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The present study explored social responses toward male victims of female-perpetrated rape by analyzing 505 comments posted on www.theGuardian.com in response to the report that Shia LaBeouf, an American actor and director, was raped by a woman. Using inductive thematic analysis, three themes were generated: Victim’s Character, Victim’s Behavior and Victim’s Story. In addition, each comment was rated regarding its general attitude toward the victim: negative, positive, or mixed. We found that 55% of the comments expressed negative, blaming attitudes toward the victim, 35% were positive and supportive, and 10% were mixed. The findings show that negative comments depict rape as a sexual act against the victim’s will, whereas positive comments portray rape as sexual acts without the victim’s consent. Additionally, negative comments addressed expectation regarding “real men” and “real rape,” whereas positive comments emphasized gender equality in rape comprehension and victim treatment. Our discussion addresses the findings within the context of traditional gender roles and perceptions of “real” rape and presents implications for education and training. Furthermore, we suggest that the existence of positive and mixed responses may indicate a possible change in boundaries of social responses not just regarding male rape victims, but for all rape victims.

The orchestrated action of genes controls complex biological phenotypes, yet the systematic discovery of gene and drug combinations that modulate these phenotypes in human cells is labor intensive and challenging to scale. Here, we created a platform for the massively parallel screening of barcoded combinatorial gene perturbations in human cells and translated these hits into effective drug combinations. This technology leverages the simplicity of the CRISPR-Cas9 system for multiplexed targeting of specific genomic loci and the versatility of combinatorial genetics en masse (Combi-GEM) to rapidly assemble barcoded combinatorial genetic libraries that can be tracked with high-throughput sequencing. We applied CombiGEM-CRISPR to create a library of 23,409 barcoded dual guide-RNA (gRNA) combinations and then perform a high-throughput pooled screen to identify gene pairs that inhibited ovarian cancer cell growth when they were targeted. We validated the growth-inhibiting effects of specific gene sets, including epigenetic regulators KDM4C/BRD4 and KDM6B/BRD4, via individual assays with CRISPR-Cas–based knockouts and RNA-interference–based knockdowns. We also tested small-molecule drug pairs directed against our pairwise hits and showed that they exerted synergistic antiproliferative effects against ovarian cancer cells. We envision that the CombiGEM-CRISPR platform will be applicable to a broad range of biological settings and will accelerate the systematic identification of genetic combinations and their translation into novel drug combinations that modulate complex human disease phenotypes.

Strict iron regulation is essential for normal brain function. The iron homeostasis, determined by the milieu of available iron compounds, is impaired in aging, neurodegenerative diseases and cancer. However, non-invasive assessment of different molecular iron environments implicating brain tissue’s iron homeostasis remains a challenge. We present a magnetic resonance imaging (MRI) technology sensitive to the iron homeostasis of the living brain (the r 1 -r 2 * relaxivity). In vitro, our MRI approach reveals the distinct paramagnetic properties of ferritin, transferrin and ferrous iron ions. In the in vivo human brain, we validate our approach against ex vivo iron compounds quantification and gene expression. Our approach varies with the iron mobilization capacity across brain regions and in aging. It reveals brain tumors’ iron homeostasis, and enhances the distinction between tumor tissue and non-pathological tissue without contrast agents. Therefore, our approach may allow for non-invasive research and diagnosis of iron homeostasis in living human brains. Assessment of different iron compounds in the living brain remains an open challenge. Here, the authors present a magnetic resonance imaging method which is sensitive to the iron homeostasis in the brain, and increases the detection of tumor tissue.

Systemic immunity supports lifelong brain function. Obesity posits a chronic burden on systemic immunity. Independently, obesity was shown as a risk factor for Alzheimer’s disease (AD). Here we show that high-fat obesogenic diet accelerated recognition-memory impairment in an AD mouse model (5xFAD). In obese 5xFAD mice, hippocampal cells displayed only minor diet-related transcriptional changes, whereas the splenic immune landscape exhibited aging-like CD4 + T-cell deregulation. Following plasma metabolite profiling, we identified free N -acetylneuraminic acid (NANA), the predominant sialic acid, as the metabolite linking recognition-memory impairment to increased splenic immune-suppressive cells in mice. Single-nucleus RNA-sequencing revealed mouse visceral adipose macrophages as a potential source of NANA. In vitro, NANA reduced CD4 + T-cell proliferation, tested in both mouse and human. In vivo, NANA administration to standard diet-fed mice recapitulated high-fat diet effects on CD4 + T cells and accelerated recognition-memory impairment in 5xFAD mice. We suggest that obesity accelerates disease manifestation in a mouse model of AD via systemic immune exhaustion. Obesity and aging increase Alzheimer’s disease (AD) risk. Here, using an AD mouse model and high-fat diet, we suggest that immune exhaustion links the two risk factors, and identify a metabolite that can hasten immune dysfunction and memory deficit.

The complexity of affected brain regions and cell types is a challenge for Huntington’s disease (HD) treatment. Here we use single nucleus RNA sequencing to investigate molecular pathology in the cortex and striatum from R6/2 mice and human HD post-mortem tissue. We identify cell type-specific and -agnostic signatures suggesting oligodendrocytes (OLs) and oligodendrocyte precursors (OPCs) are arrested in intermediate maturation states. OL-lineage regulators OLIG1 and OLIG2 are negatively correlated with CAG length in human OPCs, and ATACseq analysis of HD mouse NeuN-negative cells shows decreased accessibility regulated by OL maturation genes. The data implicates glucose and lipid metabolism in abnormal cell maturation and identify PRKCE and Thiamine Pyrophosphokinase 1 ( TPK1 ) as central genes. Thiamine/biotin treatment of R6/1 HD mice to compensate for TPK1 dysregulation restores OL maturation and rescues neuronal pathology. Our insights into HD OL pathology spans multiple brain regions and link OL maturation deficits to abnormal thiamine metabolism. Here the authors evaluate single cell gene expression from mouse and human Huntington’s disease brains, finding incomplete oligodendrocyte maturation and pathways involved. Treating mice with thiamine/biotin ameliorates molecular pathology.

PurposeSocial identity theory describes how an individual’s behaviors and choices are influenced by social group membership, including those related to financial planning. Social group behavior can also be influenced by structural barriers. The primary cause of poverty at retirement stems from the lack of financial planning for retirement. Underprivileged populations tend to have limited access to resources thus, they have difficulty saving for retirement. This study aims to identify barriers to financial planning among underprivileged populations through the framework of the social identity theory.Design/methodology/approachThis qualitative study examines key aspects of retirement planning among underprivileged populations using the social identity theory. Findings were based on 32 in-depth interviews with individuals from the Arab population in Israel.FindingsFour central themes emerged from the interviews, detailing the motivations for financial planning for retirement: social identity, pension literacy, reliance on the national social security network and (lack of) trust in the state and the pension system.Originality/valueBy utilizing the social identity theory, this study identifies potential barriers retirement planning among people from underprivileged populations. Understanding these barriers is vital for policymakers globally, due to the expected increase in the rate of older adults in coming years. Lack of proper retirement planning can lead to an increased rate of poverty among older adults.

In recent years, the assay for transposase-accessible chromatin using sequencing (ATAC-Seq) has become a fundamental tool of epigenomic research. However, it is difficult to perform this technique on frozen samples because freezing cells before extracting nuclei can impair nuclear integrity and alter chromatin structure, especially in fragile cells such as neurons. Our aim was to develop a protocol for freezing neuronal cells that is compatible with ATAC-Seq; we focused on a disease-relevant cell type, namely motor neurons differentiated from induced pluripotent stem cells (iMNs) from a patient affected by spinal muscular atrophy. We found that while flash-frozen iMNs are not suitable for ATAC-Seq, the assay is successful with slow-cooled cryopreserved cells. Using this method, we were able to isolate high quality, intact nuclei, and we verified that epigenetic results from fresh and cryopreserved iMNs quantitatively agree.

Human adipose depots are functionally distinct. Yet, recent single-nucleus RNA sequencing (snRNA-seq) analyses largely uncovered overlapping or similar cell-type landscapes. We hypothesized that adipocyte subtypes, differentiation trajectories and/or intercellular communication patterns could illuminate this depot similarity–difference gap. For this, we performed snRNA-seq of human subcutaneous or visceral adipose tissues (five or ten samples, respectively). Of 27,665 adipocyte nuclei in both depots, most were ‘classical’, namely enriched in lipid metabolism pathways. However, we also observed ‘nonclassical’ adipocyte subtypes, enriched in immune-related, extracellular matrix deposition (fibrosis), vascularization or angiogenesis or ribosomal and mitochondrial processes. Pseudo-temporal analysis showed a developmental trajectory from adipose progenitor cells to classical adipocytes via nonclassical adipocytes, suggesting that the classical state stems from loss, rather than gain, of specialized functions. Last, intercellular communication routes were consistent with the different inflammatory tone of the two depots. Jointly, these findings provide a high-resolution view into the contribution of cellular composition, differentiation and intercellular communication patterns to human fat depot differences. Single-nucleus RNA sequencing of human visceral and subcutaneous adipose tissues is used to identify adipocyte subpopulations and explore their developmental trajectories and interactions.

High-throughput screening and gene signature analyses frequently identify lead therapeutic compounds with unknown modes of action (MoAs), and the resulting uncertainties can lead to the failure of clinical trials. We developed an approach for uncovering MoAs through an interpretable machine learning model of transcriptomics, epigenomics, metabolomics, and proteomics. Examining compounds with beneficial effects in models of Huntington’s Disease, we found common MoAs for compounds with unrelated structures, connectivity scores, and binding targets. The approach also predicted highly divergent MoAs for two FDA-approved antihistamines. We experimentally validated these effects, demonstrating that one antihistamine activates autophagy, while the other targets bioenergetics. The use of multiple omics was essential, as some MoAs were virtually undetectable in specific assays. Our approach does not require reference compounds or large databases of experimental data in related systems and thus can be applied to the study of agents with uncharacterized MoAs and to rare or understudied diseases.

Circular extrachromosomal DNA (ecDNA) in patient tumors is an important driver of oncogenic gene expression, evolution of drug resistance and poor patient outcomes. Applying computational methods for the detection and reconstruction of ecDNA across a retrospective cohort of 481 medulloblastoma tumors from 465 patients, we identify circular ecDNA in 82 patients (18%). Patients with ecDNA-positive medulloblastoma were more than twice as likely to relapse and three times as likely to die within 5 years of diagnosis. A subset of tumors harbored multiple ecDNA lineages, each containing distinct amplified oncogenes. Multimodal sequencing, imaging and CRISPR inhibition experiments in medulloblastoma models reveal intratumoral heterogeneity of ecDNA copy number per cell and frequent putative ‘enhancer rewiring’ events on ecDNA. This study reveals the frequency and diversity of ecDNA in medulloblastoma, stratified into molecular subgroups, and suggests copy number heterogeneity and enhancer rewiring as oncogenic features of ecDNA. Circular extrachromosomal DNA in high-risk medulloblastoma contributes to tumor heterogeneity and associates with relapse and survival. Enhancer rewiring events involving known oncogenes are frequent events, affecting transcription and proliferation.