Combination of Resting State fMRI, DTI, and sMRI Data to Discriminate Schizophrenia by N-way MCCA + jICA

Multimodal brain imaging data have shown increasing utility in answering both scientifically interesting and clinically relevant questions. Each brain imaging technique provides a different view of brain function or structure, while multimodal fusion capitalizes on the strength of each and may uncover hidden relationships that can merge findings from separate neuroimaging studies. However, most current approaches have focused on pair-wise fusion and there is still relatively little work on N-way data fusion and examination of the relationships among multiple data types. We recently developed an approach called “mCCA + jICA” as a novel multi-way fusion method which is able to investigate the disease risk factors that are either shared or distinct across multiple modalities as well as the full correspondence across modalities. In this paper, we applied this model to combine resting state fMRI (amplitude of low-frequency fluctuation, ALFF), gray matter (GM) density, and DTI (fractional anisotropy, FA) data, in order to elucidate the abnormalities underlying schizophrenia patients (SZs, n = 35) relative to healthy controls (HCs, n = 28). Both modality-common and modality-unique abnormal regions were identified in SZs, which were then used for successful classification for seven modality-combinations, showing the potential for a broad applicability of the mCCA + jICA model and its results. In addition, a pair of GM-DTI components showed significant correlation with the positive symptom subscale of Positive and Negative Syndrome Scale (PANSS), suggesting that GM density changes in default model network along with white-matter disruption in anterior thalamic radiation are associated with increased positive PANSS. Findings suggest the DTI anisotropy changes in frontal lobe may relate to the corresponding functional/structural changes in prefrontal cortex and superior temporal gyrus that are thought to play a role in the clinical expression of SZ

A high-resolution map of human evolutionary constraint using 29 mammals.

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ∼4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ∼60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease

“Getting to Zero” Among Men Who Have Sex with Men in China: a Review of the HIV Care Continuum

Purpose of Review To review the literature on progress towards UNAIDS 90-90-90 targets for HIV prevention and treatment among men who have sex with men (MSM) in China. Recent Findings China has made progress towards UNAIDS 90-90-90 targets among MSM. However, socio-structural barriers, including HIV-related stigma and homophobia, persist at each stage of the HIV care continuum, leading to substantial levels of attrition and high risk of forward HIV transmission. Moreover, access to key prevention tools, such as pre-exposure prophylaxis, is still limited. Multilevel interventions, many using digital intervention, have been shown effective in pragmatic randomized controlled trials in China. Summary Multilevel interventions incorporating digital health have led to significant improvement in engagement of Chinese MSM in the HIV care continuum. However, interventions that address socio-structural determinants, including HIV-related stigma and discrimination, towards Chinese MSM are needed

A High-Resolution Map of Human Evolutionary Constraint Using 29 Mammals

The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ~4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ~60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease.National Human Genome Research Institute (U.S.)National Institute of General Medical Sciences (U.S.) (Grant number GM82901)National Science Foundation (U.S.). Postdoctural Fellowship (Award 0905968)National Science Foundation (U.S.). Career (0644282)National Institutes of Health (U.S.) (R01-HG004037)Alfred P. Sloan Foundation.Austrian Science Fund. Erwin Schrodinger Fellowshi

Echinococcus multilocularis and Echinococcus shiquicus in a small mammal community on the eastern Tibetan Plateau : host species composition, molecular prevalence, and epidemiological implications

Background The eastern part of the Tibetan Plateau is now recognized as an endemic region with the highest reported human infection rates in the world of human alveolar echinococcosis (AE) caused by Echinococcus multilocularis. Existing epidemiological studies on AE have mainly focused on the synanthropic environment, while basic parasitological and ecological aspects in wildlife host species remain largely unknown, especially for small mammal hosts. Therefore, we examined small mammal host species composition, occurrence, and the prevalence of both E. multilocularis and E. shiquicus in Shiqu County (Sichuan Province, China), eastern Tibetan Plateau. Results In total, 346 small mammals from five rodent and one pika species were trapped from four randomly set 0.25 ha square plots. Two vole species, Lasiopodomys fuscus (n = 144) and Microtus limnophilus (n = 44), and the plateau pika (Ochotona curzoniae) (n = 135), were the three most-dominant species trapped. Although protoscoleces of E. multilocularis and E. shiquicus were only observed in L. fuscus and O. curzoniae, respectively, cox1 and nad1 gene DNA of E. shiquicus was detected in all the small mammal species except for Neodon irene, whereas E. multilocularis was detected in the three most-dominant species. The overall molecular prevalence of Echinococcus species was 5.8 (95% CI: 3.3–8.2%) ~ 10.7% (95% CI: 7.4–14.0%) (the conservative prevalence to the maximum prevalence with 95% CI in parentheses), whereas for E. multilocularis it was 4.3 (95% CI: 2.2–6.5%) ~ 6.7% (95% CI: 4.0–9.3%), and 1.5 (95% CI: 0.2–2.7%) ~ 4.1% (95% CI: 2.0–6.1%) for E. shiquicus. The prevalence of both E. multilocularis and E. shiquicus, was significantly higher in rodents (mainly voles) than in pikas. Phylogenetic analyses revealed that Echinococcus haplotypes of cox1 from small mammal hosts were actively involved in the sylvatic and anthropogenic transmission cycles of E. multilocularis in the eastern Tibetan Plateau. Conclusions In contrast to previous studies, the current results indicated that rodent species, rather than pikas, are probably more important natural intermediate hosts of E. multilocularis and E. shiquicus in the eastern Tibetan Plateau. Thus, understanding interspecific dynamics between rodents and pikas is essential to studies of the echinococcosis transmission mechanism and human echinococcosis prevention in local communities. Keywords: Echinococcus multilocularis, E. shiquicus, Small mammal Prevalence, Tibetan Platea

Daily or Nondaily Vaping and Smoking Cessation Among Smokers

ImportanceAn important public health goal is to increase tobacco cessation, but there is limited research on associations of vaping with tobacco cessation.ObjectiveTo estimate the association of vaping with long-term tobacco cessation among US cigarette smokers who used electronic nicotine delivery systems (ENDS; ie, e-cigarettes) in 2017.Design, setting, and participantsThis cohort study used a nationally representative sample of US cigarette smokers from the Population Assessment of Tobacco and Health cohort at wave 4 (2017) with follow-up at wave 6 (2021). Data were analyzed from June 2023 to June 2024.ExposureWave 4 ENDS use: daily, nondaily, or no use.Main outcomes and measuresThe primary outcomes were 12 or more months' abstinence from cigarette smoking and 12 or more months' abstinence from both cigarette and ENDS use, ascertained at wave 6. Propensity score matching was used to control confounding on 14 potential confounders, including interest in quitting, income, age, education, nondaily smoking, and presence of a smoke-free home.ResultsA total of 6013 smokers were included in the sample (3634 aged ≥35 years [weighted percentage, 65.2%]; 3182 female [weighted percentage, 46.5%]). Among smokers who vaped daily (228 individuals), an estimated 20.9% (95% CI, 15.0% to 26.8%) were abstinent from cigarette smoking at follow-up, compared with 14.3% abstinence (95% CI, 13.0% to 15.5%) among smokers who did not vape (5070 individuals) and 12.6% abstinence (95% CI, 9.8% to 15.4%) among smokers who vaped nondaily (715 individuals). Compared with similar propensity score-matched smokers who did not vape, smoking cessation was 4.1 percentage points lower among those who vaped daily (95% CI, -11.9 to 3.6 percentage points; P = .30), a nonsignificant difference. Smoking cessation was 5.3 percentage points lower among those who vaped nondaily (95% CI, -9.1 to -1.5 percentage points; P = .01) compared with similar propensity score-matched controls. Considering abstinence from both smoking and vaping, compared with matched controls, smokers who vaped daily had lower abstinence at follow-up by 14.7 percentage points (95% CI, -20.2 to -9.2 percentage points; P < .001), and those who vaped nondaily had lower abstinence by 7.2 percentage points (95% CI, -10.7 to -3.8 percentage points; P < .001).Conclusions and relevanceIn this representative cohort study of US smokers who used ENDS, neither daily nor nondaily vaping was associated with increased smoking cessation, and each was associated with reduced tobacco abstinence, suggesting that careful adjustment of confounding is critical in studies of ENDS and smoking cessation

A Perspective of the Cross-Tissue Interplay of Genetics, Epigenetics, and Transcriptomics, and Their Relation to Brain Based Phenotypes in Schizophrenia

Genetic association studies of psychiatric disorders have provided unprecedented insight into disease risk profiles with high confidence. Yet, the next research challenge is how to translate this rich information into mechanisms of disease, and further help interventions and treatments. Given other comprehensive reviews elsewhere, here we want to discuss the research approaches that integrate information across various tissue types. Taking schizophrenia as an example, the tissues, cells, or organisms being investigated include postmortem brain tissues or neurons, peripheral blood and saliva, in vivo brain imaging, and in vitro cell lines, particularly human induced pluripotent stem cells (iPSC) and iPSC derived neurons. There is a wealth of information on the molecular signatures including genetics, epigenetics, and transcriptomics of various tissues, along with neuronal phenotypic measurements including neuronal morphometry and function, together with brain imaging and other techniques that provide data from various spatial temporal points of disease development. Through consistent or complementary processes across tissues, such as cross-tissue methylation quantitative trait loci (QTL) and expression QTL effects, systemic integration of such information holds the promise to put the pieces of puzzle together for a more complete view of schizophrenia disease pathogenesis

A Cdh3-β-catenin-laminin signaling axis in a subset of breast tumor leader cells control leader cell polarization and directional collective migration

Carcinoma dissemination can occur when heterogeneous tumor and tumor-stromal cell clusters migrate together via collective migration. Cells at the front lead and direct collective migration, yet how these leader cells form and direct migration are not fully appreciated. From live videos of primary mouse and human breast tumor organoids in a 3D microfluidic system mimicking native breast tumor microenvironment, we developed 3D computational models, which hypothesize that leader cells need to generate high protrusive forces and overcome extracellular matrix (ECM) resistance at the leading edge. From single-cell sequencing analyses, we find that leader cells are heterogeneous and identify and isolate a keratin 14- and cadherin-3-positive subpopulation sufficient to lead collective migration. Cdh3 controls leader cell protrusion dynamics through local production of laminin, which is required for integrin/focal adhesion function. Our findings highlight how a subset of leader cells interact with the microenvironment to direct collective migration

Cigarette smoking decline among US young adults from 2000 to 2019, in relation to state-level cigarette price and tobacco control expenditure

ObjectiveTo investigate the association of state-level cigarette price and tobacco control expenditure with the large 2000-2019 decline in cigarette smoking among US 18-24 year-olds.MethodsSmoking behaviour was assessed in the 24 most populous US states using the 1992-2019 Tobacco Use Supplements to the Current Population Survey; association with price and expenditure was tested using adjusted logistic regression. States were ranked by inflation-adjusted average price and tobacco control expenditure and grouped into tertiles. State-specific time trends were estimated, with slope changes in 2001/2002 and 2010/2011.ResultsBetween 2000 and 2010, the odds of smoking among US young adults decreased by a third (adjusted OR, AOR 0.68, 95% CI 0.56 to 0.84). By 2019, these odds were one-quarter of their 2000 level (AOR 0.24, 95% CI 0.19 to 0.31). Among states in the lowest tertile of price/expenditure tobacco control activity, initially higher young adult smoking decreased by 13 percentage points from 2010 to 2018-2019, to a prevalence of 5.6% (95% CI 4.5% to 6.8%), equal to that in the highest tobacco-control tertile of states (6.5%, 95% CI 5.2% to 7.8%). Neither state tobacco control spending (AOR 1.0, 95% CI 0.999 to 1.002) nor cigarette price (AOR 0.96, 95% CI: 0.92 to 1.01) were associated with young adult smoking in statistical models. In 2019, seven states had prevalence over 3 SDs higher than the 24-state mean.ConclusionNational programmes may have filled a gap in state-level interventions, helping drive down the social acceptability of cigarette smoking among young adults across all states. Additional interventions are needed to assist high-prevalence states to further reduce smoking

Genetic Markers of White Matter Integrity in Schizophrenia Revealed by Parallel ICA

It is becoming a consensus that white matter integrity is compromised in schizophrenia (SZ), however the underlying genetics remains elusive. Evidence suggests a polygenic basis of the disorder, which involves various genetic variants with modest individual effect sizes. In this work, we used a multivariate approach, parallel independent component analysis (P-ICA), to explore the genetic underpinnings of white matter abnormalities in SZ. A pre-filtering step was first applied to locate 6527 single nucleotide polymorphisms (SNPs) discriminating patients from controls with a nominal uncorrected p-value of 0.01. These potential susceptibility loci were then investigated for associations with fractional anisotropy (FA) images in a cohort consisting of 73 SZ patients and 87 healthy controls (HC). A significant correlation (r = −0.37, p = 1.25 × 10−6 ) was identified between one genetic factor and one FA component after controlling for scanning site, ethnicity, age, and sex. The identified FA-SNP association remained stable in a 10-fold validation. A 5000-run permutation test yielded a p-value of 2.00 × 10−4 . The FA component reflected decreased white matter integrity in the forceps major for SZ patients. The SNP component was overrepresented in genes whose products are involved in corpus callosum morphology (e.g., CNTNAP2, NPAS3, and NFIB) as well as canonical pathways of synaptic long term depression and protein kinase A signaling. Taken together, our finding delineates a part of genetic architecture underlying SZ-related FA reduction, emphasizing the important role of genetic variants involved in neural development