals to design treatment plans for adults with schizophrenia spectrum disorders, offering potential benefits related to the quality of life and cognitive abilities of this population. PROSPERO registration number: CRD42023392295. [ABSTRACT FROM AUTHOR]

Limited research has explored the specific impact of voice-hearing experiences upon the social relating of adolescents. This study examined the associations of voice-hearing in youth with social relating, and putative explanatory factors. An observational, cross-sectional design using a clinical comparison group was employed to examine historical and concurrent associations with voice-hearing. Thirty-four young people (age 14–18 years) with voice-hearing experiences and 34 young people who did not hear voices were recruited from NHS mental health services. Participants completed measures about social relating and potential explanatory factors. Analyses of covariance were used to examine between-group differences. Voice-hearers scored higher on negative schematic beliefs (self-beliefs, partial η2 =.163, p =.001; other-beliefs, partial η2 =.152, p =. 002) and depressive and anxiety symptoms (partial η2 =.23 and partial η2 =.24, p-s <. 001 respectively). The two groups did not differ significantly on childhood trauma levels (partial η2 =.02, p =.273), however, the voice-hearing group scored lower on premorbid adjustment (partial η2 =.19, p <.001). Hearing voices in help-seeking youth could be an indicator for social relating issues and holding negative schematic beliefs, and may be an indicator for of increased psychopathological complexity. Although poorer premorbid adjustment might indicate an early vulnerability to social relating difficulties, voice-hearing might be an aggravating factor and one that requires treatment. [ABSTRACT FROM AUTHOR]

Schizophrenia (SZ) is a severe mental disorder associated with a variety of linguistic deficits, and recently it has been suggested that these deficits are caused by an underlying impairment in the ability to build complex syntactic structures and complex semantic relations. Aiming at contributing to determining the specific linguistic profile of SZ, we investigated the usage of pronominal subjects and sentence types in two corpora of oral dream and waking reports produced by speakers with SZ and participants without SZ (NSZ), both native speakers of Brazilian Portuguese. Narratives of 40 adult participants (20 SZ, and 20 NSZ–sample 1), and narratives of 31 teenage participants (11 SZ undergoing first psychotic episode, and 20 NSZ–sample 2) were annotated and statistically analyzed. Overall, narratives of speakers with SZ presented significantly higher rates of matrix sentences, null pronouns—particularly null 3Person referential pronouns—and lower rates of non-anomalous truncated sentences. The high rate of matrix sentences correlated significantly with the total PANSS scores, suggesting an association between the overuse of simple sentences and SZ symptoms in general. In contrast, the high rate of null pronouns correlated significantly with positive PANSS scores, suggesting an association between the overuse of null pronominal forms and the positive symptoms of SZ. Finally, a cross-group analysis between samples 1 and 2 indicated a higher degree of grammatical impairment in speakers with multiple psychotic episodes. Altogether, the results strengthen the notion that deficits at the pronominal and sentential levels constitute a cross-cultural linguistic marker of SZ. [ABSTRACT FROM AUTHOR]

Antibiotic use in livestock production is one of the drivers of antibiotic resistance and a shift towards better and reduced antibiotic usage is urgently required. In Vietnam, where there are frequent reports of the misuse and overuse of antibiotics, little attention has been paid to farmers who have successfully changed their practices. This qualitative study aims to understand the transition process of Vietnamese chicken farmers toward reduced antibiotic usage. We conducted semi-structured interviews with 18 chicken farmers, 13 drug sellers, and 5 traders using participatory tools and a socio-anthropological approach. We explored the farmers' histories, current and past antibiotic usage, methods used to reduce antibiotic use, and motivations and barriers to changing practices. Through the thematic analysis of the farmers' transcripts, we identified technical, economic, and social factors that influence change. Out of eighteen farmers, we identified ten farmers who had already reduced antibiotic usage. The main motivations included producing quality chickens (tasty and safe) while reducing farm expenditures. Barriers were related to poor biosecurity in the area, market failures, and the farmers' lack of knowledge. Innovation led to overcome these obstacles included the local development of handmade probiotics and the organization of farmer cooperatives to overcome economic difficulties and guarantee product outlets. Knowledge was increased by workshops organized at the communal level and the influence of competent veterinarians in the area. We showed that the transition process was influenced by several components of the system rather than by any individual alone. Our study demonstrated that local initiatives to reduce antibiotic use in Vietnamese chicken production do exist. As changes depend on the system in which stakeholders are embedded, systemic lock-ins must be removed to allow practices to change. The promotion of locally-developed solutions should be further encouraged. [ABSTRACT FROM AUTHOR]

Imprinted genes are regulated by DNA methylation of imprinted differentially methylated regions (iDMRs). An increasing number of patients with congenital imprinting disorders (IDs) exhibit aberrant methylation at multiple imprinted loci, multi-locus imprinting disturbance (MLID). We examined MLID and its possible impact on clinical features in patients with IDs. Genome-wide DNA methylation analysis (GWMA) using blood leukocyte DNA was performed on 13 patients with Beckwith–Wiedemann syndrome (BWS), two patients with Silver–Russell syndrome (SRS), and four controls. HumanMethylation850 BeadChip analysis for 77 iDMRs (809 CpG sites) identified three patients with BWS and one patient with SRS showing additional hypomethylation, other than the disease-related iDMRs, suggestive of MLID. Two regions were aberrantly methylated in at least two patients with BWS showing MLID: PPIEL locus (chromosome 1: 39559298 to 39559744), and FAM50B locus (chromosome 6: 3849096 to 3849469). All patients with BWS- and SRS-MLID did not show any other clinical characteristics associated with additional involved iDMRs. Exome analysis in three patients with BWS who exhibited multiple hypomethylation did not identify any causative variant related to MLID. This study indicates that a genome-wide approach can unravel MLID in patients with an apparently isolated ID. Patients with MLID showed only clinical features related to the original IDs. Long-term follow-up studies in larger cohorts are warranted to evaluate any possible phenotypic consequences of other disturbed imprinted loci. [ABSTRACT FROM AUTHOR]

Background: The high prevalence of overweight and obesity in children from Latin America (LA) have been related to obesogenic food environments. Besides, the negative effects of the Covid-19 pandemic should also be considered. The objective of this research was to describe and compare the perceptions of parents, teachers, and experts in LA of food environments at home and school that favor healthy habits in schoolchildren in pre Covid-19 stage and during the pandemic. Methods: This study used a survey self-reporting regarding conditions at home and the school favoring healthy habits, for three profiles: parents, primary school teachers, and experts. A fisher exact test was used to establish the difference between the response categories between countries and profiles. Logistic regression models were used to determine the probability of response in the levels of importance adjusted for sex and nationality. Results: Information from 954 questionnaires was reported: 48.4% experts, 32.0% teachers, and 19.6% parents. There were differences in the perception of food environments at school between profiles (p<0.001). In multivariate logistic regression models, experts and teachers were 20% more likely to give greater importance to elements of the food environment at school compared to parents (p<0.001). Conclusions: Our findings showed that parents were less likely to perceive important elements of the school food environment compared to experts and teachers. Interventions are required to improve healthy eating environments that consider children's interpersonal mediators. [ABSTRACT FROM AUTHOR]

The production, distribution and use of copper objects and the development of metallurgical skills in Neolithic Northern Central Europe and Southern Scandinavia are linked to early centres of copper metallurgy of South East Central Europe and Southeast Europe. A total of 45 Neolithic copper objects, until now the largest sample of Early Neolithic objects from the Northern Central European Plain and Southern Scandinavia, were selected for new lead isotope analyses. They aided in the identification of the origin of the copper: These new analyses indicate that the copper ore deposits in Southeastern Europe, especially from the Serbian mining areas, were used for the Early Neolithic northern artefacts (ca. 4100–3300 BC). The most likely sources of copper for the few Middle Neolithic artefacts (ca. 3300–2800 BC) seem to be from the Slovak Ore Mountains, the Serbian mining areas and the Eastern Alps, whereas deposits of the Slovak Ore Mountains and the Alpine region were used for the Late Neolithic and the Early Bronze Age (ca. 2300–1700 BC) artefacts. For the artefacts dated after 2000 BC, the Great Orme mine in Wales also appears to have been the source of copper for the analysed metals. The use of copper from different regions of Europe probably reflects changing social and cultural connectivities on a European scale and the changing chronology of copper exploitation. [ABSTRACT FROM AUTHOR]

Silver-Russell syndrome (SRS) is a rare imprinting disorder characterized by prenatal and postnatal growth retardation. The two principal causes of SRS are loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (UPD(7)mat). Knowledge of the neuropsychological profile of SRS remains sparse and incomplete even if several difficulties related to attention and learning have been reported both in the literature and by patients with SRS. These difficulties could be the result of troubles in different cognitive domains, but also of executive dysfunction. Nevertheless, executive functioning has never been investigated, even though executive functions play an essential role in psychological development, and are extensively involved in daily life. The present study explored the executive functioning of individuals with SRS due to UPD(7)mat or 11p15 LOM. A battery of executive tasks assessing cognitive flexibility, inhibitory control, and working memory, together with a task assessing sustained attention, was administered to 19 individuals with SRS (13–39 years) and 19 healthy controls. The Behavior Rating Inventory of Executive Function was also completed by the participants' families. The results showed that participants with SRS had similar performance (z-scores) to our controls, in a context of normal intellectual efficiency. Group comparisons with Bayesian statistics showed a single difference between the 11p15 LOM and control groups: the completion time for part A of the Trail Making Test appeared to be longer in the 11p15 LOM group than in the control group. However, at the clinical level, several participants with SRS had clinically significant scores on various measures of EFs. Thus, the cognitive phenotype of SRS did not appear to be characterized by executive dysfunction, but individuals with SRS could be at high risk of developing executive dysfunction or attention-deficit/hyperactivity disorder. These results provide new insights into the neuropsychological profile of individuals with SRS. [ABSTRACT FROM AUTHOR]

In 2016, a Stollhof-type copper hoard was found during an excavation in Magyaregres, Hungary. It was placed in a cooking pot, and deposited upside down within the boundaries of an Early Copper Age settlement. Similar hoards dating to the end of the 5th millennium BCE are well-known from Central Europe, however, this hoard represents the only one so far with thoroughly documented finding circumstances. The hoard contained 681 pieces of copper, 264 pieces of stone and a single Spondylus bead, along with 19 pieces of small tubular spiral copper coils, three spiral copper bracelets, and two large, spectacle spiral copper pendants. Until now, information on the provenance of raw materials and how such copper artefacts were manufactured has not been available. The artefacts were studied under optical microscopes to reveal the manufacturing process. Trace elemental composition (HR-ICP-MS) and lead isotope ratios (MC-ICP-MS) were measured to explore the provenance of raw materials. The ornaments were rolled or folded and coiled from thin sheets of copper using fahlore copper probably originating from the Northwestern Carpathians. A complex archaeological approach was employed to reveal the provenance, distribution and the social roles the ornaments could have played in the life of a Copper Age community. Evidence for local metallurgy was lacking in contemporaneous Transdanubian sites, therefore it is likely that the items of the hoard were manufactured closer to the raw material source, prior to being transported to Transdanubia as finished products. The method of deposition implies that such items were associated with special social contexts, represented exceptional values, and the context of deposition was also highly prescribed. The Magyaregres hoard serves as the first firm piece of evidence for the existence of a typologically independent Central European metallurgical circle which exploited the raw material sources located within its distribution. [ABSTRACT FROM AUTHOR]

This article discusses the socioeconomic dynamics of metal consumption patterns in the 3rd millennium BC north-central Anatolian site of Resuloğlu (Çorum, Turkey). The socio-political structure of the site confirms a nonstate, socially complex community with a range of hierarchical and heterarchical expressions. This study presents the results of archaeological, compositional (n = 307), and isotopic (n = 45) analyses of the complete metal collection of Resuloğlu uncovered through two decades of systematic excavations with a well-established chronology. The elemental compositions of metal objects obtained with pXRF combined with lead isotope analysis denote a high diversity in alloy types and sources. The compositional analysis highlights the consumption of various binary and ternary alloys for different object types. The lead isotope ratios confirm the use of both in proximity to metallic sources and access to macro-regional trade extending from the Black Sea coast towards the Taurus Mountain range. The site appears as a part of linkages whereby goods and valuables were exchanged within decentralized networks of middle-range societies. The diversity in metal consumption suggests group-driven choices and networks rather than top-down control of social elites. This allows us to confront the conventional approach to the role of metals as the primary motivator for social complexity and inequality in all parts of the 3rd millennium BC Anatolia. [ABSTRACT FROM AUTHOR]

With the advent of high-throughput assays, a large number of biological experiments can be carried out. Image-based assays are among the most accessible and inexpensive technologies for this purpose. Indeed, these assays have proved to be effective in characterizing unknown functions of genes and small molecules. Image analysis pipelines have a pivotal role in translating raw images that are captured in such assays into useful and compact representation, also known as measurements. CellProfiler is a popular and commonly used tool for this purpose through providing readily available modules for the cell/nuclei segmentation, and making various measurements, or features, for each cell/nuclei. Single cell features are then aggregated for each treatment replica to form treatment "profiles". However, there may be several sources of error in the CellProfiler quantification pipeline that affects the downstream analysis that is performed on the profiles. In this work, we examined various preprocessing approaches to improve the profiles. We consider the identification of drug mechanisms of action as the downstream task to evaluate such preprocessing approaches. Our enhancement steps mainly consist of data cleaning, cell level outlier detection, toxic drug detection, and regressing out the cell area from all other features, as many of them are widely affected by the cell area. Our experiments indicate that by performing these time-efficient preprocessing steps, image-based profiles can preserve more meaningful information compared to raw profiles. In the end, we also suggest possible avenues for future research. [ABSTRACT FROM AUTHOR]

Therapeutic targeting of the estrogen receptor (ER) is a clinically validated approach for estrogen receptor positive breast cancer (ER+ BC), but sustained response is limited by acquired resistance. Targeting the transcriptional coactivators required for estrogen receptor activity represents an alternative approach that is not subject to the same limitations as targeting estrogen receptor itself. In this report we demonstrate that the acetyltransferase activity of coactivator paralogs CREBBP/EP300 represents a promising therapeutic target in ER+ BC. Using the potent and selective inhibitor CPI-1612, we show that CREBBP/EP300 acetyltransferase inhibition potently suppresses in vitro and in vivo growth of breast cancer cell line models and acts in a manner orthogonal to directly targeting ER. CREBBP/EP300 acetyltransferase inhibition suppresses ER-dependent transcription by targeting lineage-specific enhancers defined by the pioneer transcription factor FOXA1. These results validate CREBBP/EP300 acetyltransferase activity as a viable target for clinical development in ER+ breast cancer. [ABSTRACT FROM AUTHOR]

Recently, it was shown that fracture risk assessment in patients with femoral bone metastases using Finite Element (FE) modeling can be performed using a calibration phantom or air-fat-muscle calibration and that non-patient-specific calibration was less favorable. The purpose of this study was to investigate if phantomless calibration can be used instead of phantom calibration when different CT protocols are used. Differences in effect of CT protocols on Hounsfield units (HU), calculated bone mineral density (BMD) and FE failure loads between phantom and two methods of phantomless calibrations were studied. Five human cadaver lower limbs were scanned atop a calibration phantom according to a standard scanning protocol and seven additional commonly deviating protocols including current, peak kilovoltage (kVp), slice thickness, rotation time, field of view, reconstruction kernel, and reconstruction algorithm. The HUs of the scans were calibrated to BMD (in mg/cm3) using the calibration phantom as well as using air-fat-muscle and non-patient-specific calibration, resulting in three models for each scan. FE models were created, and failure loads were calculated by simulating an axial load on the femur. HU, calculated BMD and failure load of all protocols were compared between the three calibration methods. The different protocols showed little variation in HU, BMD and failure load. However, compared to phantom calibration, changing the kVp resulted in a relatively large decrease of approximately 10% in mean HU and BMD of the trabecular and cortical region of interest (ROI), resulting in a 13.8% and 13.4% lower failure load when air-fat-muscle and non-patient-specific calibrations were used, respectively. In conclusion, while we observed significant correlations between air-fat-muscle calibration and phantom calibration as well as between non-patient-specific calibration and phantom calibration, our sample size was too small to prove that either of these calibration approaches was superior. Further studies are necessary to test whether air-fat-muscle or non-patient-specific calibration could replace phantom calibration in case of different scanning protocols. [ABSTRACT FROM AUTHOR]

In this paper we present the first results of an interdisciplinary research project focused on Late Bronze Age metallurgy in the western and central Balkans. The comprehensive chemical and lead isotope analysis, and a strict consideration of archaeological criteria, has provided a deeper insight into supra regional metal exchange networks between the 14th and 9th century BC in this part of Europe. Particularly interesting and surprising are results regarding the provenance of raw materials for copper production, which have a chemical composition and lead isotope ratios that closely correspond to ore deposits in the southern Alps (North Italy). Based on the examination of 57 objects of different functions, chronology and distribution, it becomes apparent that copper from the southern Alps was almost an omnipresent raw material in the territories of the western and central Balkans with only a few finds from North Macedonia to indicate alternative sources. The analyses demonstrate that the reuse of fahlore-based copper is attested for the first time in the regions under study. The remarkable fact that other archaeological parameters do not indicate such an intensive connection between the Balkan area and Northern Italy raises a number of questions. The sustained and long-lasting networks of raw material procurement stand in contrast to the expected cultural interaction between metal producing and metal consuming prehistoric societies. The results of this work also highlight the currently underestimated role of the southern Alps as one of the main copper producing areas in Bronze Age Europe, and demonstrate for the first time that the region of western and central Balkans was one of the major recipients. [ABSTRACT FROM AUTHOR]

Previous studies have shown an increase of insulin-like growth factor-2 (IGF2) in animal models of neuropathic pain. We aimed to examine the hypothesis that reducing the expression of IGF2 using intrathecal IGF2 small-interfering RNA (siRNA) would attenuate the development of neuropathic pain in rats after spared nerve injury (SNI). Male Wistar rats were divided into three groups: sham-operated group, in which surgery was performed to cut the muscles without injuring the nerves; SNI group, in which SNI surgery was performed to sever the nerves; and SNI + siRNA IGF2 group, in which SNI surgery was performed, and IGF2-siRNA was administered intrathecally 1 day after SNI. The rats were assessed for mechanical allodynia and cold allodynia 1 day before surgery (baseline), and at 2, 4, 6, 8, and 10 days after siRNA treatment. The rat spinal cord was collected for quantitative polymerase chain reaction and western blot analysis. Compared with the SNI group, rats that received IGF2 siRNA showed a significantly increased SNI-induced paw-withdrawal threshold to metal filament stimulation from Day 4 to Day 10 after SNI surgery. IGF2 siRNA significantly decreased the response duration from the acetone test from Day 2 to Day 10 following SNI surgery. SNI increased IGF2 mRNA expression on Day 2 and increased IGF2 protein expression on Day 8 and Day 10 in the spinal cord of the SNI rats. However, the above-mentioned effects of IGF2 mRNA and protein expression were significantly inhibited in the SNI + IGF2 siRNA group. We demonstrated that intrathecal administration of IGF2 siRNA provided significant inhibition of SNI-induced neuropathic pain via inhibition of IGF2 expression in the spinal cord. The analgesic effect lasted for 10 days. Further exploration of intrathecal IGF2 siRNA administration as a potential therapeutic strategy for neuropathic pain is warranted. [ABSTRACT FROM AUTHOR]

High titers of anti-NMDAR1 autoantibodies in brain cause anti-NMDAR1 encephalitis that displays psychiatric symptoms of schizophrenia and/or other psychiatric disorders in addition to neurological symptoms. Low titers of anti-NMDAR1 autoantibodies are reported in the blood of a subset of the general human population and psychiatric patients. Since ~0.1–0.2% of blood circulating antibodies cross the blood-brain barriers and antibodies can persist for months and years in human blood, it is important to investigate whether chronic presence of these blood circulating anti-NMDAR1 autoantibodies may impair human cognitive functions and contribute to the development of psychiatric symptoms. Here, we generated mice carrying low titers of anti-NMDAR1 autoantibodies in blood against a single antigenic epitope of mouse NMDAR1. Mice carrying the anti-NMDAR1 autoantibodies are healthy and display no differences in locomotion, sensorimotor gating, and contextual memory compared to controls. Chronic presence of the blood circulating anti-NMDAR1 autoantibodies, however, is sufficient to impair T-maze spontaneous alternation in the integrity of blood-brain barriers across all 3 independent mouse cohorts, indicating a robust cognitive deficit in spatial working memory and/or novelty detection. Our studies implicate that chronic presence of low titers of blood circulating anti-NMDAR1 autoantibodies may impair cognitive functions in both the general healthy human population and psychiatric patients. [ABSTRACT FROM AUTHOR]

Glutamate plays diverse roles in neuronal cells, affecting cell energetics and reactive oxygen species (ROS) generation. These roles are especially vital for neuronal cells, which deal with high amounts of glutamate as a neurotransmitter. Our analysis explored neuronal glutamate implication in cellular energy metabolism and ROS generation, using a kinetic model that simulates electron transport details in respiratory complexes, linked ROS generation and metabolic reactions. The analysis focused on the fact that glutamate attenuates complex II inhibition by oxaloacetate, stimulating the latter's transformation into aspartate. Such a mechanism of complex II activation by glutamate could cause almost complete reduction of ubiquinone and deficiency of oxidized form (Q), which closes the main stream of electron transport and opens a way to massive ROS generating transfer in complex III from semiquinone radicals to molecular oxygen. In this way, under low workload, glutamate triggers the respiratory chain (RC) into a different steady state characterized by high ROS generation rate. The observed stepwise dependence of ROS generation on glutamate concentration experimentally validated this prediction. However, glutamate's attenuation of oxaloacetate's inhibition accelerates electron transport under high workload. Glutamate-oxaloacetate interaction in complex II regulation underlies the observed effects of uncouplers and inhibitors and acceleration of Ca2+ uptake. Thus, this theoretical analysis uncovered the previously unknown roles of oxaloacetate as a regulator of ROS generation and glutamate as a modifier of this regulation. The model predicted that this mechanism of complex II activation by glutamate might be operative in situ and responsible for excitotoxicity. Spatial-time gradients of synthesized hydrogen peroxide concentration, calculated in the reaction-diffusion model with convection under a non-uniform local approximation of nervous tissue, have shown that overproduction of H2O2 in a cell causes excess of its level in neighbor cells. [ABSTRACT FROM AUTHOR]

Based on 550 metal analyses, this study sheds decisive light on how the Nordic Bronze Age was founded on metal imports from shifting ore sources associated with altered trade routes. On-and-off presence of copper characterised the Neolithic. At 2100–2000 BC, a continuous rise in the flow of metals to southern Scandinavia begins. First to arrive via the central German Únětician hubs was high-impurity metal from the Austrian Inn Valley and Slovakia; this was complemented by high-tin British metal, enabling early local production of tin bronzes. Increased metal use locally fuelled the leadership competitions visible in the metal-led material culture. The Únětice downfall c.1600 BC resulted for a short period in a raw materials shortage, visible in the reuse of existing stocks, but stimulated direct Nordic access to the Carpathian basin. This new access expedited innovations in metalwork with reliance on chalcopyrite from Slovakia, as well as opening new sources in the eastern Alps, along an eastern route that also conveyed Baltic amber as far as the Aegean. British metal plays a central role during this period. Finally, from c.1500 BC, when British copper imports ceased, the predominance of novel northern Italian copper coincides with the full establishment of the NBA and highlights a western route, connecting the NBA with the southern German Tumulus culture and the first transalpine amber traffic. [ABSTRACT FROM AUTHOR]

Hallucinations occur along a continuum of normal functioning. Investigating the factors related to this experience in nonclinical individuals may offer important information for understanding the etiology of hallucinations in psychiatric populations. In this study we test the relationship between psychosis proneness, loneliness, and auditory hallucinations in a nonclinical sample using the White Christmas paradigm. Seventy-six undergraduate students participated in this study. We found that slightly more than half of our participants endorsed a hallucinatory experience during the White Christmas paradigm. However, we did not observe a relationship between the number of hallucinatory experiences and schizotypy, propensity to hallucinate, or loneliness. Moreover, there were no differences on these measures between individuals who reported hearing a hallucination during the White Christmas paradigm relative to those who did not. Thus, there may be other contextual factors not investigated in this study that might clarify the mechanism by which auditory hallucinations are experienced in a nonclinical population. [ABSTRACT FROM AUTHOR]

Glutamate transporters are essential for removing the neurotransmitter glutamate from the synaptic cleft. Glutamate transport across the membrane is associated with elevator-like structural changes of the transport domain. These structural changes require initial binding of the organic substrate to the transporter. Studying the binding pathway of ligands to their protein binding sites using molecular dynamics (MD) simulations requires micro-second level simulation times. Here, we used three methods to accelerate aspartate binding to the glutamate transporter homologue Gltph and to investigate the binding pathway. 1) Two methods using user-defined forces to prevent the substrate from diffusing too far from the binding site. 2) Conventional MD simulations using very high substrate concentrations in the 0.1 M range. The final, substrate bound states from these methods are comparable to the binding pose observed in crystallographic studies, although they show more flexibility in the side chain carboxylate function. We also captured an intermediate on the binding pathway, where conserved residues D390 and D394 stabilize the aspartate molecule. Finally, we investigated glutamate binding to the mammalian glutamate transporter, excitatory amino acid transporter 1 (EAAT1), for which a crystal structure is known, but not in the glutamate-bound state. Overall, the results obtained in this study reveal new insights into the pathway of substrate binding to glutamate transporters, highlighting intermediates on the binding pathway and flexible conformational states of the side chain, which most likely become locked in once the hairpin loop 2 closes to occlude the substrate. [ABSTRACT FROM AUTHOR]

Detailed insights in both visual effects of light and effects beyond vision due to manipulations in illuminance and correlated color temperature (CCT) are needed to optimize study protocols as well as to design light scenarios for practical applications. This study investigated temporal dynamics and interindividual variability in subjective evaluations of sensation, comfort and mood as well as subjective and objective measures of alertness, arousal and thermoregulation following abrupt transitions in illuminance and CCT in a mild cold environment. The results revealed that effects could be uniquely attributed to changes in illuminance or CCT. No interaction effects of illuminance and CCT were found for any of these markers. Responses to the abrupt transitions in illuminance and CCT always occurred immediately and exclusively amongst the subjective measures. Most of these responses diminished over time within the 45-minute light manipulation. In this period, no responses were found for objective measures of vigilance, arousal or thermoregulation. Significant interindividual variability occurred only in the visual comfort evaluation in response to changes in the intensity of the light. The results indicate that the design of dynamic light scenarios aimed to enhance human alertness and vitality requires tailoring to the individual to create visually comfortable environments. [ABSTRACT FROM AUTHOR]

Fractal dimensions and characteristic periodicities were evaluated in normal sentences, computer-generated word salads, and word salads from schizophrenia patients, in both Japanese and English, using the random walk patterns of vowels. In normal sentences, the walking curves were smooth with gentle undulations, whereas computer-generated word salads were rugged with mechanical repetitions, and word salads from patients with schizophrenia were unreasonably winding with meaningless repetitive patterns or even artistic cohesion. These tendencies were similar in both languages. Fractal dimensions between normal sentences and word salads of schizophrenia were significantly different in Japanese [1.19 ± 0.09 (n = 90) and 1.15 ± 0.08 (n = 45), respectively] and English [1.20 ± 0.08 (n = 91), and 1.16 ± 0.08 (n = 42)] (p < 0.05 for both). Differences in long-range (>10) periodicities between normal sentences and word salads from schizophrenia patients were predominantly observed at 25.6 (p < 0.01) in Japanese and 10.7 (p < 0.01) in English. The differences in fractal dimension and characteristic periodicities of relatively long-range (>10) presented here are sensitive to discriminate between schizophrenia and healthy mental state, and could be implemented in social robots to assess the mental state of people in care. [ABSTRACT FROM AUTHOR]

Glypican-5 (GPC5) is a heparan sulfate proteoglycan (HSPG) localized to the plasma membrane. We previously reported that in the human mesenchymal stem cell line UE6E7T-3, GPC5 is overexpressed in association with transformation and promotes cell proliferation by acting as a co-receptor for Sonic hedgehog signaling. In this study, we found using immunofluorescence microscopy that in transformed cells (U3DT), GPC5 localized not only at primary cilia on the cell surface, but also at the leading edge of migrating cells, at the intercellular bridge and blebs during cytokinesis, and in extracellular vesicles. In each subcellular region, GPC5 colocalized with fibroblast growth factor receptor (FGFR) and the small GTPases Rab11 and ARF6, indicating that GPC5 is delivered to these regions by Rab11-associated recycling endosomes. These colocalizations suggest that GPC5 plays an important role in FGF2 stimulation of cell migration, which was abrogated by knockdown of GPC5. Our findings indicate that GPC5 plays a role in regulation of U3DT cell migration and provides several insights into the functions of GPC5 that could be elucidated by future studies. [ABSTRACT FROM AUTHOR]

Mental illness often emerges during the formative years of adolescence and young adult development and interferes with the establishment of healthy educational, vocational, and social foundations. Despite the severity of symptoms and decline in functioning, the time between illness onset and receiving appropriate care can be lengthy. A method by which to objectively identify early signs of emerging psychiatric symptoms could improve early intervention strategies. We analyzed a total of 405,523 search queries from 105 individuals with schizophrenia spectrum disorders (SSD, N = 36), non-psychotic mood disorders (MD, N = 38) and healthy volunteers (HV, N = 31) utilizing one year's worth of data prior to the first psychiatric hospitalization. Across 52 weeks, we found significant differences in the timing (p<0.05) and frequency (p<0.001) of searches between individuals with SSD and MD compared to HV up to a year in advance of the first psychiatric hospitalization. We additionally identified significant linguistic differences in search content among the three groups including use of words related to sadness and perception, use of first and second person pronouns, and use of punctuation (all p<0.05). In the weeks before hospitalization, both participants with SSD and MD displayed significant shifts in search timing (p<0.05), and participants with SSD displayed significant shifts in search content (p<0.05). Our findings demonstrate promise for utilizing personal patterns of online search activity to inform clinical care. [ABSTRACT FROM AUTHOR]

The archaeometallurgical and archaeological research carried out in Anatolia has provided numerous examples of diverse alloying practices representing different levels of societal interaction, from the extraction of ores to the trade of finished goods and high level gift exchange among elites. While discussions abound about the exploitation of mines, mining settlements, possible origins of artifacts, resources of copper, arsenic, and especially tin to improve our knowledge about Anatolian Bronze Age mining and metallurgy, uncommon alloying practices including the use of antimony, nickel, or lead have long remained in the shadows of scholarly research. With the aim of bringing attention to the diversity in alloying practices in Anatolian metallurgy, this article focuses on the use of antimony through an appraisal of archaeological and textual evidence from Bronze Age Anatolia. Archaeometric data from several Early Bronze Age sites are re-examined alongside new data emerging from Resuloğlu (Çorum, Turkey) to explain the reduction of the variety of alloy types used. Portable-XRF analysis of artifacts from Resuloğlu and mineralogical analysis of an antimony-bearing ore fragment present evidence of use of antimony at the region during the Early Bronze Age. This period is followed by disappearance of antimony in material record until the Iron Age, while textual records weakly refer to its circulation within the region. This paper considers geological, technological, and socio-economic factors to explain why the use of antimony alloys falls dormant after the Early Bronze Age. The political and economic change towards centralization over geological and technological factors is proposed as an explanation. [ABSTRACT FROM AUTHOR]

Congenital heart defects (CHDs) affect approximately 1% of newborns. Epidemiological studies have identified several genetically-mediated maternal phenotypes (e.g., pregestational diabetes, chronic hypertension) that are associated with the risk of CHDs in offspring. However, the role of the maternal genome in determining CHD risk has not been defined. We present findings from gene-level, genome-wide studies that link CHDs to maternal effect genes as well as to maternal genes related to hypertension and proteostasis. Maternal effect genes, which provide the mRNAs and proteins in the oocyte that guide early embryonic development before zygotic gene activation, have not previously been implicated in CHD risk. Our findings support a role for and suggest new pathways by which the maternal genome may contribute to the development of CHDs in offspring. [ABSTRACT FROM AUTHOR]

The paper discusses results of an interdisciplinary research project integrating lead isotope, chemical, and archaeological analysis of 20 early metal objects from central Italy. The aim of the research was to develop robust provenance hypotheses for 4th and 3rd millennia BC metals from an important, yet hitherto neglected, metallurgical district in prehistoric Europe, displaying precocious copper mining and smelting, as well as socially significant uses of metals in 'Rinaldone-style' burials. All major (and most minor) ore bodies from Tuscany and neighbouring regions were characterised chemically and isotopically, and 20 Copper Age axe-heads, daggers and halberds were sampled and analysed. The objects were also reassessed archaeologically, paying special attention to find context, typology, and chronology. This multi-pronged approach has allowed us to challenge received wisdom concerning the local character of early metal production and exchange in the region. The research has shown that most objects were likely manufactured in west-central Italy using copper from Southern Tuscany and, quite possibly, the Apuanian Alps. A few objects, however, display isotopic and chemical signatures compatible with the Western Alpine and, in one case, French ore deposits. This shows that the Copper Age communities of west-central Italy participated in superregional exchange networks tying together the middle/upper Tyrrhenian region, the western Alps, and perhaps the French Midi. These networks were largely independent from other metal displacement circuits in operation at the time, which embraced the north-Alpine region and the south-eastern Alps, respectively. [ABSTRACT FROM AUTHOR]

The BXD family has become one of the preeminent genetic reference populations to understand the genetic and environmental control of phenotypic variation. Here we evaluate the responses to different levels of fat in the diet using both chow diet (CD, 13–18% fat) and a high-fat diet (HFD, 45–60% fat). We studied cohorts of BXD strains, both inbred parents C57BL/6J and DBA/2J (commonly known as B6 and D2, respectively), as well as B6D2 and D2B6 reciprocal F1 hybrids. The comparative impact of genetic and dietary factors was analyzed by profiling a range of phenotypes, most prominently their cecum bacterial composition. The parents of the BXDs and F1 hybrids express limited differences in terms of weight and body fat gain on CD. In contrast, the strain differences on HFD are substantial for percent body fat, with DBA/2J accumulating 12.5% more fat than C57BL/6J (P < 0.0001). The F1 hybrids born to DBA/2J dams (D2B6F1) have 10.6% more body fat (P < 0.001) than those born to C57BL/6J dams. Sequence analysis of the cecum microbiota reveals important differences in bacterial composition among BXD family members with a substantial shift in composition caused by HFD. Relative to CD, the HFD induces a decline in diversity at the phylum level with a substantial increase in Firmicutes (+13.8%) and a reduction in Actinobacteria (-7.9%). In the majority of BXD strains, the HFD also increases cecal sIgA (P < 0.0001)—an important component of the adaptive immunity response against microbial pathogens. Host genetics modulates variation in cecum bacterial composition at the genus level in CD, with significant quantitative trait loci (QTLs) for Oscillibacter mapped to Chr 3 (18.7–19.2 Mb, LRS = 21.4) and for Bifidobacterium mapped to Chr 6 (89.21–89.37 Mb, LRS = 19.4). Introduction of HFD served as an environmental suppressor of these QTLs due to a reduction in the contribution of both genera (P < 0.001). Relations among liver metabolites and cecum bacterial composition were predominant in CD cohort, but these correlations do not persist following the shift to HFD. Overall, these findings demonstrate the important impact of environmental/dietary manipulation on the relationships between host genetics, gastrointestinal bacterial composition, immunological parameters, and metabolites—knowledge that will help in the understanding of the causal sources of metabolic disorders. [ABSTRACT FROM AUTHOR]

The secreted protein, insulin-like growth factor 2 (IGF2), plays a central role in fetal and prenatal growth and development, and is regulated at the genetic level by parental imprinting, being expressed predominantly from the paternally derived chromosome in mice and humans. Here, IGF2/Igf2 and its locus has been examined in 19 mammals from 13 orders spanning ~166 million years of evolutionary development. By using human or mouse DNA segments as queries in genome analyses, and by assessing gene expression using RNA-sequencing libraries, more complexity was identified within IGF2/Igf2 than was annotated previously. Multiple potential 5’ non-coding exons were mapped in most mammals and are presumably linked to distinct IGF2/Igf2 promoters, as shown for several species by interrogating RNA-sequencing libraries. DNA similarity was highest in IGF2/Igf2 coding exons; yet, even though the mature IGF2 protein was conserved, versions of 67 or 70 residues are produced secondary to species-specific maintenance of alternative RNA splicing at a variable intron-exon junction. Adjacent H19 was more divergent than IGF2/Igf2, as expected in a gene for a noncoding RNA, and was identified in only 10/19 species. These results show that common features, including those defining IGF2/Igf2 coding and several non-coding exons, were likely present at the onset of the mammalian radiation, but that others, such as a putative imprinting control region 5’ to H19 and potential enhancer elements 3’ to H19, diversified with speciation. This study also demonstrates that careful analysis of genomic and gene expression repositories can provide new insights into gene structure and regulation. [ABSTRACT FROM AUTHOR]

The origin of the tin used for the production of bronze in the Eurasian Bronze Age is still one of the mysteries in prehistoric archaeology. In the past, numerous studies were carried out on archaeological bronze and tin objects with the aim of determining the sources of tin, but all failed to find suitable fingerprints. In this paper we investigate a set of 27 tin ingots from well-known sites in the eastern Mediterranean Sea (Mochlos, Uluburun, Hishuley Carmel, Kfar Samir south, Haifa) that had been the subject of previous archaeological and archaeometallurgical research. By using a combined approach of tin and lead isotopes together with trace elements it is possible to narrow down the potential sources of tin for the first time. The strongly radiogenic composition of lead in the tin ingots from Israel allows the calculation of a geological model age of the parental tin ores of 291 ± 17 Ma. This theoretical formation age excludes Anatolian, central Asian and Egyptian tin deposits as tin sources since they formed either much earlier or later. On the other hand, European tin deposits of the Variscan orogeny agree well with this time span so that an origin from European deposits is suggested. With the help of the tin isotope composition and the trace elements of the objects it is further possible to exclude many tin resources from the European continent and, considering the current state of knowledge and the available data, to conclude that Cornish tin mines are the most likely suppliers for the 13th–12th centuries tin ingots from Israel. Even though a different provenance seems to be suggested for the tin from Mochlos and Uluburun by the actual data, these findings are of great importance for the archaeological interpretation of the trade routes and the circulation of tin during the Late Bronze Age. They demonstrate that the trade networks between the eastern Mediterranean and some place in the east that are assumed for the first half of the 2nd millennium BCE (as indicated by textual evidence from Kültepe/Kaneš and Mari) did not exist in the same way towards the last quarter of the millennium. [ABSTRACT FROM AUTHOR]

Eleven biconical vessels from the Copper Age sites Pietrele and Blejeşti (Romania) have been investigated using p-XRF. In most cases, traces of lead could be measured on their surfaces. Samples of slag-like material from two vessels and the clay of one vessel were investigated using laboratory methods, namely SEM, XRD, LIA and optical microscopy. The vessels were obviously used as a kind of crucible in which slag-like remains and galena ore were detected. It still remains unclear as to what final product was gained by smelting galena in this way. The amount of these such vessels in the Pietrele settlement, their appearance as grave goods in Pietrele and Vărăști (Romania), and their supposed occurrence in a number of other Copper Age settlements in Romania and Bulgaria show the significance of this phenomenon. It must have been a widespread and more or less well known practice, an important part of cultural habit during a particular period in the Lower Danube region and likely even farther afield. For the first time, extensive experimentation with lead ore can be shown in a clear chronological horizon, ca. 4400–4300 BCE in southeastern Europe. [ABSTRACT FROM AUTHOR]

Operant conditioning is a crucial tool in neuroscience research for probing brain function. While molecular, anatomical and even physiological techniques have seen radical increases in throughput, efficiency, and reproducibility in recent years, behavioural tools have somewhat lagged behind. Here we present a fully automated, high-throughput system for self-initiated conditioning of up to 25 group-housed, radio-frequency identification (RFID) tagged mice over periods of several months and >106 trials. We validate this “AutonoMouse” system in a series of olfactory behavioural tasks and show that acquired data is comparable to previous semi-manual approaches. Furthermore, we use AutonoMouse to systematically probe the impact of graded olfactory bulb lesions on olfactory behaviour, demonstrating that while odour discrimination in general is robust to even most extensive disruptions, small olfactory bulb lesions already impair odour detection. Discrimination learning of similar mixtures as well as learning speed are in turn reliably impacted by medium lesion sizes. The modular nature and open-source design of AutonoMouse should allow for similar robust and systematic assessments across neuroscience research areas. [ABSTRACT FROM AUTHOR]

Aims: Theory of Mind (ToM) is often impaired in early and chronic phases of psychosis and it is often suggested that poor ToM is a trait vulnerability for psychosis. The aim of this study was to examine in an adolescent sample whether childhood ToM abilities can predict psychotic experiences over a period of six years and whether this is mediated by social functioning. To examine whether ToM is a specific predictor for psychosis, symptoms of depression and anxiety were also examined. Materials and methods: A baseline case-control sample (T0: age 7–8 years) with and without auditory vocal hallucinations (AVH) in the general population was assessed after five years (T1: age 12–13 years) on ToM ability (ToM Storybook Frank), and after eleven years (T2: age 18–19 years) on psychotic experiences (Community Assessment of Psychic Experiences; CAPE), depressive and anxiety symptoms (Depression Anxiety and Stress Scale; DASS-21), and social functioning (Groningen Questionnaire on Social Behaviour; GSVG-45). Analyses were conducted on a subsample of 157 adolescents aged 18–19 years (T2) who had data available on ToM ability at T1. Results: ToM at T1 was not predictive of psychotic experiences after six years (from age 12–13 to age 18–19) and social functioning was also not a mediator. ToM was not associated with psychopathology in general (depressive and anxiety symptoms) over six years (from age 12–13 to age 18–19). Conclusions: The current study found no evidence for a longitudinal association between ToM ability and psychotic experiences, social functioning, and symptoms of depression and anxiety, in adolescence. [ABSTRACT FROM AUTHOR]

Molecular tools adapted from bacterial CRISPR (Clustered Regulatory Interspaced Short Palindromic Repeats) systems for adaptive immunity have become widely used for plant genome engineering, both to investigate gene functions and to engineer desirable traits. A number of different Cas (CRISPR-associated) nucleases are now used but, as most studies performed to date have engineered different targets using a variety of plant species and molecular tools, it has been difficult to draw conclusions about the comparative performance of different nucleases. Due to the time and effort required to regenerate engineered plants, efficiency is critical. In addition, there have been several reports of mutations at sequences with less than perfect identity to the target. While in some plant species it is possible to remove these so-called 'off-targets' by backcrossing to a parental line, the specificity of genome engineering tools is important when targeting specific members of closely-related gene families, especially when recent paralogues are co-located in the genome and unlikely to segregate. Specificity is also important for species that take years to reach sexual maturity or that are clonally propagated. Here, we directly compare the efficiency and specificity of Cas nucleases from different bacterial species together with engineered variants of Cas9. We find that the nucleotide content of the target correlates with efficiency and that Cas9 from Staphylococcus aureus (SaCas9) is comparatively most efficient at inducing mutations. We also demonstrate that 'high-fidelity' variants of Cas9 can reduce off-target mutations in plants. We present these molecular tools as standardised DNA parts to facilitate their re-use. [ABSTRACT FROM AUTHOR]

Blebs are cellular protrusions observed in migrating cells and in cells undergoing spreading, cytokinesis, and apoptosis. Here we investigate the flow of cytoplasm during bleb formation and the concurrent changes in cell volume using zebrafish primordial germ cells (PGCs) as an in vivo model. We show that bleb inflation occurs concomitantly with cytoplasmic inflow into it and that during this process the total cell volume does not change. We thus show that bleb formation in primordial germ cells results primarily from redistribution of material within the cell rather than being driven by flow of water from an external source. [ABSTRACT FROM AUTHOR]

The efficacy of animal signals is strongly influenced by the structure of the habitat in which they are propagating. In recent years, the habitat structure of temperate forests has been increasingly subject to modifications from foraging by white-tailed deer (Odocoileus virginianus). Increasing deer numbers and the accompanying browsing have been shown to alter vegetation structure and thus the foraging, roosting, and breeding habitats of many species. However, despite a large body of literature on the effects of vegetation structure on sound propagation, we do not yet know what impact deer browsing may have on acoustic communication. Here we used playback experiments to determine whether sound fidelity and amplitude of white noise, pure tones, and trills differed between deer-browsed and deer-excluded plots. We found that sound fidelity, but not amplitude, differed between habitats, with deer-browsed habitats having greater sound fidelity than deer-excluded habitats. Difference in sound propagation characteristics between the two habitats could alter the efficacy of acoustic communication through plasticity, cultural evolution or local adaptation, in turn influencing vocally-mediated behaviors (e.g. agonistic, parent-offspring, mate selection). Reduced signal degradation suggests vocalizations may retain more information, improving the transfer of information to both intended and unintended receivers. Overall, our results suggest that deer browsing impacts sound propagation in temperate deciduous forest, although much work remains to be done on the potential impacts on communication. [ABSTRACT FROM AUTHOR]

Genomic imprinting is important for normal brain development and aberrant imprinting has been associated with impaired cognition. We studied the imprinting status in selected imprints (H19, IGF2, SNRPN, PEG3, MEST1, NESPAS, KvDMR, IG-DMR and ZAC1) by pyrosequencing in blood samples from longitudinal cohorts born in 1936 (n = 485) and 1921 (n = 223), and anterior hippocampus, posterior hippocampus, periventricular white matter, and thalamus from brains donated to the Aberdeen Brain Bank (n = 4). MEST1 imprint methylation was related to childhood cognitive ability score (-0.416 95% CI -0.792,-0.041; p = 0.030), with the strongest effect evident in males (-0.929 95% CI -1.531,-0.326; p = 0.003). SNRPN imprint methylation was also related to childhood cognitive ability (+0.335 95%CI 0.008,0.663; p = 0.045). A significant association was also observed for SNRPN methylation and adult crystallised cognitive ability (+0.262 95%CI 0.007,0.517; p = 0.044). Further testing of significant findings in a second cohort from the same region, but born in 1921, resulted in similar effect sizes and greater significance when the cohorts were combined (MEST1; -0.371 95% CI -0.677,-0.065; p = 0.017; SNRPN; +0.361 95% CI 0.079,0.643; p = 0.012). For SNRPN and MEST1 and four other imprints the methylation levels in blood and in the five brain regions were similar. Methylation of the paternally expressed, maternally methylated genes SNRPN and MEST1 in adult blood was associated with cognitive ability in childhood. This is consistent with the known importance of the SNRPN containing 15q11-q13 and the MEST1 containing 7q31-34 regions in cognitive function. These findings, and their sex specific nature in MEST1, point to new mechanisms through which complex phenotypes such as cognitive ability may be inherited. These mechanisms are potentially relevant to both the heritable and non-heritable components of cognitive ability. The process of epigenetic imprinting—within SNRPN and MEST1 in particular—and the factors that influence it, are worthy of further study in relation to the determinants of cognitive ability. [ABSTRACT FROM AUTHOR]