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Estimation of autocorrelation timescales with Approximate Bayesian Computations
No full textTimescales characterize the pace of change for many dynamic processes in nature: radioactive decay, metabolization of substances, memory decay in neural systems, and epidemic spreads. Measuring timescales from experimental data can reveal underlying mechanisms and constrain theoretical models. Timescales are usually estimated by fitting the autocorrelation of sample time-series with exponential decay functions. We show that this standard procedure often fails to recover the correct timescales, exhibiting large estimation errors due to a statistical bias in autocorrelations of finite data samples. To overcome this bias, we develop a method using adaptive Approximate Bayesian Computations. Our method estimates the timescales by fitting the autocorrelation of sample data with a generative model based on a mixture of Ornstein-Uhlenbeck processes. The method accounts for finite sample size and noise in data and returns a posterior distribution of timescales quantifying the estimation uncertainty. We demonstrate how the posterior distribution can be used for model selection to compare alternative hypotheses about the dynamics of the underlying process. Our method accurately recovers the correct timescales on synthetic data from various processes with known ground truth dynamics. We illustrate its application to electrophysiological recordings from the primate cortex
Maternal experience-dependent cortical plasticity in mice is circuit- and stimulus-specific and requires MECP2
No full textThe neurodevelopmental disorder Rett syndrome is caused by mutations in the gene Mecp2 Misexpression of the protein MECP2 is thought to contribute to neuropathology by causing dysregulation of plasticity. Female heterozygous Mecp2 mutants (Mecp2(het) ) failed to acquire a learned maternal retrieval behavior when exposed to pups, an effect linked to disruption of parvalbumin-expressing inhibitory interneurons (PV) in the auditory cortex. Nevertheless, how dysregulated PV networks affect the neural activity dynamics that underlie auditory cortical plasticity during early maternal experience is unknown. Here we show that maternal experience in wild-type adult female mice (WT) triggers suppression of PV auditory responses. We also observe concomitant disinhibition of auditory responses in deep-layer pyramidal neurons that is selective for behaviorally-relevant pup vocalizations. These neurons further exhibit sharpened tuning for pup vocalizations following maternal experience. All of these neuronal changes are abolished in Mecp2(het) , suggesting that they are an essential component of maternal learning. This is further supported by our finding that genetic manipulation of GABAergic networks that restores accurate retrieval behavior in Mecp2(het) also restores maternal experience-dependent plasticity of PV. Our data are consistent with a growing body of evidence that cortical networks are particularly vulnerable to mutations of Mecp2 in PV neurons. Moreover, our work links, for the first time, impaired in vivo cortical plasticity in awake Mecp2 mutant animals to a natural, ethologically-relevant behavior.SIGNIFICANCE STATEMENTRett syndrome is a genetic disorder that includes language communication problems. Nearly all Rett syndrome is caused by mutations in the gene that produces the protein MECP2, which is important for changes in brain connectivity believed to underlie learning. We previously showed that female Mecp2 mutants fail to learn a simple maternal care behavior performed in response to their pups' distress cries. This impairment appeared to critically involve inhibitory neurons in the auditory cortex called parvalbumin neurons. Here we record from these neurons before and after maternal experience, and we show that they adapt their response to pup calls during maternal learning in non-mutants, but not in mutants. This adaptation is partially restored by a manipulation that improves learning
Conserved chromosomal functions of RNA interference
No full textRNA interference (RNAi), a cellular process through which small RNAs target and regulate complementary RNA transcripts, has well-characterized roles in post-transcriptional gene regulation and transposon repression. Recent studies have revealed additional conserved roles for RNAi proteins, such as Argonaute and Dicer, in chromosome function. By guiding chromatin modification, RNAi components promote chromosome segregation during both mitosis and meiosis and regulate chromosomal and genomic dosage response. Small RNAs and the RNAi machinery also participate in the resolution of DNA damage. Interestingly, many of these lesser-studied functions seem to be more strongly conserved across eukaryotes than are well-characterized functions such as the processing of microRNAs. These findings have implications for the evolution of RNAi since the last eukaryotic common ancestor, and they provide a more complete view of the functions of RNAi
Somatic Tissue Engineering in Mouse Models Reveals an Actionable Role for WNT Pathway Alterations in Prostate Cancer Metastasis.
No full textTo study genetic factors influencing the progression and therapeutic responses of advanced prostate cancer, we developed a fast and flexible system that introduces genetic alterations relevant to human disease directly into the prostate glands of mice using tissue electroporation. These electroporation-based genetically engineered mouse models (EPO-GEMM) recapitulate features of traditional germline models and, by modeling genetic factors linked to late-stage human disease, can produce tumors that are metastatic and castration-resistant. A subset of tumors with alterations acquired spontaneous WNT pathway alterations, which are also associated with metastatic prostate cancer in humans. Using the EPO-GEMM approach and an orthogonal organoid-based model, we show that WNT pathway activation drives metastatic disease that is sensitive to pharmacologic WNT pathway inhibition. Thus, by leveraging EPO-GEMMs, we reveal a functional role for WNT signaling in driving prostate cancer metastasis and validate the WNT pathway as therapeutic target in metastatic prostate cancer. SIGNIFICANCE: Our understanding of the factors driving metastatic prostate cancer is limited by the paucity of models of late-stage disease. Here, we develop EPO-GEMMs of prostate cancer and use them to identify and validate the WNT pathway as an actionable driver of aggressive metastatic disease.
Variable and sexually conflicting selection on Silene stellata floral traits by a putative moth pollinator selective agent
Get PDFConflicting selection is an important evolutionary mechanism because it impedes directional evolution and helps to maintain phenotypic variation. It can arise when mutualistic and antagonistic selective agents exert opposing selection on the same trait and when distinct phenotypic optima are favored by different fitness components. In this study, we test for conflicting selection through different sexual functions of the hermaphroditic plant, Silene stellata during its early and late flowering season. We find selection is consistently stronger during the early flowering season, which aligns with the activity peak of the pollinating seed predator Hadena ectypa. Importantly, we observe sex-specific selection on petal dimensions to have opposite signs. We propose that the observed sexually conflicting selection on petal design results from the negative selection through female function for the avoidance of oviposition and the subsequent fruit predation by H. ectypa larvae and the positive selection through male function for pollen export by H. ectypa adults. The Silene-Hadena interaction has previously been considered to be largely parasitic. Our findings suggest a trade-off mechanism that could thwart the evolution of an "escape route" from the nocturnal pollination syndrome by Silene spp. and contribute to the long-term maintenance of the Silene-Hadena system
Famotidine Use Is Associated With Improved Clinical Outcomes in Hospitalized COVID-19 Patients: A Propensity Score Matched Retrospective Cohort Study
No full textNovel Insights Into Breast Cancer Copy Number Genetic Heterogeneity Revealed by Single-Cell Genome Sequencing
Get PDFCopy number alterations (CNAs) play an important role in molding the genomes of breast cancers and have been shown to be clinically useful for prognostic and therapeutic purposes. However, our knowledge of intra-tumoral genetic heterogeneity of this important class of somatic alterations is limited. Here, using single-cell sequencing, we comprehensively map out the facets of copy number alteration heterogeneity in a cohort of breast cancer tumors. Ou/var/www/html/elife/12-05-2020/backup/r analyses reveal: genetic heterogeneity of non-tumor cells (i.e. stroma) within the tumor mass; the extent to which copy number heterogeneity impacts breast cancer genomes and the importance of both the genomic location and dosage of sub-clonal events; the pervasive nature of genetic heterogeneity of chromosomal amplifications; and the association of copy number heterogeneity with clinical and biological parameters such as polyploidy and estrogen receptor negative status. Our data highlight the power of single-cell genomics in dissecting, in its many forms, intra-tumoral genetic heterogeneity of CNAs, the magnitude with which CNA heterogeneity affects the genomes of breast cancers, and the potential importance of CNA heterogeneity in phenomena such as therapeutic resistance and disease relapse
Cigarette Smoke Exposure and Inflammatory Signaling Increase the Expression of the SARS-CoV-2 Receptor ACE2 in the Respiratory Tract
No full textThe factors mediating fatal SARS-CoV-2 infections are poorly understood. Here, we show that cigarette smoke causes a dose-dependent upregulation of Angiotensin Converting Enzyme 2 (ACE2), the SARS-CoV-2 receptor, in rodent and human lungs. Using single-cell sequencing data, we demonstrate that ACE2 is expressed in a subset of secretory cells in the respiratory tract. Chronic smoke exposure triggers the expansion of this cell population and a concomitant increase in ACE2 expression. In contrast, quitting smoking decreases the abundance of these secretory cells and reduces ACE2 levels. Finally, we demonstrate that ACE2 expression is responsive to inflammatory signaling and can be upregulated by viral infections or interferon treatment. Taken together, these results may partially explain why smokers are particularly susceptible to severe SARS-CoV-2 infections. Furthermore, our work identifies ACE2 as an interferon-stimulated gene in lung cells, suggesting that SARS-CoV-2 infections could create positive-feedback loops that increase ACE2 levels and facilitate viral dissemination
Tumor-associated Macrophages and Macrophage-Related Immune Checkpoint Expression in Sarcomas
No full textEarly trials for immune checkpoint inhibitors in sarcomas have delivered mixed results, and efforts to improve outcomes now look to combinatorial strategies with novel immunotherapeutics, including some that target macrophages. To enhance our understanding of the sarcoma immune landscape, we quantified and characterized tumor-associated macrophage infiltration and expression of the targetable macrophage-related immune checkpoint CD47/SIRPα across sarcoma types. We surveyed immunohistochemical expression of CD68, CD163, CD47, and SIRPα in tissue microarrays of 1242 sarcoma specimens (spanning 24 types). Non-translocation sarcomas, particularly undifferentiated pleomorphic sarcoma and dedifferentiated liposarcoma, had significantly higher counts of both CD68+ and CD163+ macrophages than translocation-associated sarcomas. Across nearly all sarcoma types, macrophages outnumbered tumor-infiltrating lymphocytes and CD163+ (M2-like) macrophages outnumbered CD68+ (M1-like) macrophages. These findings were supported by data from The Cancer Genome Atlas, which showed a correlation between increasing macrophage contributions to immune infiltration and several measures of DNA damage. CD47 expression was bimodal, with most cases showing either 0% or >90% tumor cell staining, and the highest CD47 scores were observed in chordoma, angiosarcoma, and pleomorphic liposarcoma. SIRPα scores correlated well with CD47 expression. Given the predominance of macrophage infiltrates over tumor-infiltrating lymphocytes, the bias toward M2-like (immunosuppressive) macrophage polarization, and the generally high scores for CD47 and SIRPα, macrophage-focused immunomodulatory agents, such as CD47 or IDO-1 inhibitors, may be particularly worthwhile to pursue in sarcoma patients, alone or in combination with lymphocyte-focused agents
Whole-Brain Profiling of Cells and Circuits in Mammals by Tissue Clearing and Light-Sheet Microscopy
No full textTissue clearing and light-sheet microscopy have a 100-year-plus history, yet these fields have been combined only recently to facilitate novel experiments and measurements in neuroscience. Since tissue-clearing methods were first combined with modernized light-sheet microscopy a decade ago, the performance of both technologies has rapidly improved, broadening their applications. Here, we review the state of the art of tissue-clearing methods and light-sheet microscopy and discuss applications of these techniques in profiling cells and circuits in mice. We examine outstanding challenges and future opportunities for expanding these techniques to achieve brain-wide profiling of cells and circuits in primates and humans. Such integration will help provide a systems-level understanding of the physiology and pathology of our central nervous system