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Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools.
To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics.
Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts.
Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = −0.34 years, s.e. = 0.08), major depression (β = −0.34 years, s.e. = 0.08), schizophrenia (β = −0.39 years, s.e. = 0.08), and educational attainment (β = −0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO.
AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses.
Designating protected areas remains a core strategy in biodiversity conservation. Despite high endemism, montane forests across the island of Java are under-represented in Indonesia's protected area network. Here, we document the montane biodiversity of Gunung Slamet, an isolated volcano in Central Java, and provide evidence to support its increased protection. During September–December 2018, we surveyed multiple sites for birds, primates, terrestrial mammals, reptiles, amphibians and vegetation. Survey methods included transects, camera traps and targeted searches at six sites, at altitudes of 970–2,512 m. We used species distribution models for birds and mammals of conservation concern to identify priority areas for protection. We recorded 99 bird species (13 globally threatened), 15 mammals (five globally threatened) and 17 reptiles and amphibians (two endemic). Our species distribution models showed considerable cross-taxon congruence between important areas on Slamet's upper slopes, generally above 1,800 m. Particularly important were records of the endemic subspecies of the Endangered Javan laughingthrush Garrulax rufifrons slamatensis, not recorded in the wild since 1925, the Endangered Javan gibbon Hylobates moloch and Javan surili Presbytis comata, and the Vulnerable Javan lutung Trachypithecus auratus and Javan leopard Panthera pardus melas. Recent forest loss has been modest, at least 280 km2 of continuous forest remain above 800 m, and our surveys show that forest habitats are in good condition. However, the mountain is widely used by trappers and hunters. Given its importance for biodiversity conservation, we discuss different options for improving the protection status of Gunung Slamet, including designation as a National Park or Essential Ecosystem.
We use three-dimensional (3-D) fully kinetic particle-in-cell simulations to study the occurrence of magnetic reconnection in a simulation of decaying turbulence created by anisotropic counter-propagating low-frequency Alfvén waves consistent with critical-balance theory. We observe the formation of small-scale current-density structures such as current filaments and current sheets as well as the formation of magnetic flux ropes as part of the turbulent cascade. The large magnetic structures present in the simulation domain retain the initial anisotropy while the small-scale structures produced by the turbulent cascade are less anisotropic. To quantify the occurrence of reconnection in our simulation domain, we develop a new set of indicators based on intensity thresholds to identify reconnection events in which both ions and electrons are heated and accelerated in 3-D particle-in-cell simulations. According to the application of these indicators, we identify the occurrence of reconnection events in the simulation domain and analyse one of these events in detail. The event is related to the reconnection of two flux ropes, and the associated ion and electron exhausts exhibit a complex 3-D structure. We study the profiles of plasma and magnetic-field fluctuations recorded along artificial-spacecraft trajectories passing near and through the reconnection region. Our results suggest the presence of particle heating and acceleration related to small-scale reconnection events within magnetic flux ropes produced by the anisotropic Alfvénic turbulent cascade in the solar wind. These events are related to current structures of the order of a few ion inertial lengths in size.
Recently developed quantitative models of psychopathology (i.e., Hierarchical Taxonomy of Psychopathology) identify an Antagonistic Externalizing spectrum that captures the psychological disposition toward criminal and antisocial behavior. The purpose of the present study was to examine relations between Antagonistic psychopathology (and associated Five-Factor model Antagonism/Agreeableness) and neural functioning related to social-cognitive Theory of Mind using a large sample (N = 973) collected as part of the Human Connectome Project (Van Essen et al., 2013a). No meaningful relations between Antagonism/Antagonistic Externalizing and Theory of Mind-related neural activity or synchrony were observed (p < .005). We conclude by outlining methodological considerations (e.g., validity of social cognition task and low test–retest reliability of functional biomarkers) that may account for these null results, and present recommendations for future research.
This study aimed to examine the predictors of cognitive performance in patients with pediatric mild traumatic brain injury (pmTBI) and to determine whether group differences in cognitive performance on a computerized test battery could be observed between pmTBI patients and healthy controls (HC) in the sub-acute (SA) and the early chronic (EC) phases of injury.
203 pmTBI patients recruited from emergency settings and 159 age- and sex-matched HC aged 8–18 rated their ongoing post-concussive symptoms (PCS) on the Post-Concussion Symptom Inventory and completed the Cogstate brief battery in the SA (1–11 days) phase of injury. A subset (156 pmTBI patients; 144 HC) completed testing in the EC (~4 months) phase.
Within the SA phase, a group difference was only observed for the visual learning task (One-Card Learning), with pmTBI patients being less accurate relative to HC. Follow-up analyses indicated higher ongoing PCS and higher 5P clinical risk scores were significant predictors of lower One-Card Learning accuracy within SA phase, while premorbid variables (estimates of intellectual functioning, parental education, and presence of learning disabilities or attention-deficit/hyperactivity disorder) were not.
The absence of group differences at EC phase is supportive of cognitive recovery by 4 months post-injury. While the severity of ongoing PCS and the 5P score were better overall predictors of cognitive performance on the Cogstate at SA relative to premorbid variables, the full regression model explained only 4.1% of the variance, highlighting the need for future work on predictors of cognitive outcomes.
Schmidt-hammer exposure-age dating (SHD) of boulders on cryoplanation terrace treads and associated bedrock cliff faces revealed Holocene ages ranging from 0 ± 825 to 8890 ± 1185 yr. The cliffs were significantly younger than the inner treads, which tended to be younger than the outer treads. Radiocarbon dates from the regolith of 3854 to 4821 cal yr BP (2σ range) indicated maximum rates of cliff recession of ~0.1 mm/yr, which suggests the onset of terrace formation before the last glacial maximum. Age, angularity, and size of clasts, together with planation across bedrock structures and the seepage of groundwater from the cliff foot, all support a process-based conceptual model of cryoplanation terrace development in which frost weathering leads to parallel cliff recession and, hence, terrace extension. The availability of groundwater during autumn freezeback is viewed as critical for frost wedging and/or the growth of segregation ice during prolonged winter frost penetration. Permafrost promotes cryoplanation by providing an impermeable frost table beneath the active layer, focusing groundwater flow, and supplying water for sediment transport by solifluction across the tread. Snow beds are considered an effect rather than a cause of cryoplanation terraces, and cryoplanation is seen as distinct from nivation.
Anecdotal evidence suggests the use of bolus tube feeding is increasing in the long-term home enteral tube feed (HETF) patients. A cross-sectional survey to assess the prevalence of bolus tube feeding and to characterise these patients was undertaken. Dietitians from ten centres across the UK collected data on all adult HETF patients on the dietetic caseload receiving bolus tube feeding (n 604, 60 % male, age 58 years). Demographic data, reasons for tube and bolus feeding, tube and equipment types, feeding method and patients’ complete tube feeding regimens were recorded. Over a third of patients receiving HETF used bolus feeding (37 %). Patients were long-term tube fed (4·1 years tube feeding, 3·5 years bolus tube feeding), living at home (71 %) and sedentary (70 %). The majority were head and neck cancer patients (22 %) who were significantly more active (79 %) and lived at home (97 %), while those with cerebral palsy (12 %) were typically younger (age 31 years) but sedentary (94 %). Most patients used bolus feeding as their sole feeding method (46 %), because it was quick and easy to use, as a top-up to oral diet or to mimic mealtimes. Importantly, oral nutritional supplements (ONS) were used for bolus feeding in 85 % of patients, with 51 % of these being compact-style ONS (2·4 kcal (10·0 kJ)/ml, 125 ml). This survey shows that bolus tube feeding is common among UK HETF patients, is used by a wide variety of patient groups and can be adapted to meet the needs of a variety of patients, clinical conditions, nutritional requirements and lifestyles.
Toys are children's first consumer products and while playing they acquire numerous skills, learn about their environment and socialise with other children and adults. Toys are adapted and used by clinicians as therapeutic devices because they allow them to create bonds and communicate with children. Aesthetical aspects should be considered early in the design process, especially since pre-schoolers’ views are still dominated by the appearance of artefacts, also known as, the perceptual salient characteristics. The study of emotions mediates the understanding of the relationships between a product, user and the process with which consumers set up preferences over products. Decisions taken in each design stage will influence whether therapeutic devices will be enjoyed by children. An experiment was carried out to test out pre-schoolers’ preferences on individual attributes: form, dimension, material (hardness and weight) and surface (appearance and texture). This study exposed dominant characteristic preferences and the fact that some are influenced by gender and age. Employing these findings in therapeutic devices will enable clinicians to better engage the children during therapy.
OBJECTIVES/SPECIFIC AIMS: Prostate cancer is the second leading cause of cancer-related death among men in the U.S. and over half of all prostate cancer patients receive radiation therapy (RT). RT induces double-strand breaks (DSBs) in DNA which are lethal to cells if not repaired. While potentially curative, 10% of low-risk patients and 50% of high-risk patients treated with RT still experience tumor recurrence. Thus, identification of novel therapeutic targets to enhance RT will likely reduce prostate cancer mortality. The only clinical approach to enhance RT is androgen deprivation therapy, which targets androgen receptor (AR) signaling; however, its use is limited due to systemic side effects. We recently reported that PRMT5 epigenetically activates AR which led us to investigate if targeting PRMT5 sensitizes prostate cancer to RT. The goal of this project is to determine if PRMT5 is a therapeutic target for prostate cancer radiosensitization and analyze its mechanistic role in response to radiation. METHODS/STUDY POPULATION: To evaluate if targeting PRMT5 may sensitize prostate cancer cells to radiation, we performed a clonogenic assay of irradiated cells. To determine if PRMT5 is required for repair of radiation-induced DSBs, we performed foci analysis via immunocytochemistry. We then used RNA-seq, qPCR, western blot, and ChIP to evaluate a potential epigenetic role of PRMT5 in activating the expression of genes critical to DSB repair. To extend our findings, we analyzed clinical data from around 18,000 of cancer patients encompassing 43 cancer types to assess if PRMT5 expression correlates with the expression of its putative target genes. RESULTS/ANTICIPATED RESULTS: Targeting PRMT5 sensitizes prostate cancer cells to radiation independently of AR status. RNA-seq analysis revealed putative PRMT5 target genes including several involved in DSB repair and G2 arrest. Mechanistically, PRMT5 functions as a master epigenetic activator of DNA damage response (DDR) genes: PRMT5 maintains the basal expression of several DDR genes including BRCA1, BRCA2, and RAD51 and is recruited upon radiation to DDR gene promoters to activate their expression via histone methylation. Targeting PRMT5 decreases expression of these genes at the protein level and hinders repair of radiation-induced DSBs in multiple cancer and non-cancer cell types. Clinically, PRMT5 expression positively correlates with the expression of these DDR genes across all 43 cancer types analyzed. DISCUSSION/SIGNIFICANCE OF IMPACT: PRMT5 acts as a master epigenetic activator of genes involved in DDR and is critical for cells to survive radiation treatment. Importantly, PRMT5 epigenetically activates multiple genes that encode for well-characterized core repair proteins involved in HR (RAD51, RAD51AP1, RAD51D, BRCA1 and BRCA2) and NHEJ (NHEJ1, Ku80, XRCC4, and DNAPKcs), which may explain why PRMT5 is essential to repair IR-induced DSBs in several cell lines. As PRMT5 is overexpressed in many human cancers and its overexpression correlates with poor prognosis, our findings suggest that more efficient DSB repair via PRMT5 overexpression in these cancers may confer survival advantages particularly following DNA damaging treatments. Lastly, because targeting DSB repair is a clinically validated therapeutic approach for cancer treatment, our findings also suggest that PRMT5 targeting may be explored as a monotherapy or in combination therapy with radiation therapy or chemotherapy for cancer treatment.
Psychotic symptoms and psychotic disorders occur at increased rates in adults with intellectual disability, including borderline intellectual functioning, compared with the general population. Little is known about the development of such symptoms in this population.
To examine whether clinical factors predictive of psychotic disorder in a familial study of schizophrenia also apply to those with intellectual disability.
Adolescents with special educational needs (SEN) were assessed with the Structured Interview for Schizotypy (SIS) and Childhood Behavioural Checklist (CBCL). These scores were used to prospectively divide participants based on their anticipated risk for psychotic disorder. A subsample were reassessed three times over 6 years, using the Positive and Negative Syndrome Scale (PANSS).
The SEN group were more symptomatic than controls throughout (Cohen's d range for PANSS subscale scores: 0.54–1.4, all P < 0.007). Over 6 years of follow-up, those above the SIS and CBCL cut-off values at baseline were more likely than those below to display morbid positive psychotic symptoms (odds ratio, 3.5; 95% CI 1.3–9.0) and develop psychotic disorder (odds ratio, 11.4; 95% CI 2.6–50.1). Baseline SIS and CBCL cut-off values predicted psychotic disorder with sensitivity of 0.67, specificity of 0.85, positive predictive value of 0.26 and negative predictive value of 0.97.
Adolescents with SEN have increased psychotic and non-psychotic symptoms. The personality and behavioural features associated with later psychotic disorder in this group are similar to those in people with familial loading. Relatively simple screening measures may help identify those in this vulnerable group who do and do not require monitoring for psychotic symptoms.
Seven half-day regional listening sessions were held between December 2016 and April 2017 with groups of diverse stakeholders on the issues and potential solutions for herbicide-resistance management. The objective of the listening sessions was to connect with stakeholders and hear their challenges and recommendations for addressing herbicide resistance. The coordinating team hired Strategic Conservation Solutions, LLC, to facilitate all the sessions. They and the coordinating team used in-person meetings, teleconferences, and email to communicate and coordinate the activities leading up to each regional listening session. The agenda was the same across all sessions and included small-group discussions followed by reporting to the full group for discussion. The planning process was the same across all the sessions, although the selection of venue, time of day, and stakeholder participants differed to accommodate the differences among regions. The listening-session format required a great deal of work and flexibility on the part of the coordinating team and regional coordinators. Overall, the participant evaluations from the sessions were positive, with participants expressing appreciation that they were asked for their thoughts on the subject of herbicide resistance. This paper details the methods and processes used to conduct these regional listening sessions and provides an assessment of the strengths and limitations of those processes.
Herbicide resistance is ‘wicked’ in nature; therefore, results of the many educational efforts to encourage diversification of weed control practices in the United States have been mixed. It is clear that we do not sufficiently understand the totality of the grassroots obstacles, concerns, challenges, and specific solutions needed for varied crop production systems. Weed management issues and solutions vary with such variables as management styles, regions, cropping systems, and available or affordable technologies. Therefore, to help the weed science community better understand the needs and ideas of those directly dealing with herbicide resistance, seven half-day regional listening sessions were held across the United States between December 2016 and April 2017 with groups of diverse stakeholders on the issues and potential solutions for herbicide resistance management. The major goals of the sessions were to gain an understanding of stakeholders and their goals and concerns related to herbicide resistance management, to become familiar with regional differences, and to identify decision maker needs to address herbicide resistance. The messages shared by listening-session participants could be summarized by six themes: we need new herbicides; there is no need for more regulation; there is a need for more education, especially for others who were not present; diversity is hard; the agricultural economy makes it difficult to make changes; and we are aware of herbicide resistance but are managing it. The authors concluded that more work is needed to bring a community-wide, interdisciplinary approach to understanding the complexity of managing weeds within the context of the whole farm operation and for communicating the need to address herbicide resistance.
Transient storage and erosion of valley fills, or sediment buffering, is a fundamental but poorly quantified process that may significantly bias fluvial sediment budgets and marine archives used for paleoclimatic and tectonic reconstructions. Prolific sediment buffering is now recognized to occur within the mountainous upper Indus River headwaters and is quantified here for the first time using optically stimulated luminescence dating, petrography, detrital zircon U-Pb geochronology, and morphometric analysis to define the timing, provenance, and volumes of prominent valley fills. This study finds that climatically modulated sediment buffering occurs over 103–104 yr time scales and results in biases in sediment compositions and volumes. Increased sediment storage coincides with strong phases of summer monsoon and winter westerlies precipitation over the late Pleistocene (32–25 ka) and mid-Holocene (~8–6 ka), followed by incision and erosion with monsoon weakening. Glacial erosion and periglacial frost-cracking drive sediment production, and monsoonal precipitation mediates sediment evacuation, in contrast to the arid Transhimalaya and monsoonal frontal Himalaya. Plateau interior basins, although volumetrically large, lack transport capacity and are consequently isolated from the modern Indus River drainage. Marginal plateau catchments that both efficiently produce and evacuate sediment may regulate the overall compositions and volumes of exported sediment from the Himalayan rain shadow.