Effect of neuroanatomy on corticomotor excitability during and after transcranial magnetic stimulation and intermittent theta burst stimulation

Individual neuroanatomy can influence motor responses to transcranial magnetic stimulation (TMS) and corticomotor excitability after intermittent theta burst stimulation (iTBS). The purpose of this study was to examine the relationship between individual neuroanatomy and both TMS response measured using resting motor threshold (RMT) and iTBS measured using motor evoked potentials (MEPs) targeting the biceps brachii and first dorsal interosseus (FDI). Ten nonimpaired individuals completed sham-controlled iTBS sessions and underwent MRI, from which anatomically accurate head models were generated. Neuroanatomical parameters established through fiber tractography were fiber tract surface area (FTSA), tract fiber count (TFC), and brain scalp distance (BSD) at the point of stimulation. Cortical magnetic field induced electric field strength (EFS) was obtained using finite element simulations. A linear mixed effects model was used to assess effects of these parameters on RMT and iTBS (post-iTBS MEPs). FDI RMT was dependent on interactions between EFS and both FTSA and TFC. Biceps RMT was dependent on interactions between EFS and and both FTSA and BSD. There was no groupwide effect of iTBS on the FDI but individual changes in corticomotor excitability scaled with RMT, EFS, BSD, and FTSA. iTBS targeting the biceps was facilitatory, and dependent on FTSA and TFC. MRI-based measures of neuroanatomy highlight how individual anatomy affects motor system responses to different TMS paradigms and may be useful for selecting appropriate motor targets when designing TMS based therapies

Effect of neuroanatomy on corticomotor excitability during and after transcranial magnetic stimulation and intermittent theta burst stimulation

Individual neuroanatomy can influence motor responses to transcranial magnetic stimulation (TMS) and corticomotor excitability after intermittent theta burst stimulation (iTBS). The purpose of this study was to examine the relationship between individual neuroanatomy and both TMS response measured using resting motor threshold (RMT) and iTBS measured using motor evoked potentials (MEPs) targeting the biceps brachii and first dorsal interosseus (FDI). Ten nonimpaired individuals completed sham-controlled iTBS sessions and underwent MRI, from which anatomically accurate head models were generated. Neuroanatomical parameters established through fiber tractography were fiber tract surface area (FTSA), tract fiber count (TFC), and brain scalp distance (BSD) at the point of stimulation. Cortical magnetic field induced electric field strength (EFS) was obtained using finite element simulations. A linear mixed effects model was used to assess effects of these parameters on RMT and iTBS (post-iTBS MEPs). FDI RMT was dependent on interactions between EFS and both FTSA and TFC. Biceps RMT was dependent on interactions between EFS and and both FTSA and BSD. There was no groupwide effect of iTBS on the FDI but individual changes in corticomotor excitability scaled with RMT, EFS, BSD, and FTSA. iTBS targeting the biceps was facilitatory, and dependent on FTSA and TFC. MRI-based measures of neuroanatomy highlight how individual anatomy affects motor system responses to different TMS paradigms and may be useful for selecting appropriate motor targets when designing TMS based therapies

Direct Evidence for Termination of Obscured Star Formation by Radiatively Driven Outflows in Reddened QSOs

We present optical to far-infrared photometry of 31 reddened QSOs that show evidence for radiatively driven outflows originating from AGN in their rest-frame UV spectra. We use these data to study the relationships between the AGN-driven outflows, and the AGN and starburst infrared luminosities. We find that FeLoBAL QSOs are invariably IR-luminous, with IR luminosities exceeding 10^{12} Solar luminosities in all cases. The AGN supplies 76% of the total IR emission, on average, but with a range from 20% to 100%. We find no evidence that the absolute luminosity of obscured star formation is affected by the AGN-driven outflows. Conversely, we find an anticorrelation between the strength of AGN-driven outflows, as measured from the range of outflow velocities over which absorption exceeds a minimal threshold, and the contribution from star formation to the total IR luminosity, with a much higher chance of seeing a starburst contribution in excess of 25% in systems with weak outflows than in systems with strong outflows. Moreover, we find no convincing evidence that this effect is driven by the IR luminosity of the AGN. We conclude that radiatively driven outflows from AGN can have a dramatic, negative impact on luminous star formation in their host galaxies. We find that such outflows act to curtail star formation such that star formation contributes less than ~25% of the total IR luminosity. We also propose that the degree to which termination of star formation takes place is not deducible from the IR luminosity of the AGN.Comment: Accepted for publication in Ap

Gut Microbiome in Patients With Early-Stage and Late-Stage Melanoma

IMPORTANCE: The gut microbiome modulates the immune system and responses to immunotherapy in patients with late-stage melanoma. It is unknown whether fecal microbiota profiles differ between healthy individuals and patients with melanoma or if microbiota profiles differ among patients with different stages of melanoma. Defining gut microbiota profiles in individuals without melanoma and those with early-stage and late-stage melanoma may reveal features associated with disease progression. OBJECTIVE: To characterize and compare gut microbiota profiles between healthy volunteers and patients with melanoma and between patients with early-stage and late-stage melanoma. DESIGN, SETTING, AND PARTICIPANTS: This single-site case-control study took place at an academic comprehensive cancer center. Fecal samples were collected from systemic treatment-naive patients with stage I to IV melanoma from June 1, 2015, to January 31, 2019, and from healthy volunteers from June 1, 2021, to January 31, 2022. Patients were followed up for disease recurrence until November 30, 2021. MAIN OUTCOMES AND MEASURES: Fecal microbiota was profiled by 16S ribosomal RNA sequencing. Clinical and pathologic characteristics, treatment, and disease recurrence were extracted from electronic medical records. Fecal microbiome diversity, taxonomic profiles and inferred functional profiles were compared between groups. RESULTS: A total of 228 participants were enrolled (126 men [55.3%]; median age, 59 [range, 21-90] years), including 49 volunteers without melanoma, 38 patients with early-stage melanoma (29 with stage I or melanoma in situ and 9 with stage II), and 141 with late-stage melanoma (66 with stage III and 75 with stage IV). Community differences were observed between patients with melanoma and volunteers. Patients with melanoma had a higher relative abundance of Fusobacterium compared with controls on univariate analysis (0.19% vs 0.003%; P \u3c .001), but this association was attenuated when adjusted for covariates (log2 fold change of 5.18 vs controls; P = .09). Microbiomes were distinct between patients with early-stage and late-stage melanoma. Early-stage melanoma had a higher alpha diversity (Inverse Simpson Index 14.6 [IQR, 9.8-23.0] vs 10.8 [IQR, 7.2-16.8]; P = .003), and a higher abundance of the genus Roseburia on univariate analysis (2.4% vs 1.2%; P \u3c .001) though statistical significance was lost with covariate adjustment (log2 fold change of 0.86 vs controls; P = .13). Multiple functional pathways were differentially enriched between groups. No associations were observed between the microbial taxa and disease recurrence in patients with stage III melanoma treated with adjuvant immunotherapy. CONCLUSIONS AND RELEVANCE: The findings of this case-control study suggest that fecal microbiota profiles were significantly different among patients with melanoma and controls and between patients with early-stage and late-stage melanoma. Prospective investigations of the gut microbiome and changes that occur with disease progression may identify future microbial targets for intervention

Detection of Epileptogenic Cortical Malformations with Surface-Based MRI Morphometry

Magnetic resonance imaging has revolutionized the detection of structural abnormalities in patients with epilepsy. However, many focal abnormalities remain undetected in routine visual inspection. Here we use an automated, surface-based method for quantifying morphometric features related to epileptogenic cortical malformations to detect abnormal cortical thickness and blurred gray-white matter boundaries. Using MRI morphometry at 3T with surface-based spherical averaging techniques that precisely align anatomical structures between individual brains, we compared single patients with known lesions to a large normal control group to detect clusters of abnormal cortical thickness, gray-white matter contrast, local gyrification, sulcal depth, jacobian distance and curvature. To assess the effects of threshold and smoothing on detection sensitivity and specificity, we systematically varied these parameters with different thresholds and smoothing levels. To test the effectiveness of the technique to detect lesions of epileptogenic character, we compared the detected structural abnormalities to expert-tracings, intracranial EEG, pathology and surgical outcome in a homogeneous patient sample. With optimal parameters and by combining thickness and GWC, the surface-based detection method identified 92% of cortical lesions (sensitivity) with few false positives (96% specificity), successfully discriminating patients from controls 94% of the time. The detected structural abnormalities were related to the seizure onset zones, abnormal histology and positive outcome in all surgical patients. However, the method failed to adequately describe lesion extent in most cases. Automated surface-based MRI morphometry, if used with optimized parameters, may be a valuable additional clinical tool to improve the detection of subtle or previously occult malformations and therefore could improve identification of patients with intractable focal epilepsy who may benefit from surgery

LSST Science Book, Version 2.0

A survey that can cover the sky in optical bands over wide fields to faint magnitudes with a fast cadence will enable many of the exciting science opportunities of the next decade. The Large Synoptic Survey Telescope (LSST) will have an effective aperture of 6.7 meters and an imaging camera with field of view of 9.6 deg^2, and will be devoted to a ten-year imaging survey over 20,000 deg^2 south of +15 deg. Each pointing will be imaged 2000 times with fifteen second exposures in six broad bands from 0.35 to 1.1 microns, to a total point-source depth of r~27.5. The LSST Science Book describes the basic parameters of the LSST hardware, software, and observing plans. The book discusses educational and outreach opportunities, then goes on to describe a broad range of science that LSST will revolutionize: mapping the inner and outer Solar System, stellar populations in the Milky Way and nearby galaxies, the structure of the Milky Way disk and halo and other objects in the Local Volume, transient and variable objects both at low and high redshift, and the properties of normal and active galaxies at low and high redshift. It then turns to far-field cosmological topics, exploring properties of supernovae to z~1, strong and weak lensing, the large-scale distribution of galaxies and baryon oscillations, and how these different probes may be combined to constrain cosmological models and the physics of dark energy.Comment: 596 pages. Also available at full resolution at http://www.lsst.org/lsst/sciboo

The case for the continued use of the genus name Mimulus for all monkeyflowers

The genus Mimulus is a well-studied group of plant species, which has for decades allowed researchers to address a wide array of fundamental questions in biology (Wu & al. 2008; Twyford & al. 2015). Linnaeus named the type species of Mimulus (ringens L.), while Darwin (1876) used Mimulus (luteus L.) to answer key research questions. The incredible phenotypic diversity of this group has made it the focus of ecological and evolutionary study since the mid-20th century, initiated by the influential work of Clausen, Keck, and Hiesey as well as their students and collaborators (Clausen & Hiesey 1958; Hiesey & al. 1971, Vickery 1952, 1978). Research has continued on this group of diverse taxa throughout the 20th and into the 21st century (Bradshaw & al. 1995; Schemske & Bradshaw 1999; Wu & al. 2008; Twyford & al. 2015; Yuan 2019), and Mimulus guttatus was one of the first non-model plants to be selected for full genome sequencing (Hellsten & al. 2013). Mimulus has played a key role in advancing our general understanding of the evolution of pollinator shifts (Bradshaw & Schemske 2003; Cooley & al. 2011; Byers & al. 2014), adaptation (Lowry & Willis 2010; Kooyers & al. 2015; Peterson & al. 2016; Ferris & Willis 2018; Troth & al. 2018), speciation (Ramsey & al. 2003; Wright & al. 2013; Sobel & Streisfeld 2015; Zuellig & Sweigart 2018), meiotic drive (Fishman & Saunders 2008), polyploidy (Vallejo-Marín 2012; Vallejo-Marín & al. 2015), range limits (Angert 2009; Sexton et al. 2011; Grossenbacher & al. 2014; Sheth & Angert 2014), circadian rhythms (Greenham & al. 2017), genetic recombination (Hellsten & al. 2013), mating systems (Fenster & Ritland 1994; Dudash & Carr 1998; Brandvain & al. 2014) and developmental biology (Moody & al. 1999; Baker & al. 2011, 2012; Yuan 2019). This combination of a rich history of study coupled with sustained modern research activity is unparalleled among angiosperms. Across many interested parties, the name Mimulus therefore takes on tremendous biological significance and is recognizable not only by botanists, but also by zoologists, horticulturalists, naturalists, and members of the biomedical community. Names associated with a taxonomic group of this prominence should have substantial inertia, and disruptive name changes should be avoided. As members of the Mimulus community, we advocate retaining the genus name Mimulus to describe all monkeyflowers. This is despite recent nomenclature changes that have led to a renaming of most monkeyflower species to other genera.Additional co-authors: Jannice Friedman, Dena L Grossenbacher, Liza M Holeski, Christopher T Ivey, Kathleen M Kay, Vanessa A Koelling, Nicholas J Kooyers, Courtney J Murren, Christopher D Muir, Thomas C Nelson, Megan L Peterson, Joshua R Puzey, Michael C Rotter, Jeffrey R Seemann, Jason P Sexton, Seema N Sheth, Matthew A Streisfeld, Andrea L Sweigart, Alex D Twyford, John H Willis, Kevin M Wright, Carrie A Wu, Yao-Wu Yua

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin