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AbstractThis study was designed to evaluate the classification accuracy of the Warrington’s Recognition Memory Test (RMT) in 167 patients (97 or 58.1% men; MAge = 40.4; MEducation= 13.8) medically referred for neuropsychological evaluation against five psychometrically defined criterion groups. At the optimal cutoff (≤42), the RMT produced an acceptable combination of sensitivity (.36-.60) and specificity (.85-.95), correctly classifying 68.4-83.3% of the sample. Making the cutoff more conservative (≤41) improved specificity (.88-.95) at the expense of sensitivity (.30-.60). Lowering the cutoff to ≤40 achieved uniformly high specificity (.91-.95) but diminished sensitivity (.27-.48). RMT scores were unrelated to lateral dominance, education, or gender. The RMT was sensitive to a three-way classification of performance validity (Pass/Borderline/Fail), further demonstrating its discriminant power. Despite a notable decline in research studies focused on its classification accuracy within the last decade, the RMT remains an effective free-standing PVT that is robust to demographic variables. Relatively low sensitivity is its main liability. Further research is needed on its cross-cultural validity (sensitivity to limited English proficiency). [ABSTRACT FROM AUTHOR]

Background: Converging lines of evidence indicate that ketamine is a rapid antidepressant for individuals with treatment-resistant depression. Hitherto, no reliable a priori predictors of ketamine response have been reported. Pharmacogenetic biomarkers have yielded mixed results regarding potential candidate genes associated with ketamine's biochemistry as reliable predictors of response. Aims: No studies have examined the effects of Val66Met and CYP2B6 genotypes on patients receiving repeated infusions of intravenous ketamine. Methods: In all, 85 participants with major depressive disorder who had previously received four infusions of intravenous ketamine were recruited to the foregoing study. Buccal swabs were collected and genotype variants across the Val66Met and CYP2B6 genes were analyzed. A repeated measures mixed linear model was used to assess change in depressive symptoms, suicidality, and anxiety, correcting for sex and age. Multiple regression was run to determine whether these genetic markers were associated with treatment efficacy for depressive severity, suicidal ideation, anxiolytic response, and degree of dissociation to intravenous ketamine. Results: Participants experienced significant overall reductions in depression, suicide, and anxiety. Overall, 25% met the response criteria and 15% met the remission criteria. However, Val66Met and CYP2B6 did not significantly predict changes in symptoms of depression, suicide, anxiety, or average dissociation. Conclusions: This study contributes to the growing literature that ketamine efficacy is unlikely to be predicted by single genes, and a pleiotropic approach may likely be necessary for developing reliable predictors of clinical benefits. [ABSTRACT FROM AUTHOR]

University campuses could become leaders in developing alternatives to policing for managing public health and safety, yet, nearly all campuses rely on campus or local police to respond to mental health emergencies. Herein, we present the available evidence for campus mobile crisis intervention teams (MCITs) as an alternative to policing, consider what colleges and universities can learn from existing community MCIT models, and propose initial steps for the development and implementation of a campus MCIT. [ABSTRACT FROM AUTHOR]

Plant roots navigate in the soil environment following the gravity vector. Cell divisions in the meristem and rapid cell growth in the elongation zone propel the root tips through the soil. Actively elongating cells acidify their apoplast to enable cell wall extension by the activity of plasma membrane AHA H+-ATPases. The phytohormone auxin, central regulator of gravitropic response and root development, inhibits root cell growth, likely by rising the pH of the apoplast. However, the role of auxin in the regulation of the apoplastic pH gradient along the root tip is unclear. Here, we show, by using an improved method for visualization and quantification of root surface pH, that the Arabidopsis thaliana root surface pH shows distinct acidic and alkaline zones, which are not primarily determined by the activity of AHA H+-ATPases. Instead, the distinct domain of alkaline pH in the root transition zone is controlled by a rapid auxin response module, consisting of the AUX1 auxin influx carrier, the AFB1 auxin co-receptor, and the CNCG14 calcium channel. We demonstrate that the rapid auxin response pathway is required for an efficient navigation of the root tip. [ABSTRACT FROM AUTHOR]

The rapid digitalization brought about by the COVID-19 pandemic has transformed the business landscape, presenting both opportunities and challenges for micro, small, and medium enterprises (MSMEs) in the Philippines. This study investigates the potential of Facebook advertising and growth hacking strategies as practical tools to unlock growth for MSMEs in this evolving context. A survey of 100 MSME owners/managers in Metro Manila examined the current usage, perceptions, and effectiveness of these digital marketing tactics. The results reveal that both Facebook advertising and growth hacking can significantly impact key metrics like revenue, profitability, customer acquisition, and retention if executed effectively. However, challenges like limited resources and digital skills constrain adoption for many MSMEs. The study's conceptual framework, grounded in the HP Growth Engine model, establishes linkages between Facebook advertising, growth hacking, and MSME growth. Statistical analysis confirms significant positive relationships, supporting the strategic integration of these approaches. Practical implications highlight the need for MSMEs to embrace Facebook advertising, implement growth hacking techniques, enhance digital literacy, and foster stakeholder collaborations. By leveraging Facebook advertising and growth hacking, Philippine MSMEs can seize growth opportunities in the post-pandemic landscape. This study provides empirical insights to guide MSMEs, marketers and policymakers in harnessing these strategies for sustainable growth. [ABSTRACT FROM AUTHOR]

This review expands our insights into how micro, small, and medium enterprises or MSMEs cope with disruption in Metro Manila in the Philippines using social media marketing. COVID-19 accelerated certain processes forcing local businesses to embrace digital marketing transformation. Thus, it enables local businesses to intensify their social media marketing (SMM) efforts to remain relevant due to a series of lockdowns and government-initiated restrictions. Based on the systematic review, the researcher proposes a conceptual framework to answer the question: How can MSMEs cope with disruption through social media marketing to attain positive brand equity? The proposed conceptual framework looked into synonymous themes such as marketing competencies (MC), omnichannel strategies (OC), and brand equity (BE). Within the process, MSMEs can optimize their social media marketing strategies as a springboard to reimagine the new normal with significance on how the business would aggrandize its resources. Moreover, as of October 2021, the entire nation has entered the post-pandemic period, making this study pertinent for local enterprises. Indeed, MSMEs attempt to bounce back from a two-year incubus. [ABSTRACT FROM AUTHOR]

Background: Clinical trials have demonstrated rapid antidepressant effects with intravenous (IV) ketamine for major depressive disorder, with relatively less research specifically for bipolar depression. Herein, we describe the real‐world effectiveness of repeated ketamine infusions for treatment‐resistant bipolar depression. Methods: This study was conducted in a community clinic in Mississauga, Ontario (Canadian Rapid Treatment Centre of Excellence; Braxia Health). In this observational study (NCT04209296), patients with treatment‐resistant bipolar I/II depression (n = 66) received four sub‐anesthetic doses of IV ketamine (0.5–0.75 mg/kg) over a two‐week period. Symptoms of depression, suicidality, anxiety, and functioning were assessed with validated self‐report measures. Results: Statistically and clinically significant antidepressant effects were observed in the overall sample, as measured by the Quick Inventory for Depression Symptomatology‐Self Report‐16 (QIDS‐SR16) with further reductions in depressive symptoms observed after each subsequent infusion (n = 66; mean QIDS‐SR16 reduction of 6.08+/−1.39; p < 0.0001). Significant reductions of suicidal thoughts (QIDS‐SR16‐Suicide Item) and anxiety (Generalized Anxiety Disorder‐7) were also observed with functional improvements on the Sheehan Disability Scale (p < 0.0001 on all measures). Moreover, the response rate (QIDS‐SR16 total score decrease ≥50% from baseline) was 35% and remission rate (QIDS‐SR16 total score ≤5) was 20% after four infusions. Infusions were generally well tolerated with treatment‐emergent hypomania observed in only three patients (4.5%) with zero cases of mania or psychosis. Conclusions: Real‐world effectiveness of IV ketamine for bipolar depression was observed. Repeated doses were associated with greater symptom reduction and adequate tolerability. [ABSTRACT FROM AUTHOR]

Introduction: Bipolar disorder (BD) is characterized by a pro-inflammatory biotype, and is a major cause of cardiovascular disease (CVD), consequently causing elevated rates of morbidity and mortality among individuals with BD.Methods: The present study is based on a 12-week clinical trial assessing the antidepressant effects of adjunctive infliximab treatment in BD. Generalized estimating equation (GEE) models were used to evaluate CVD risk in people with BD following adjunctive infliximab treatment at baseline and week 12. Participants (baseline: n = 40; endpoint: 33) were randomized for an infliximab-treatment or placebo group. CVD-risk was calculated using Framingham risk scores (FRS), mean arterial blood pressure (MAP) and total cholesterol (TC).Results: There was no main effect of treatment on FRS in infliximab-treated participants compared to controls (p = 0.408). Similarly, there were no significant differences in MAP between the infliximab-treated and control group (p = 0.796). The effect of treatment on TC was not significant (p = 0.130), however, an evaluation across time suggested the main effect of the group was significant at week 0 (p = 0.01), but not week 12 (p = 0.219).Limitations: Cardiovascular disease was not an outcome of the original clinical trial, and our participant group did not have a high CVD-risk at baseline.Conclusion: There were no significant treatment effects of infliximab on FRS, MAP and TC. The current study highlights the complexity of immune-system targets that influence CVD in psychiatric populations. Future studies should include a large scale, combinatorial omnibus biomarker approach to evaluate the immune and vascular link in BD. [ABSTRACT FROM AUTHOR]

Summary: Sleep disturbances are commonly reported in patients with treatment‐resistant depression (TRD). Available data have shown that intravenous (IV) ketamine is an effective treatment for patients with TRD and growing data suggest ketamine may improve overall sleep architecture. In the present study, we evaluated whether changes in sleep symptoms mediated the anti‐depressive and/or anti‐suicidal effects of IV ketamine and whether improvement in sleep correlated with a higher likelihood of achieving response or remission. Adults with TRD received four infusions of IV ketamine at a community‐based clinic. Total depressive symptom severity was measured with the Quick Inventory Depressive Symptoms Self‐Report 16‐Item (QIDS‐SR16) at baseline and was repeated across four infusions. Suicidal ideation (SI) and four sleep symptoms were measured using the SI item and the five sleep items on the QIDS‐SR16. A total of 323 patients with TRD received IV ketamine. Self‐reported improvements in insomnia, night‐time restlessness, hypersomnia, early morning waking, and total sleep were significant partial mediators to the improvements observed in depression severity. Similarly, insomnia, night‐time restlessness, early morning waking and total sleep improvements mediated the reduction of IV ketamine on SI. All sleep items, except for hypersomnia, were associated with an increased likelihood of achieving response or remission. Notably, each point improvement in total sleep score was significantly associated with achieving responder/remitter status (odds ratio 3.29, 95% confidence interval 2.00–5.41). Insomnia, sleep restlessness, early morning waking and total sleep improvements were significant mediators of antidepressant and anti‐suicidal improvements in patients with TRD receiving IV ketamine. [ABSTRACT FROM AUTHOR]

The ability of plants to sense and orient their root growth towards gravity is studied in many laboratories. It is known that manual analysis of image data is subjected to human bias. Several semi-automated tools are available for analysing images from flatbed scanners, but there is no solution to automatically measure root bending angle over time for vertical-stage microscopy images. To address these problems, we developed ACORBA, which is an automated software that can measure root bending angle over time from vertical-stage microscope and flatbed scanner images. ACORBA also has a semi-automated mode for camera or stereomicroscope images. It represents a flexible approach based on both traditional image processing and deep machine learning segmentation to measure root angle progression over time. As the software is automated, it limits human interactions and is reproducible. ACORBA will support the plant biologist community by reducing labour and increasing reproducibility of image analysis of root gravitropism. [ABSTRACT FROM AUTHOR]

Ketamine is a dissociative anesthetic used worldwide for anesthesia, pain management, treatment resistant depression (TRD) and suicidality. Predictors of antidepressant response and adverse effects to ketamine remain poorly understood due to contradictory results. The objective of the systematic review herein is to identify and evaluate the extant literature assessing pharmacogenomic predictors of ketamine clinical benefits and adverse effects. Electronic databases were searched from inception to July 2021 to identify relevant articles. Twelve articles involving 1,219 participants with TRD, 75 who underwent elective surgeries and received ketamine as an anesthetic, 49 with pain, and 68 healthy participants met the inclusion criteria and enrolled to this review. While identified articles reported mixed results, three predictors emerged: 1) Val66Met (rs6265) brain derived neurotrophic factor (BDNF; Met allele) was associated with reduced antidepressant and anti-suicidal effects, 2) CYP2B6*6 (e.g., CYB2B6 metabolizer) was associated with more severe dissociative effects and 3) NET allelic (rs28386840) variant were associated with greater cardiovascular complications (e.g., moderate to severe treatment emergent hypertension). Several important limitations were identified, most notably the small sample sizes and heterogeneity of study design and results. Taken together, preliminary evidence suggests the potential for pharmacogenomic testing to inform clinical practices; however, further research is needed to better determine genetic variants of greatest importance and the clinical validity of pharmacogenomics to help guide ketamine treatment planning. [ABSTRACT FROM AUTHOR]

Bone mineral density (BMD) changes during the life span, increasing rapidly during adolescence, plateauing in the third decade of life, and subsequently entering a phase of age-related decline. In women, menopause leads to accelerated bone loss and an increase in fracture risk. Between peak bone mass attainment and menopause, BMD is generally stable and the risk of fracture is typically low. This time period is marked by life events such as pregnancy and lactation, which transiently decrease BMD, yet their long-term effects on fracture risk are less certain. BMD may also be altered by exposure to medications that affect bone metabolism (e.g., contraceptives, glucocorticoids, antidiabetic medications, antiepileptic drugs). Although oral contraceptives are often believed to be neutral with regard to bone health, depot medroxyprogesterone acetate (DMPA) and gonadotropin-releasing hormone (GnRH) agonists have been associated with decreases in BMD. Development of newer medical therapies, principally GnRH antagonists (e.g., ASP1707, elagolix, linzagolix, relugolix), for treatment of endometriosis-associated pelvic pain and heavy menstrual bleeding due to uterine fibroids has renewed interest in the short- and long-term impacts of changes in BMD experienced by premenopausal women. It is important to understand how these drugs influence BMD and put the findings into context with regard to measurement variability and naturally occurring factors that influence bone health. This review summarizes what is known about the effects on bone health pregnancy, lactation, and use of DMPA, GnRH agonists, and GnRH antagonists in premenopausal women and potential consequences later in life. ClinicalTrials.gov identifier: NCT03213457. [ABSTRACT FROM AUTHOR]

Palliative radiation is used to relieve pain and bleeding in patients with locally advanced head and neck cancers. Lower doses are utilized to meet normal tissue tolerances, limiting the duration of palliation. Lattice therapy can achieve intratumoral dose escalation while sparing surrounding tissues, but a standard approach does not exist. In this study, we explore the impact of variation in the values and distributions of peak and valley doses in palliative lattice treatment plans. Five-fraction volumetric-arc based (VMAT) lattice plans were generated using a customized Python v3.6 script. For each combination of peak/valley doses and sphere size and spacing, a bounding box was generated around the gross tumor volume (GTV) and divided into equal segments in the x, y, and z planes. Individual spheres were constructed for a given parameter set and those fully encompassed within the target contracted by 2 cm were used to create peak dose targets with values of 30, 40, and 50 Gy. A valley dose of 20 Gy was chosen to match standard dosing for 5-fraction palliative plans and the associated target volumes were generated by subtracting an 8 mm expansion of the peak dose spheres from the overall target volume. Multi-criteria optimization (MCO) was used to generate a final plan. The planning target volume (PTV) was a uniform 3-mm expansion from the GTV. Target volume and OAR dosimetric parameters were analyzed using Mann-Whitney U and Kruskal-Wallis testing. A total of 72 unique plans were evaluated for 4 patients with large GTV sizes ranging from 159 to 413 cm3. The median time to generate an individual plan using the automated script was 20 minutes (IQR, 18 - 23). Median values of mean GTV and PTV doses were 27.9 Gy (IQR, 24.7 - 30.3) and 26.7 Gy (IQR, 23.9 - 29.1), respectively. Further analysis was then limited to plans containing ablative 50 Gy dose spheres. For these 24 plans, mean GTV and PTV doses increased to a median of 31.7 Gy (IQR, 29.6 - 33.3) and 29.6 Gy (IQR, 27.8 - 31.0), respectively. Mean doses to 1, 2, and 4 cm expansions around the GTV for this cohort had median values of 19.5 Gy, 15.1 Gy, and 9.7 Gy, respectively. Median doses to 0.03 cc of mandible, spinal cord, and esophagus were 28.2 Gy (range, 7.0 - 35.7), 14.7 Gy (range, 9.8 - 18.8), and 8.7 Gy (range, 0.8 - 16.2), respectively. Mean GTV dose was dependent on sphere spacing (median 29.9 Gy for 4 cm spacing vs. 33.5 Gy for 3 cm, p<0.001), but not on sphere size (median 31.3 Gy for 2 cm vs. 31.8 Gy for 1.5 cm vs. 31.5 Gy for 1 cm, p = 0.968). VMAT-based lattice planning allows dose escalation to bulky head and neck tumors, including significant coverage with ablative doses while meeting normal tissue constraints. Thus, lattice plans could enhance palliation while reducing toxicity. Mean target coverage is dependent on sphere spacing. Use of automated plan generation could also facilitate clinical application. [ABSTRACT FROM AUTHOR]

Background: Depression severity and efficacy measurement scales employed for rapid-acting treatments (e.g., ketamine) were initially validated in adults receiving conventional monoamine-based antidepressants. The emergence of rapid-acting antidepressants in psychiatry provides the impetus for outcome measures that have been validated as sensitive to change with rapid-acting treatments. Herein, we provide results validating the McIntyre and Rosenblat Rapid Response Scale (MARRRS).Methods: Adults with treatment-resistant depression (TRD) receiving intravenous (IV) ketamine had depressive symptoms measured with the 16-Item Quick Inventory Depressive Symptoms Self-Report (QIDS-SR-16) and MARRRS at baseline and as a repeated measure across an acute course of four infusions. The MARRRS is a self-report measure assessing depressive symptoms during the past 72 hours.Results: Sixty-four patients (Mage = 45.4 ± 13.5) were included. The MARRRS had a high internal consistency across acute infusions as determined by Cronbach's alpha (0.84 to 0.94). There was significant convergent validity between the QIDS-SR-16 and MARRRS total scores across infusions (rs(292) = .87, p < .001); the MARRRS was also sensitive to change (rs(49) = .70, p < .001). Exploratory factor analysis revealed that MARRRS items loaded onto two factors (i.e., dysphoria and psychic anxiety) accounting for 63.4% of the total variance.Limitations: Heterogenous sample of adults with TRD receiving open-label treatment without placebo comparison.Conclusion: The MARRRS is a brief validated self-report metric of depression symptom severity that is sensitive to change with the rapid-acting antidepressant ketamine. Measuring outcomes with the MARRRS informs treatment progress and facilitates treatment decisions in persons receiving the rapid-acting antidepressant ketamine. Studies of other rapid-acting antidepressants should incorporate outcome measures that are validated as sensitive to change with rapid-acting antidepressants. [ABSTRACT FROM AUTHOR]

More effective treatments for people with psychotic disorders are urgently required. Here, we make three suggestions for progress: 1. Targeting the disorders' core phenomenological features ('phenomenological phenotype'), 2. Addressing social disconnection, isolation and loneliness, and 3. Leveraging 'hot' cognitions and using symptom capture approaches that combine psychotherapy with advances in technology and neuroscience. [ABSTRACT FROM AUTHOR]

Background: Dissociation is a treatment-emergent adverse event commonly associated with IV ketamine, often measured using the 23-item Clinician-Administered Dissociative States Scale (CADSS). The objective of this study was to develop a short form version of the CADSS for easier clinical use.Methods: Retrospective data of 260 patients with treatment-resistant depression (TRD) receiving IV ketamine were randomly divided into two datasets. The first dataset (n = 130) was leveraged to develop a brief 6-item version of the CADSS (CADSS-6) based on items most sensitive to ketamine-induced dissociation. The CADSS-6 questions were then applied to the second dataset (n = 130) and the Spearman's correlation between the full-length CADSS and the CADSS-6 were assessed.Results: The CADSS-6 was developed from questions 1, 2, 6, 7, 15, and 22 from the full length CADSS. There was a strong significant correlation between the CADSS-6 total score and the CADSS total score at infusions 1 (rs(106) = 0.92, p < 0.001), 2 (rs(100) = 0.91, p < 0.001), 3(rs(99) = 0.95, p < 0.001) and 4 (rs(102) = 0.94, p < 0.001).Limitations: The CADSS-6 was developed using a retrospective data; therefore, the scale remains unvalidated in this population.Conclusions: The CADSS-6 presented herein was sensitive to dissociation experienced by patients receiving IV ketamine. Overall, the CADSS-6 was strongly correlated at each infusion with the full-length CADSS. While future studies should look to validate the CADSS-6 in a TRD sample, this scale offers clinicians a brief assessment that can be used to characterize symptoms of dissociation. [ABSTRACT FROM AUTHOR]

Background: Individuals meeting criteria for treatment-resistant depression (TRD) are differentially affected by high levels of anxiety symptoms. Aims: There is a need to identify the efficacy of novel rapid-onset treatments in adults with mood disorders and comorbid anxious-distress. Methods: This study included patients with treatment-resistant major depressive disorder (MDD) or bipolar disorder (BD) who were receiving intravenous (IV) ketamine treatment at a community-based clinic.Anxious-distress was proxied using items from the Quick Inventory of Depressive Symptomatology–Self Report 16-item (QIDS-SR16) and Generalized Anxiety Disorder 7-item (GAD7) scales. The difference in QIDS-SR16 total score, QIDS-SR16 suicidal ideation (SI) item and GAD7 score were analyzed between groups. Results: A total of 209 adults with MDD (n = 177) and BD (n = 26) were included in this analysis. From this sample, 94 patients (mean = 45 ± 13.9 years) met the criteria for anxious-distress. Individuals meeting the criteria for anxious-distress exhibited a significantly greater reduction in QIDS-SR16 total score following four infusions (p = 0.02) when compared with patients not meeting the anxious-distress criteria. Both anxious-distressed and low-anxiety patients exhibited a significant reduction in SI (p < 0.0001) following four infusions.Finally, there was a significantly greater reduction in anxiety symptoms in the anxious-distress group compared with the non–anxious distress group following three (p = 0.02) and four infusions (p < 0.001). Conclusion: Patients with TRD and prominent anxiety receiving IV ketamine exhibited a significant reduction in depressive, SI and anxiety symptoms. [ABSTRACT FROM AUTHOR]

Background: Anhedonia is a trans-diagnostic, multidimensional phenotype that mediates patient outcomes and suicidality. Convergent evidence suggests that ketamine may be effective in targeting measures of anhedonia in adults with treatment resistant depression (TRD).Methods: This retrospective, post-hoc analysis included 203 (x̄ = 45 ± 14.6 years of age) patients receiving four infusions of intravenous (IV) ketamine at a community-based clinic. The primary outcome measure was change in anhedonia severity, as measured by the Snaith-Hamilton Pleasure Scale (SHAPS). Secondary measures sought to determine if improvement on the SHAPS mediated the effect of repeated IV ketamine infusions on symptoms of depression and suicidal ideations, as measured by the Quick Inventory for Depression Symptomatology-Self Report 16-Item (QIDS-SR16) and anxiety, as measured using the Generalized Anxiety Disorder-7 (GAD-7).Results: After adjusting for age, sex, primary diagnosis, concomitant medication, body mass index, and baseline depression severity, there was a statistically significant reduction in symptoms of anhedonia with IV ketamine treatment (F (2, 235.6) = 31.6, p < 0.001). Improvements in depressive symptoms, suicidal ideation, and anxiety symptoms with repeated-dose IV ketamine were significantly partially mediated by reduction in anhedonic severity. Moreover, the combination of number of infusions received and change in anhedonic severity accounted for 26% of the variance in depressive score improvements.Limitations: This is a post-hoc analysis of retrospective data and lacks a control group.Conclusion: Ketamine was effective in improving measures of anhedonia in this large, well-characterized community-based sample of adults with TRD. Improvements in anhedonia also partially mediated the significant improvement in depressive symptoms, suicidality, and anxiety. [ABSTRACT FROM AUTHOR]

Background: The effectiveness, tolerability, and safety of intravenous (IV) ketamine in adults with treatment resistant depression (TRD) receiving care in real-word settings is insufficiently characterized. Herein, results from a naturalistic, retrospective study are presented from a Canadian outpatient IV ketamine clinic.Methods: Adults (N = 213; Mage = 45) with Major Depressive Disorder or Bipolar Disorder, with a minimum of Stage 2 antidepressant resistance, received IV ketamine at a community-based multi-disciplinary clinic. The primary outcome measure was change from baseline to post-infusion 4 on the Quick Inventory for Depression Symptomatology-Self Report-16 (QIDS-SR16; n = 190). Secondary measures included QIDS-SR16-measured response and remission rates, changes from baseline to endpoint in Generalized Anxiety Disorder-7 Scale (GAD-7; n = 188) and the Sheehan Disability Scale (SDS; n = 168).Results: Significant improvement in total depressive symptoms severity (p < 0.0001) was observed after four infusions of IV ketamine 0.5-0.75 mg/kg. Moreover, the response rate (QIDS-SR16 total score change ≥ 50%) was 27% and remission (QIDS-SR16 total score ≤5) rate was 13%. Patients receiving IV ketamine exhibited anxiolytic effects (p < 0.0001,), improved overall psychosocial function (p < 0.0001), and reduced suicidal ideation (p < 0.0001). Compared to the baseline infusion, dissociation severity significantly reduced in subsequent infusions.Limitations: This was a naturalistic, retrospective study, without a control group.Conclusions: IV ketamine was safe, well-tolerated, and effective at improving depressive, anxiety, and functional impairment symptoms in a well-characterized cohort of adults with TRD. [ABSTRACT FROM AUTHOR]

Introduction: Cardiac adaptation to sustained exercise in the athletes is established. However, exercise‐associated effect on the cardiac function of the elderly has to be elucidated. The aim of this study was to analyse left (LV) and right ventricular (RV) characteristics at different levels of chronic exercise in the senior heart. Materials and methods: We studied 178 participants in the World Senior Games (mean age 68 ± 8 years, 86 were men; 48%). Three groups were defined based on the type and intensity of sports: low‐, moderate‐ and high‐intensity level. Exclusion criteria were coronary artery disease, atrial fibrillation, valvular heart disease or uncontrolled hypertension. LV and RV size and function were evaluated with an echocardiogram. Results: LV trans‐mitral inflow deceleration time decreased in parallel to the intensity of chronic exercise: 242 ± 54 ms in low‐, 221 ± 52 ms in moderate‐ and 215 ± 58 ms in high‐intensity level, p =.03. Left atrial volume index (LAVI) was larger in high‐intensity group, p =.001. The LAVI remained significantly larger when adjusting for age, gender, heart rate, hypertension and diabetes (p =.002). LV and RV sizes were larger in the high‐intensity group. LV ejection fraction and RV systolic function evaluated by tissue Doppler velocity, atrioventricular plane displacement and strain did not differ between groups. Conclusion: Left ventricular diastolic filling is not only preserved, but may also be enhanced in long‐term, top‐level senior athletes. Moreover, LV and RV systolic function remain unchanged at different levels of exercise. This supports the beneficial effects of endurance exercise participation in senior hearts. [ABSTRACT FROM AUTHOR]

Orchid pollinia have the potential to make a valuable contribution to current techniques of germplasm storage and assisted reproduction, yet information regarding their preservation and their ability to remain viable over time is currently limited. Dactylorhiza fuchsii and Disa uniflora were used as models for investigating potential techniques for storing orchid pollinia. Initially, freshly harvested pollinia of Dact. fuchsii were incubated at 25 °C and 100% RH (relative humidity) for up to 7 days and germinated in vitro. For pollinia from both species, moisture sorption isotherms were constructed and thermal fingerprints generated using differential scanning calorimetry (DSC). Pollinia were stored at three temperatures (5, − 18 and − 196 °C) after equilibration at four different RHs (5, 33, 50 and 75%) and germinated. The isotherms and DSC results varied between species. Compared with D. uniflora, pollinia of Dact. fuchsii consistently equilibrated at higher moisture content (MC) for each RH, had less detectable lipids by DSC and had shorter lifespans, remaining viable after 3–4 months only at − 20 and − 196 °C and at low RH (5 and 33%). Both species' pollinia stored well at − 20 °C and − 196 °C, although there was some evidence of a small loss of viability under cryopreservation. In conclusion, pollen of these two species can be stored successfully for at least 3–4 months, and to maximize the pre-storage quality, it is recommended that fresh pollen is collected from flowers just prior to anthesis. [ABSTRACT FROM AUTHOR]

Binary regression models for spatial data are commonly used in disciplines such as epidemiology and ecology. Many spatially referenced binary data sets suffer from location error, which occurs when the recorded location of an observation differs from its true location. When location error occurs, values of the covariates associated with the true spatial locations of the observations cannot be obtained. We show how a change of support (COS) can be applied to regression models for binary data to provide coefficient estimates when the true values of the covariates are unavailable, but the unknown location of the observations are contained within nonoverlapping arbitrarily shaped polygons. The COS accommodates spatial and nonspatial covariates and preserves the convenient interpretation of methods such as logistic and probit regression. Using a simulation experiment, we compare binary regression models with a COS to naive approaches that ignore location error. We illustrate the flexibility of the COS by modeling individual‐level disease risk in a population using a binary data set where the locations of the observations are unknown but contained within administrative units. Our simulation experiment and data illustration corroborate that conventional regression models for binary data that ignore location error are unreliable, but that the COS can be used to eliminate bias while preserving model choice. [ABSTRACT FROM AUTHOR]

The mechanisms underlying the response and adaptation of plants to excess of trace elements are not fully described. Here, we analysed the importance of protein lysine methylation for plants to cope with cadmium. We analysed the effect of cadmium on lysine‐methylated proteins and protein lysine methyltransferases (KMTs) in two cadmium‐sensitive species, Arabidopsis thaliana and A. lyrata, and in three populations of A. halleri with contrasting cadmium accumulation and tolerance traits. We showed that some proteins are differentially methylated at lysine residues in response to Cd and that a few genes coding KMTs are regulated by cadmium. Also, we showed that 9 out of 23 A. thaliana mutants disrupted in KMT genes have a tolerance to cadmium that is significantly different from that of wild‐type seedlings. We further characterized two of these mutants, one was knocked out in the calmodulin lysine methyltransferase gene and displayed increased tolerance to cadmium, and the other was interrupted in a KMT gene of unknown function and showed a decreased capacity to cope with cadmium. Together, our results showed that lysine methylation of non‐histone proteins is impacted by cadmium and that several methylation events are important for modulating the response of Arabidopsis plants to cadmium stress. The mechanisms underlying the response and adaptation of plants to excess of trace elements are not fully described. Here, we showed that lysine methylation of non‐histone proteins is part of the regulatory mechanisms helping plants to cope with the toxic metal cadmium. [ABSTRACT FROM AUTHOR]

Methylation patterns established and maintained at CpG sites may be altered by single nucleotide polymorphisms (SNPs) within these sites and may affect the regulation of nearby genes. Our aims were to: 1) identify and generate a database of SNPs potentially subject to epigenetic control by DNA methylation via their involvement in creating, removing or displacing CpG sites (meSNPs), and; 2) investigate the association of these meSNPs with CpG islands (CGIs), and with methylation profiles of DNA extracted from tissues from cattle with divergent feed efficiencies detected using MIRA-Seq. Using the variant annotation for 56,969,697 SNPs identified in Run5 of the 1000 Bull Genomes Project and the UMD3.1.1 bovine reference genome sequence assembly, we identified and classified 12,836,763 meSNPs according to the nature of variation created at CpGs. The majority of the meSNPs were located in intergenic regions (68%) or introns (26.3%). We found an enrichment (p<0.01) of meSNPs located in CGIs relative to the genome as a whole, and also in differentially methylated sequences in tissues from animals divergent for feed efficiency. Seven meSNPs, located in differentially methylated regions, were fixed for methylation site creating (MSC) or destroying (MSD) alleles in the differentially methylated genomic sequences of animals differing in feed efficiency. These meSNPs may be mechanistically responsible for creating or deleting methylation targets responsible for the differential expression of genes underlying differences in feed efficiency. Our methyl SNP database (dbmeSNP) is useful for identifying potentially functional "epigenetic polymorphisms" underlying variation in bovine phenotypes. [ABSTRACT FROM AUTHOR]

The breadth and depth of literature examining ethics is considerable, and spans numerous disciplines. As a result, a multidisciplinary review would be helpful, particularly from related fields such as developmental psychology, social psychology, and marketing. The present review begins to fill this need by providing a summary of important philosophical positions, theories, and models on ethical decision-making. The review also highlights some of the more important organizational and cultural factors as well as empirically tested individual difference variables that impact ethical judgments and behaviors. By providing a summary that spans across multiple disciplines, the present review can serve as an important resource to researchers and decisionmakers who are interested in a broad understanding of both the historical, and more recent important findings on unethical behavior and decision-making. [ABSTRACT FROM AUTHOR]

The purpose of this prospective trial was to assess patient and physician reported toxicity in anal cancer patients undergoing definitive chemoradiation with intensity modulated proton therapy (IMPT). Patients with AJCC v8 Stage II-III disease were treated with IMPT using a multi-field, split-target technique using robust optimization with dose prescribed as per RTOG 0529 (50.4-54 Gy). All patients received two cycles of 5-fluorouracil and Mitomycin concurrently with radiation. Toxicity was assessed at baseline, weekly during chemoradiation and in follow-up using physician graded CTCAE v 4.0 and PRO-CTCAE for relevant domains (17 items). The primary endpoint was to define point estimates and 95% CI for ≥ grade 2/3 GI, GU, Dermatologic, and Hematologic toxicity within 90 days from treatment. The proportion of PRO-CTCAE questions scored ≥ 3 for each domain was compared to baseline. Survival outcomes were assessed using the Kaplan-Meier method. The proportion of ≥ grade 2 and ≥ grade 3 toxicities were compared to historic IMRT patients treated on RTOG 0529 using Fisher's exact test. Fourteen patients were enrolled from 2017-2020. The median age was 56 (range 31-85) with 50% female participants. Eleven patients (79%) had Stage III disease. The respective T/N stages are T2 (n=5, 36%), T3 (n=7, 50%), T4 (n=1,7%), N0 (n=2,14%), N1 (n=9,64%), and N2 (n=3,21%). All patients completed prescribed treatment with 1 patient requiring a treatment break. Table 1 shows rates of ≥ grade 2/3 CTCAE events for IMPT. Rates of patient reported Derm and GU toxicity were low at baseline with a peak at week 6 (91% and 58% PRO-CTCAE items ≥grade 3, respectively) and normalization to baseline 3 months after IMPT. In contrast, the proportion of high grade PRO-CTCAE GI scores was 40% at baseline which persisted through 1 year post treatment. A complete clinical response at 6 months was observed in 11 patients (79%). The median overall survival was not reached with a median follow-up is 32.5 months. The 2 years overall, progression-free, and colostomy free survival was 92%, 64%, and 85%, respectively. Median time to progression was 9 months with local only (n=2,14%), local and distant (n=2,14%) and distant (n=1,7%) recurrence patterns. In this single arm trial, rates of clinician reported toxicity with IMPT were similar to IMRT. High grade PRO-CTCAE events were common during IMPT. GU and Derm events normalized at 3 months from treatment but high-grade GI symptoms persisted to12 months and were similar to baseline. Additional measures are needed to minimize acute and chronic toxicity related chemoradiation. [ABSTRACT FROM AUTHOR]

In postmenopausal women, osteoporotic fractures are more common than stroke, myocardial infarction, and breast cancer combined, and fractures can be costly and result in disability or death. Because there are no signs or symptoms of osteoporosis other than fracture, risk assessment is necessary to identify those at higher risk for clinical events. For women, a clinical fracture risk assessment (FRAX) is appropriate at menopause. Bone mineral density (BMD) measurement is recommended for women at age 65, and earlier for those who have risk factors. Adequate calcium, vitamin D, and weight-bearing exercise are important for bone health at all ages, and those at high risk for fracture based on BMD or FRAX should be offered medical therapy to reduce fracture risk after an appropriate medical evaluation. Bisphosphonates can accumulate in bone, so after a period of treatment, lower risk patients may be offered a period off drug therapy. However, the effects of denosumab are not sustained when treatment is discontinued, so there is no “drug holiday” with denosumab. Anabolic therapy can be offered to those with higher risk for fracture. Although rare safety concerns regarding atypical femoral fracture and osteonecrosis of the jaw have received prominent attention, for patients who are appropriately treated according to National Osteoporosis Foundation guidelines, the benefit of hip fracture risk reduction far outweighs the risk of these uncommon side effects. Accurate information for patients and shared decision-making are important for acceptance and persistent with appropriate treatment. [ABSTRACT FROM AUTHOR]

Protein methylation is a very diverse, widespread, and important post-translational modification affecting all aspects of cellular biology in eukaryotes. Methylation on the side-chain of lysine residues in histones has received considerable attention due to its major role in determining chromatin structure and the epigenetic regulation of gene expression. Over the last 20 years, lysine methylation of non-histone proteins has been recognized as a very common modification that contributes to the fine-tuned regulation of protein function. In plants, our knowledge in this field is much more fragmentary than in yeast and animal cells. In this review, we describe the plant enzymes involved in the methylation of non-histone substrates, and we consider historical and recent advances in the identification of non-histone lysine-methylated proteins in photosynthetic organisms. Finally, we discuss our current knowledge about the role of protein lysine methylation in regulating molecular and cellular functions in plants, and consider challenges for future research. [ABSTRACT FROM AUTHOR]

Diffusion tensor imaging (DTI) is an MRI-based technique that delineates white matter tracts in the brain by tracking the diffusion of water in neural tissue. This methodology, known as "tractography", has been extensively applied in clinical neuroscience to explore nervous system architecture and diseases. More recently, tractography has been used to assist with neurosurgical targeting in functional neurosurgery. This review provides an overview of DTI principles, and discusses current applications of tractography for improving and helping develop novel deep brain stimulation (DBS) targets. [ABSTRACT FROM AUTHOR]

The northern elephant seal, Mirounga angustirostris, was heavily hunted and declared extinct in the 19th century. However, a colony remained on remote Guadalupe Island, Mexico and the species has since repopulated most of its historical distribution. Here, we present a comprehensive evaluation of genetic variation in the species. First, we assess the effect of the demographic bottleneck on microsatellite variability and compare it with that found in other pinnipeds, demonstrating levels of variation similar to that in species that continue to be threatened with extinction. Next, we use sequence data from these markers to demonstrate that some of the limited polymorphism predates the bottleneck. However, most contemporary variation appears to have arisen recently and persisted due to exponential growth. We also describe how we use the range in allele size of microsatellites to estimate ancestral effective population size before the bottleneck, demonstrating a large reduction in effective size. We then employ a classical method for bacteria to estimate the microsatellite mutation rate in the species, deriving an estimate that is extremely similar to that estimated for a similar set of loci in humans, indicating consistency of microsatellite mutation rates in mammals. Finally, we find slight significant structure between some geographically separated colonies, although its biological significance is unclear. This work demonstrates that genetic analysis can be useful for evaluating the population biology of the northern elephant seal, in spite of the bottleneck that removed most genetic variation from the species. [ABSTRACT FROM AUTHOR]

This study aimed to evaluate the effect of various zirconia surface pretreatments on the adhesion between full contour 3Y-TZP zirconia and glaze, and the shear bond strength (SBS) between glazed/3Y-TZP and resin cement. Specimens were allocated into groups: GL-glaze; AL+GL-sandblasting with Al 2 O 3 +GL; CJ+GL-tribochemical silica coating (Cojet ® /CJ)+GL; PS+GL-piranha solution+GL; and CJ. Adhesion between 3Y-TZP and GL was evaluated using the scratch test. Surface topography and glaze thickness were evaluated by using a scanning electron microscope (SEM). For SBS, glazed/3Y-TZP surface was etched with hydrofluoric acid and a silane was applied. For CJ only the silane was applied. Samples were tested after 24 h (24 h wet) or after 15,000 thermal cycles and 90 days storage (thermocycled). After SBS, the type of failure was classified as: adhesive, mixed or cohesive. The data were analyzed using two-way ANOVA and Tukey's test. SEM analysis after scratch test revealed circular cracks in the GL group and conformal cracks in the others groups. SEM micrographs suggested that zirconia specimens submitted to airborne-particle abrasion presents rougher and porous surface when compared to surfaces treated with GL and PS. The glaze layer was approximately 1.86 µm thick in all groups. After 24 h, SBS test showed highest values for AL+GL and CJ+GL and were significantly higher when compared to the GL group. Differences were not significant between PS+GL and the other groups. After aging (thermocycling+storage), groups GL and CJ presented no statistically significant difference compared to 24 h and aged AL+GL, CJ+GL and PS+GL groups. The predominant type of failure was mixed. 3Y-TZP surface treatment with glaze application could be considered as an alternative treatment, since it yielded a similar resin bond strength without the need for airborne-particle abrasion. [ABSTRACT FROM AUTHOR]

Background: Ketamine is an emerging treatment for treatment-resistant depression (TRD) associated with rapid and robust improvements in depressive symptoms and suicidality. However, the efficacy and safety of ketamine in transitional age youth (TAY; age 18–25) populations remains understudied. Methods: In this retrospective analysis, TAY patients (n = 52) receiving ketamine for TRD were matched for sex, primary diagnosis, baseline depression severity, and treatment resistance with a general adult (GA) sample (age 30–60). Patients received four ketamine infusions over 2 weeks (0.5–0.75 mg/kg over 40 min). The primary outcome was the change in Quick Inventory of Depressive Symptomatology Self-Report 16-item (QIDS-SR16) over time. Secondary outcomes were changes in QIDS-SR16 suicidal ideation (SI) item, anxiety (Generalized Anxiety Disorder 7-item (GAD-7)), and adverse effects (ClinicalTrials.gov: NCT04209296). Results: A significant main effect of infusions on reduction of total QIDS-SR16 (p < 0.001), QIDS-SR16 SI (p < 0.001), and GAD-7 (p < 0.001) scores was observed in the TAY group with moderate effect sizes, indicative of clinically significant improvements in depression, anxiety, and suicidality. There were no significant differences between TAY and GA groups on these measures over time, suggesting comparable improvements in both groups. Safety and tolerability outcomes were comparable between groups with only mild, transient adverse effects observed. Conclusion: Ketamine was associated with comparable clinical benefits, safety, and tolerability in a TAY sample as compared to a matched GA TRD sample. [ABSTRACT FROM AUTHOR]

A novel class of upconversion luminescent nanocrystals of Yb/Tm:calcium deficient hydroxyapatite were synthesized by co-precipitation method in aqueous solution (pH adjusted to 6) and specially heat-treated with microwave radiation at different temperatures (from 900 °C to 1000 °C) and times (2–10 min) to produce small nanocrystals of Yb/Tm:β-tricalcium phosphate (β-TCP). As a result, we report for the first time, a single-phase Yb/Tm-doped β-TCP nanocrystals with a mean crystallite size of 55.3 nm. This material has an efficient visible luminescence from the 1 G 4 (blue emission) and 3 F 2 (red emission) and near infrared emission from the 3 H 4 excited states of Tm 3+ induced by the Yb 3+ →Tm 3+ energy transfer under laser excitation (Yb 3+ ) at 972 nm. This β-TCP activated by Yb 3+ and Tm 3+ ions constitutes a new nano-fluoroprobe that can be used as optical contrast agents, affording high resolution and sensitivity for visible-near infrared applications. [ABSTRACT FROM AUTHOR]

The ZaP and ZaP-HD Flow Z-pinch experiments at the University of Washington have successfully demonstrated that sheared plasma flows can be used as a stabilization mechanism over a range of parameters that has not previously been accessible to long-lived Z-pinch configurations. The stabilization is effective even when the plasma column is compressed to small radii, producing predicted increases in magnetic field and electron temperature. The flow shear value, extent, and duration are shown to be consistent with theoretical models of the plasma viscosity, which places a design constraint on the maximum axial length of a sheared flow stabilized Z-pinch. Measurements of the magnetic field topology indicate simultaneous azimuthal symmetry and axial uniformity along the entire 100 cm length of the Z-pinch plasma. Separate control of plasma acceleration and compression has increased the accessible plasma parameters and has generated stable plasmas with radii of 0.3 cm, as measured with a high resolution digital holographic interferometer. Compressing the plasma with higher pinch currents has produced high magnetic fields (8.5 T) and electron temperatures (1 keV) with an electron density of 2 x 1017 cm-3, while maintaining plasma stability for many Alfvén times (approximately 50 µs). The results suggest that sheared flow stabilization can be applied to extend Z-pinch plasma parameters to high energy densities. [ABSTRACT FROM AUTHOR]

Europium-doped hydroxyapatite (HA), beta-tricalcium phosphate (β-TCP) and biphasic phosphate nanopowders were synthesized by co-precipitation method and their crystal structures and fluorescence properties were investigated depending on the pH of the starting solution. In the range of pH 6–10, HA and β-TCP phases coexist. The β-TCP proportion increased as the pH of the solution decreased, while HA yields decreased. At pH below 6, monophasic β-TCP powder was obtained after thermal treatment. In particular, HA and β-TCP can be used as luminescent materials when activated by Eu 3+ ions in substitution of Ca 2+ ions. Herein, the Eu 3+ ions doped HA and β-TCP phase composition were analyzed in order to investigate the fluorescence emission of the HA, β-TCP and biphasic compounds. Eu-doped HA exhibited a red-orange emission at 575 nm with several minor peaks at 610–640 nm, while Eu-doped β-TCP had an unexpected strong red emission at 610–620 nm and a secondary band at 590–600 nm. In fact, the Eu:β-TCP integrated emission area is almost 20-fold higher than Eu:HA for the same europium ion concentration. These results demonstrate the potential of Eu:β-TCP as biomarker for medical applications, as drug release and targeting based on their luminescent properties. [ABSTRACT FROM AUTHOR]

The use of counterfeit versions of luxury brands is a growing phenomenon. Viewing their use by others may lead consumers to change their perceptions of the genuine brand. In several experiments, female participants viewed (or imagined) a female of varying social classes using a counterfeit or genuine product and were subsequently asked about the genuine luxury brand. While people were drawn toward the genuine brand more when in-groups than out-groups used counterfeits, asymmetries occurred. Higher classes denigrated the brand when lower (versus higher) classes used counterfeit brands, but lower classes did not denigrate when higher classes used them. A conceptual account, based on asymmetries of social hierarchies and greater uncertainty of counterfeit (than genuine) product benefits, was supported, with feelings of connection to the luxury brand as mediator. Asymmetric effects were reduced among consumers highly familiar with the genuine brand. Implications for marketing and protection from brand dilution are discussed. [ABSTRACT FROM AUTHOR]

We report 1212 radial-velocity (RV) measurements obtained in the years 2009-2013 using an iodine cell for the spectroscopic binary ν Octantis (K1 III/IV). This system (abin ~ 2.6 au, P ~ 1050 d) is conjectured to have a Jovian planet with a semimajor axis half that of the binary host. The extreme geometry only permits long-term stability if the planet is in a retrograde orbit. Whilst the reality of the planet (P ~ 415 d) remains uncertain, other scenarios (stellar variability or apsidal motion caused by a yet unobserved third star) continue to appear substantially less credible based on cross-correlation function bisectors, line-depth ratios and many other independent details. If this evidence is validated but the planet is disproved, the claims of other planets using RVs will be seriously challenged. We also describe a significant revision to the previously published RVs and the full set of 1437 RVs now encompasses nearly 13 yr. The sensitive orbital dynamics allow us to constrain the 3D architecture with a broad prior probability distribution on the mutual inclination, which with posterior samples obtained from an N-body Markov chain Monte Carlo is found to be 152:5±0.70.6. None of these samples are dynamically stable beyond 106 yr. However, a grid search around the best-fitting solution finds a region that has many models stable for 107 yr, and includes one model within 1σ that is stable for at least 108 yr. The planet's exceptional nature demands robust independent verification and makes the theoretical understanding of its formation a worthy challenge. [ABSTRACT FROM AUTHOR]

• At least one dose of a SARS-CoV-2 vaccine was associated with a protective effect against long COVID. • Long COVID trajectory following vaccination was mixed, with most patients reporting no changes. • Evidence supports SARS-CoV-2 vaccination for the prevention of long COVID. Empirical evidence addressing the association between SARS-CoV-2 vaccination and long COVID would guide public health priorities and inform personal health decisions. Herein, the co-primary objectives are to determine the differential risk of long COVID in vaccinated versus unvaccinated patients, and the trajectory of long COVID following vaccination. Of 2775 articles identified via systematic search, 17 were included, and 6 were meta-analyzed. Meta-analytic results determined that at least one vaccine dose was associated with a protective effect against long COVID (OR 0.539, 95% CI 0.295–0.987, p = 0.045, N = 257 817). Qualitative analysis revealed that trajectories of pre-existing long COVID following vaccination were mixed, with most patients reporting no changes. The evidence herein supports SARS-CoV-2 vaccination for the prevention of long COVID, and recommends long COVID patients adhere to standard SARS-CoV-2 vaccination schedules. [ABSTRACT FROM AUTHOR]

To overcome the ethical and technical limitations of in vivo human disease models, the broader scientific community frequently employs model organism-derived cell lines to investigate disease mechanisms, pathways, and therapeutic strategies. Despite the widespread use of certain in vitro models, many still lack contemporary genomic analysis supporting their use as a proxy for the affected human cells and tissues. Consequently, it is imperative to determine how accurately and effectively any proposed biological surrogate may reflect the biological processes it is assumed to model. One such cellular surrogate of human disease is the established mouse neural precursor cell line, SN4741, which has been used to elucidate mechanisms of neurotoxicity in Parkinson disease for over 25 years. Here, we are using a combination of classic and contemporary genomic techniques – karyotyping, RT-qPCR, single cell RNA-seq, bulk RNA-seq, and ATAC-seq – to characterize the transcriptional landscape, chromatin landscape, and genomic architecture of this cell line, and evaluate its suitability as a proxy for midbrain dopaminergic neurons in the study of Parkinson disease. We find that SN4741 cells possess an unstable triploidy and consistently exhibits low expression of dopaminergic neuron markers across assays, even when the cell line is shifted to the non-permissive temperature that drives differentiation. The transcriptional signatures of SN4741 cells suggest that they are maintained in an undifferentiated state at the permissive temperature and differentiate into immature neurons at the non-permissive temperature; however, they may not be dopaminergic neuron precursors, as previously suggested. Additionally, the chromatin landscapes of SN4741 cells, in both the differentiated and undifferentiated states, are not concordant with the open chromatin profiles of ex vivo, mouse E15.5 forebrain- or midbrain-derived dopaminergic neurons. Overall, our data suggest that SN4741 cells may reflect early aspects of neuronal differentiation but are likely not a suitable proxy for dopaminergic neurons as previously thought. The implications of this study extend broadly, illuminating the need for robust biological and genomic rationale underpinning the use of in vitro models of molecular processes. [ABSTRACT FROM AUTHOR]

We estimate the impact of tariffs faced by US agricultural exports on farmland rents. The localized tariff is determined by the average of tariffs across trading partners for the crops produced within the county. We utilize shift-share designs to avoid endogeneity concerns that arise because factors affecting rents could also affect trade flows and cropping patterns. Using the county-level data from 2008 to 2017, we find that a one percentage point decrease in the localized tariff increases rents by 3%–6%. The 2018 Chinese retaliatory tariffs would have decreased rents by about 3% in the absence of any government support. • We estimate the impact of tariffs faced by US agricultural exports on farmland rents. • We find that a 1% point decrease in the localized tariff increases rents by 3%–6%. • The 2018 Chinese tariff would have decreased rent by 3% in the absence of any payment. [ABSTRACT FROM AUTHOR]

Background: The rate of transition to psychotic disorder in ultra high risk (UHR) patients has declined in recent cohorts. The reasons for this are unclear, but may include a lead-time bias, earlier intervention, a change in clinical characteristics of cohorts, and treatment changes.Aims: In this paper we examined the two possibilities related to reduction in duration of symptoms prior to clinic entry, i.e., lead-time bias and earlier intervention.Method: The sample consisted of all UHR research participants seen at the PACE clinic, Melbourne between 1993 and 2006 (N=416), followed for a mean of 7.5years (the 'PACE 400' cohort). Duration of symptoms was analysed by four baseline year time periods. Analysis of transition rate by duration of symptoms was restricted to more homogenous sub-samples (pre-1998 and pre-2001) in order to minimize confounding effects of change in patient characteristics or treatments. These cohorts were divided into those with a short and long duration of symptoms using a cut-point approach.Results: Duration of symptoms prior to entry did not reduce significantly between 1993 and 2006 (p=0.10). The group with a short duration of symptoms showed lower transition rates and did not catch up in transition rate compared to the long duration of symptoms group.Discussion: These data suggest that, while earlier intervention or lead-time bias do not fully account for the declining transition rate in UHR cohorts, it appears that earlier intervention may have exerted a stronger influence on this decline than length of follow-up period (lead-time bias). [ABSTRACT FROM AUTHOR]

Crystallographic studies of insulin bound to receptor domains have defined the primary hormone-receptor interface. Weinvestigated the role of TyrB26, a conserved aromatic residue at this interface. To probe the evolutionary basis for such conservation, we constructed 18 variants at B26. Surprisingly, nonaromatic polar or charged side chains (such as Glu, Ser, or ornithine (Orn)) conferred high activity, whereas the weakestbinding analogs contained Val, Ile, and Leu substitutions. Modeling of variant complexes suggested that the B26 side chains pack within a shallow depression at the solvent-exposed periphery of the interface. This interface would disfavor large aliphatic side chains. The analogs with highest activity exhibited reduced thermodynamic stability and heightened susceptibility to fibrillation. Perturbed self-assembly was also demonstrated in studies of the charged variants (Orn and Glu); indeed, the GluB26 analog exhibited aberrant aggregation in either the presence or absence of zinc ions. Thus, although TyrB26 is part of insulin's receptor-binding surface, our results suggest that its conservation has been enjoined by the aromatic ring's contributions to native stabilityand self-assembly. We envisage that such classical structural relationships reflect the implicit threat of toxic misfolding (rather than hormonal function at the receptor level) as a general evolutionary determinant of extant protein sequences. [ABSTRACT FROM AUTHOR]

We discuss an on-line tool that facilitates access to the large collection of climate impacts on crop yields produced by the Agricultural Model Intercomparison and Improvement Project. This collection comprises the output of seven crop models which were run on a global grid using climate data from five different general circulation models under the current set of representative pathways. The output of this modeling endeavor consists of more than 36,000 publicly available global grids at a spatial resolution of one half degree. We offer flexible ways to aggregate these data while reducing the technical barriers implied by learning new download platforms and specialized formats. The tool is accessed trough any standard web browser without any special bandwidth requirement. [ABSTRACT FROM AUTHOR]

The effect of administration of nanoliposome encapsulated malunggay (Moringa oleifera) phenolic extract in dogs given cholesterol on body fat and hepatic and renal ultrasonograms was investigated in this study. Six adult male dogs were given cholesterol without (T1) or with non-encapsulated (T2) and nanoliposome encapsulated (T3) malunggay (M. oleifera) phenolic extract. Data on the back fat thickness, body condition score and hepatic and renal ultrasonograms were collected at weeks 0, 1 and 5. Dogs in T3 showed inconsistent changes in the back fat thickness and body condition score. Moreover, T3 dogs exhibited decrease in both hepatic and renal echo mean values. The initial findings suggest that monitoring of the liver and kidney in cases of dyslipidemia or hyperlipidemia should be considered since ultrasonogram results indicate probable development of liver and kidney problems. Further studies are recommended to verify these results. [ABSTRACT FROM AUTHOR]

A 3-week-old miniature donkey was evaluated for tenesmus and constipation resulting from atresia ani. The foal was also diagnosed with hypospadias extending from its perineum to the glans penis and caudoventral penile deviation. A common opening on the perineum allowed faeces and urine to be excreted together, preventing complete intestinal obstruction. Surgical correction of the atresia ani was performed, along with resection of the incomplete urethra, nonfunctional penis and testes. The anal and perineal reconstruction procedures resolved the miniature donkey's difficulty in defaecation. The anourethral portion of the repair healed, but the anoperineal portion dehisced and healed by second intention. The client was satisfied with the outcome. [ABSTRACT FROM AUTHOR]

In this work, we present the synthesis, characterization and the luminescence properties of Ca 10 (PO 4 ) 6 (OH) 2 (hydroxyapatite/HAp) nanocrystals doped with europium trivalent ions. The most important processes that lead to europium emissions in the visible region were identified. Eu:HAp nanopowder excited at 394 nm (or 460 nm) exhibits several emissions: (i) weak emissions at 579 nm, 592 nm and 616 nm due to the 5 D 0 → 7 F 0 , 5 D 0 → 7 F 1 and 5 D 0 → 7 F 2 transitions, respectively, with europium ion occupying site I in hydroxyapatite structure and (ii) strong emissions due to the 5 D 0 → 7 F 0 (574 nm), 5 D 0 → 7 F 1 (602 nm) and 5 D 0 → 7 F 2 (610–630 nm) transitions, when Eu 3+ is occupying site II. The emission spectrum and the time-resolved luminescence analysis showed that the HAp nanocrystals (nanopowder) thermally treated at temperature (T) between 500 and 800 °C have a change in the initial Eu 3+ site distribution of 100 % of Eu 3+ at site I to a more stable one where the majority of europium ions are at site II: 30% remains at site I and 70% migrates to site II. In addition, an enhancement of the Eu 3+ emission intensity is observed due to the increasing crystallite size. A time-resolved luminescence investigation using a short pulse laser excitation at 460 nm was employed to measure the luminescence decays and to determine the most important mechanisms involved in the deexcitation process of 5 D 0 excited state of Eu 3+ , where it is seen a fast (2.9 μs) energy transfer from Eu 3+ - site I (donor) to Eu 3+ - site II (acceptor) in the thermally treated nanopowders with T > 500 °C. The initial presence of 100% of Eu 3+ at site I in the synthesized nanocrystals is gradually modified by the thermal treatments with temperatures above 500 °C by thermal activation of Ca 2+ vacancy (the charge compensator) diffusion through the HAp lattice, which propitiates the Ca 2+ - vacancies and Eu 3+ ions to exchange positions in the lattice. By this thermal activated mechanism, Eu 3+ ion migrates through the lattice until get the final distribution of 30% at site I and 70% at site II. As a result, the complete description of the Eu 3+ ( 5 D 0 ) decay and the energy transfer process from Eu 3+ (site I) → Eu 3+ (site II) were proposed. [ABSTRACT FROM AUTHOR]

BackgroundThe late positive potential (LPP) is an event-related potential component that is sensitive to the motivational salience of stimuli. Children with a parental history of depression, an indicator of risk, have been found to exhibit an attenuated LPP to emotional stimuli. Research on depressive and anxiety disorders has organized these conditions into two empirical classes: distress and fear disorders. The present study examined whether parental history of distress and fear disorders was associated with the LPP to emotional stimuli in a large sample of adolescent girls.MethodThe sample of 550 girls (ages 13.5–15.5 years) with no lifetime history of depression completed an emotional picture-viewing task and the LPP was measured in response to neutral, pleasant and unpleasant pictures. Parental lifetime history of psychopathology was determined via a semi-structured diagnostic interview with a biological parent, and confirmatory factor analysis was used to model distress and fear dimensions.ResultsParental distress risk was associated with an attenuated LPP to all stimuli. In contrast, parental fear risk was associated with an enhanced LPP to unpleasant pictures but was unrelated to the LPP to neutral and pleasant pictures. Furthermore, these results were independent of the adolescent girls’ current depression and anxiety symptoms and pubertal status.ConclusionsThe present study demonstrates that familial risk for distress and fear disorders may have unique profiles in terms of electrocortical measures of emotional information processing. This study is also one of the first to investigate emotional/motivational processes underlying the distress and fear disorder dimensions. [ABSTRACT FROM AUTHOR]

Transthoracic echocardiography is the most widely used imaging test in cardiology. Although completely noninvasive, transthoracic echocardiography has a well-established role in the diagnosis of numerous cardiovascular diseases, and also provides critical qualitative and quantitative information on their prognosis and pathophysiological processes. The aim of this Review is to outline the broad principles of transthoracic echocardiography, including the traditional techniques of two-dimensional, colour, and spectral Doppler echocardiography, and newly developed advances including tissue Doppler, myocardial deformation imaging, torsion, stress echocardiography, contrast and three-dimensional echocardiography. The advantages and disadvantages, clinical application, prognostic value, and salient research findings of each modality are described. Advances in complex imaging techniques are expected to continue unabated, and this Review highlights technical improvements that will influence the diagnosis and improve our understanding of cardiovascular function and disease. [ABSTRACT FROM AUTHOR]

An analysis of imposed dynamo current drive (IDCD) [T.R. Jarboe et al., Nucl. Fusion 52 083017 (2012)] reveals: (a) current drive on closed flux surfaces seems possible without relaxation, reconnection, or other flux-surface-breaking large events; (b) the scale size of the key physics may be smaller than is often computationally resolved; (c) helicity can be sustained across closed flux; and (d) IDCD current drive is parallel to the current which crosses the magnetic field to produce the current driving force. In addition to agreeing with spheromak data, IDCD agrees with selected tokamak data. [ABSTRACT FROM AUTHOR]