Search

BACKGROUND AND HYPOTHESIS: Schizophrenia (SZ) and bipolar disorder (BD) share genetic risk factors, yet patients display differential levels of cognitive impairment. We hypothesized a genome-transcriptome-functional connectivity (frontoparietal)-cognition pathway linked to SZ-versus-BD differences, and conducted a multiscale study to delineate this pathway. STUDY DESIGNS: Large genome-wide studies provided single nucleotide polymorphisms (SNPs) conferring more risk for SZ than BD, and we identified their regulated genes, namely SZ-biased SNPs and genes. We then (a) computed the polygenic risk score for SZ (PRSSZ) of SZ-biased SNPs and examined its associations with imaging-based frontoparietal functional connectivity (FC) and cognitive performances; (b) examined the spatial correlation between ex vivo postmortem expressions of SZ-biased genes and in vivo, SZ-related FC disruptions across frontoparietal regions; (c) investigated SZ-versus-BD differences in frontoparietal FC; and (d) assessed the associations of frontoparietal FC with cognitive performances. STUDY RESULTS: PRSSZ of SZ-biased SNPs was significantly associated with frontoparietal FC and working memory test scores. SZ-biased genes expressions significantly correlated with SZ-versus-BD differences in FC across frontoparietal regions. SZ patients showed more reductions in frontoparietal FC than BD patients compared to controls. Frontoparietal FC was significantly associated with test scores of multiple cognitive domains including working memory, and with the composite scores of all cognitive domains. CONCLUSIONS: Collectively, these multiscale findings support the hypothesis that SZ-biased genetic risk, through transcriptome regulation, is linked to frontoparietal dysconnectivity, which in turn contributes to differential cognitive deficits in SZ-versus BD, suggesting that potential biomarkers for more precise patient stratification and treatment.

Axonally synthesized proteins support nerve regeneration through retrograde signaling and local growth mechanisms. RNA binding proteins (RBP) are needed for this and other aspects of post-transcriptional regulation of neuronal mRNAs, but only a limited number of axonal RBPs are known. We used targeted proteomics to profile RBPs in peripheral nerve axons. We detected 76 proteins with reported RNA binding activity in axoplasm, and levels of several change with axon injury and regeneration. RBPs with altered levels include KHSRP that decreases neurite outgrowth in developing CNS neurons. Axonal KHSRP levels rapidly increase after injury remaining elevated up to 28 days post axotomy. Khsrp mRNA localizes into axons and the rapid increase in axonal KHSRP is through local translation of Khsrp mRNA in axons. KHSRP can bind to mRNAs with 3'UTR AU-rich elements and targets those transcripts to the cytoplasmic exosome for degradation. KHSRP knockout mice show increased axonal levels of KHSRP target mRNAs, Gap43, Snap25, and Fubp1, following sciatic nerve injury and these mice show accelerated nerve regeneration in vivo. Together, our data indicate that axonal translation of the RNA binding protein Khsrp mRNA following nerve injury serves to promote decay of other axonal mRNAs and slow axon regeneration.

BackgroundStructural neuroimaging studies have identified similarities in the brains of individuals diagnosed with schizophrenia (SZ) and bipolar I disorder (BP), with overlap in regions of gray matter (GM) deficits between the two disorders. Recent studies have also shown that the symptom phenotypes associated with SZ and BP may allow for a more precise categorization than the current diagnostic criteria. In this study, we sought to identify GM alterations that were unique to each disorder and whether those alterations were also related to unique symptom profiles.Materials and methodsWe analyzed the GM patterns and clinical symptom presentations using independent component analysis (ICA), hierarchical clustering, and n-way biclustering in a large (N ∼ 3,000), merged dataset of neuroimaging data from healthy volunteers (HV), and individuals with either SZ or BP.ResultsComponent A showed a SZ and BP < HV GM pattern in the bilateral insula and cingulate gyrus. Component B showed a SZ and BP < HV GM pattern in the cerebellum and vermis. There were no significant differences between diagnostic groups in these components. Component C showed a SZ < HV and BP GM pattern bilaterally in the temporal poles. Hierarchical clustering of the PANSS scores and the ICA components did not yield new subgroups. N-way biclustering identified three unique subgroups of individuals within the sample that mapped onto different combinations of ICA components and symptom profiles categorized by the PANSS but no distinct diagnostic group differences.ConclusionThese multivariate results show that diagnostic boundaries are not clearly related to structural differences or distinct symptom profiles. Our findings add support that (1) BP tend to have less severe symptom profiles when compared to SZ on the PANSS without a clear distinction, and (2) all the gray matter alterations follow the pattern of SZ < BP < HV without a clear distinction between SZ and BP.

The direct effect of genetic variations on clinical phenotypes within schizophrenia (SZ) remains elusive. We examined the previously identified association of reduced gray matter concentration in the insula - medial prefrontal cortex and a quantitative trait locus located in 12q24 in a SZ dataset. The main analysis was performed on 1461 SNPs and 830 participants. The highest contributing SNPs were localized in five genes including TMEM119, which encodes a microglial marker, that is associated with neuroinflammation and Alzheimer's disease. The gene set in 12q4 may partially explain brain alterations in SZ, but they may also relate to other psychiatric and developmental disorders.

In particle accelerators, RF cavities are used to accelerate charged particle beams to designed high energy for physical applications. In a typical accelerator design, the optimization of RF cavities and the optimization of beam dynamics are carried out in separate studies. For a more general and unrestricted accelerator design, a coupled optimization of the RF cavities and the beam parameters is required. For this coupled optimization problem, we have developed an integrated electromagnetics and beam dynamics workflow management system. Within this system, the geometries for a set of cavity components are first adjusted; the field modes are then computed with an electromagnetics program, and imported into a beam dynamics program for beam dynamics simulation. This workflow is encapsulated into a parallel multi-objective optimizer to achieve the integrated accelerator design optimization. A multi fidelity strategy is developed to improve the speed of the optimizer. This integrated global optimization capability is illustrated using a photoinjector design example and yields an improved design.

Genetic factors are known to influence both risk for schizophrenia (SZ) and variation in brain structure. A pressing question is whether the genetic underpinnings of brain phenotype and the disorder overlap. Using multivariate analytic methods and focusing on 1,402 common single-nucleotide polymorphisms (SNPs) mapped from the Psychiatric Genomics Consortium (PGC) 108 regions, in 777 discovery samples, we identified 39 SNPs to be significantly associated with SZ-discriminating gray matter volume (GMV) reduction in inferior parietal and superior temporal regions. The findings were replicated in 609 independent samples. These 39 SNPs in chr6:28308034-28684183 (6p22.1), the most significant SZ-risk region reported by PGC, showed regulatory effects on both DNA methylation and gene expression of postmortem brain tissue and saliva. Furthermore, the regulated methylation site and gene showed significantly different levels of methylation and expression in the prefrontal cortex between cases and controls. In addition, for one regulated methylation site we observed a significant in vivo methylation-GMV association in saliva, suggesting a potential SNP-methylation-GMV pathway. Notably, the risk alleles inferred for GMV reduction from in vivo imaging are all consistent with the risk alleles for SZ inferred from postmortem data. Collectively, we provide evidence for shared genetic risk of SZ and regional GMV reduction in 6p22.1 and demonstrate potential molecular mechanisms that may drive the observed in vivo associations. This study motivates dissecting SZ-risk variants to better understand their associations with focal brain phenotypes and the complex pathophysiology of the illness.

We present two methods for rapid evaluation of two-dimensional retarded time integrals. For example, such integrals arise as the z=0 trace U(t,x,y,0) of a solution U(t,x,y,z) to 3+1 wave equation □U=−2f(t,x,y)δ(z) forced by a “sheet source” at z=0. The spatial Fourier transform of a two-dimensional retarded time integral involves a temporal convolution with the zeroth order Bessel function J0(t). Appealing to work by Alpert, Greengard, and Hagstrom and by Xu and Jiang on rational approximation in the Laplace-transform domain, our first method relies on approximation of J0(t) as a sum of exponential functions. We achieve approximations with double precision accuracy near t≃0, and maintain single precision accuracy out to T≃108. Our second method involves evolution of the 3+1 wave equation in a “thin block” above the sheet, adopting the radiation boundary conditions of Hagstrom, Warburton, and Givoli based on complete plane wave expansions. We review their technique, present its implementation for our problem, and present new results on the nonlocal spacetime form of radiation boundary conditions. Our methods are relevant for the sheet-bunch formulation of the Vlasov–Maxwell system, although here we only test methods on a model problem, a Gaussian source following an elliptical orbit. Our concluding section discusses the complexity of both methods in comparison with naive evaluation of a retarded-time integral.

We study coherent synchrotron radiation (CSR) in a perfectly conducting vacuum chamber of rectangular cross section, in a formalism allowing an arbitrary sequence of bends and straight sections. We apply the paraxial method in the frequency domain, with a Fourier development in the vertical coordinate but with no other mode expansions. A line charge source is handled numerically by a new method that rids the equations of singularities through a change of dependent variable. The resulting algorithm is fast compared to earlier methods, works for short bunches with complicated structure, and yields all six field components at any space-time point. As an example we compute the tangential magnetic field at the walls. From that one can make a perturbative treatment of the Poynting flux to estimate the energy deposited in resistive walls. The calculation was motivated by a design issue for LCLS-II, the question of how much wall heating from CSR occurs in the last bend of a bunch compressor and the following straight section. Working with a realistic longitudinal bunch form of r.m.s. length 10.4 μm and a charge of 100 pC we conclude that the radiated power is quite small (28 W at a 1 MHz repetition rate), and all radiated energy is absorbed in the walls within 7 m along the straight section.

We study coherent synchrotron radiation (CSR) in a perfectly conductingvacuum chamber of rectangular cross section, in a formalism allowing anarbitrary sequence of bends and straight sections. We apply the paraxial methodin the frequency domain, with a Fourier development in the vertical coordinatebut with no other mode expansions. A line charge source is handled numericallyby a new method that rids the equations of singularities through a change ofdependent variable. The resulting algorithm is fast compared to earliermethods, works for short bunches with complicated structure, and yields all sixfield components at any space-time point. As an example we compute thetangential magnetic field at the walls. From that one can make a perturbativetreatment of the Poynting flux to estimate the energy deposited in resistivewalls. The calculation was motivated by a design issue for LCLS-II, thequestion of how much wall heating from CSR occurs in the last bend of a bunchcompressor and the following straight section. Working with a realisticlongitudinal bunch form of r.m.s. length $10.4~\mu$m and a charge of 100 pC weconclude that the radiated power is quite small (28 W at a 1 MHz repetitionrate), and all radiated energy is absorbed in the walls within 7 m along thestraight section.

• In people with cancer, exercise positively influences health-related quality of life (HRQoL), but it remains unclear which exercise modality produces the best results. Maintaining HRQoL for cancer survivors is a health challenge. • Exercise is the main nonpharmacological intervention for improving physical fitness, fatigue, and physical and psychological well-being—all of which are dimensions of HRQoL. • Combined (aerobic and resistance) exercise should be recommended as the best option to improve HRQoL during and after cancer treatment. The positive influence of most types of exercise has been reported repeatedly, but what the most effective exercise approaches are for improving health-related quality of life (HRQoL) in people with cancer remains unknown. The aim of this systematic review and network meta-analysis was to synthesize the evidence from intervention studies to assess the effects of different types of exercise on HRQoL during and after cancer treatment. MEDLINE, SPORTDiscus, the Cochrane Library, Web of Science, and Scopus were searched for randomized controlled trials aimed at testing the effects of exercise interventions meant to improve HRQoL in people with cancer. Separate analyses were conducted for HRQoL as measured by general and cancer-specific questionnaires. We also evaluated whether the effects of exercise were different during and after cancer treatment in both the physical and mental HRQoL domains. In total, 93 studies involving 7435 people with cancer were included. Network effect size estimates comparing exercise intervention vs. usual care were significant for combined exercise (0.35, 95% confidence interval (95%CI): 0.14–0.56) for HRQoL as measured by general questionnaires, and for combined (0.31, 95%CI: 0.13–0.48), mind–body exercise (0.54, 95%CI: 0.18–0.89), and walking (0.39, 95%CI: 0.04–0.74) for HRQoL as measured by cancer-specific questionnaires. Exercise programs combining aerobic and resistance training can be recommended to improve HRQoL during and after cancer treatment. The scarcity and heterogeneity of these studies prevents us from making recommendations about other exercise modalities due to insufficient evidence. [Display omitted] [ABSTRACT FROM AUTHOR]

Evidence on the association between nut consumption and depression is mainly based on cross-sectional studies. This study aims to analyse whether nut consumption is prospectively associated with the risk of depression in adults. This study was conducted using the United Kingdom (UK) Biobank resource. Data from middle-aged and older UK adults who participated in this cohort between 2007–2012 (baseline) and 2013–2020 (follow-up) were analysed. Baseline information on nut consumption was obtained with the Oxford WebQ 24-h questionnaire. Depression, defined as a self-reported physician diagnosis of depression or antidepressant use, was assessed at baseline and follow-up. Hazard regression models estimating the predictive ability of nut consumption for the risk of developing depression were adjusted for sociodemographic, lifestyle, and health confounders. A total of 13,504 participants (mean age 57.5 ± 7.2 years, 50.7% female) free of depression at baseline were included in the analyses. After a mean follow-up of 5.3 ± 2.4 years, 1122 (8.3%) incident cases of depression were identified. Compared with no nut consumption, the daily consumption of >0 to 1 serving of 30 g of nuts was associated with a lower risk of depression (hazard ratio, HR = 0.83; 95% confidence interval, CI: 0.71–0.97) regardless of all potential confounders considered. In stratified analyses, a decreased risk of depression was more clearly observed in UK adults with adequate weight control, a healthy lifestyle, and better health status than in their counterparts (p < 0.05). Low-to-moderate nut consumption (>0 to 1 serving of 30 g/day) was associated with a 17% lower risk of depression during a 5.3-year follow-up compared with no nut consumption in a large sample of middle-aged and older UK adults. This protective association is enhanced in the absence of other known risk factors for depression. [ABSTRACT FROM AUTHOR]

Uruguay was enrolled in the fourth edition of the Global Matrix on physical activity-related indicators in children and adolescents with the aim of producing its second Report Card and analyses on the ten core indicators. A harmonized development process proposed by the Active Healthy Kids Global Alliance was followed. The best available scientific and grey literature was systematically searched for all the indicators included in the Report Card (Overall Physical Activity, Organized Sport Participation, Active Play, Active Transportation, Sedentary Behavior, Physical Fitness, Family and Peers, School, Community and Environment, and Government). A grading scale ranging from A to F was used. A new approach was used to grade the Government indicator according to the Active Healthy Kids Global Alliance guidance. New information was identified and 7 out of 10 indicators were graded, while there were 3 out of 10 indicators with incomplete information to be graded. An gender-based analysis was included in this second Report Card, providing separate grades for 5 of the indicators [girls/boys]: Overall Physical Activity [F/F], Organized Sport Participation [F/D], Active Transportation [C/C], Sedentary Behavior [D+/D+], and Community and Environment [D+/C-]. The comparison between 2018 and 2022 analysis showed a decrease in Overall Physical Activity and Organized Sport Participation, while the sources of influence School and Government obtained a higher grade in comparison with the previous Report Card. Uruguay has developed its second version of the Report Card on physical activity-related indicators in children and adolescents. The gender analysis showed inequalities between girls and boys. In summary, behavioral indicators have decreased while sources of influence have risen along the time. [ABSTRACT FROM AUTHOR]

Only a few studies have assessed the association between a proinflammatory diet and the risk of depression in older adults, and they have rendered weak results. The present study analysed the association between the Dietary Inflammatory Index (DII) and incident self-reported diagnosis or symptoms of depression in two cohorts of community-dwelling older adults in Spain. We used data from the Seniors-ENRICA-I (SE-I) and Seniors-ENRICA-II (SE-II) cohorts. In both cohorts, the baseline DII was calculated from habitual food consumption estimated with a validated computer-based diet history. The incidence of both physician self-reported diagnosis of depression and mild-to-major depressive symptoms (≥3 on the 10-item Geriatric Depression Scale) was analysed. Logistic regression models were adjusted for the main potential confounders, such as sociodemographics, lifestyles, and comorbidities. The results of both cohorts were pooled using a random effects model. Among the 1627 participants in SE-I (mean age 71.5 ± 5.5 y, 53.1% women) and the 1579 in SE-II (mean age 71.4 ± 4.2, 46.7% women), 86 (5.3%) and 140 (8.9%) incident cases of depression were identified after a mean 3.2-y and 2.3-y follow-up, respectively. The fully adjusted odds ratio (95% confidence interval) of incident depression for the highest (the highest proinflammatory diet) versus the lowest quartile of DII was 2.76 (1.25–6.08, p-for-trend = 0.005) in the SE-I, 1.90 (1.04–3.40, p-for-trend = 0.005) in the SE-II and 2.07 (1.01–3.13) in the pooled cohorts. The results were consistent across strata defined by sex, age, physical activity, loneliness/poor social network, and morbidity. A proinflammatory dietary pattern is associated with depression risk in older adults. Future research should evaluate whether reducing the inflammatory component of diet leads to reduced depression symptoms in this population. [ABSTRACT FROM AUTHOR]