bluuebunny/crossref_metadata_2025_split huggingface dataset:
Visual snow syndrome: a review on diagnosis, pathophysiology, and treatment
Authors: Traber Ghislaine L. , Piccirelli Marco , Michels Lars 
Published: November 2019

Purpose of review
Visual snow is considered a disorder of central visual processing resulting in a perturbed perception of constant bilateral whole-visual field flickering or pixelation. When associated with additional visual symptoms, it is referred to as visual snow syndrome. Its pathophysiology remains elusive. This review highlights the visual snow literature focusing on recent clinical studies that add to our understanding of its clinical picture, pathophysiology, and treatment.

Recent findings
Clinical characterization of visual snow syndrome is evolving, including a suggested modification of diagnostic criteria. Regarding pathophysiology, two recent studies tested the hypothesis of dysfunctional visual processing and occipital cortex hyperexcitability using electrophysiology. Likewise, advanced functional imaging shows promise to allow further insights into disease mechanisms. A retrospective study now provides Class IV evidence for a possible benefit of lamotrigine in a minority of patients.

Summary
Scientific understanding of visual snow syndrome is growing. Major challenges remain the subjective nature of the disease, its overlap with migraine, and the lack of quantifiable outcome measures, which are necessary for clinical trials. In that context, refined perceptual assessment, objective electrophysiological parameters, as well as advanced functional brain imaging studies, are promising tools in the pipeline.
Replicating Global Brain Connectivity as an Imaging Marker for Depression – Influence of Preprocessing Strategies and Randomized Placebo-Controlled Ketamine Treatment
Authors: Kraus Christoph , Mkrtchian Anahit , Kadriu Bashkim , Nugent Allison C. , Zarate Carlos A. , Evans Jennifer W. 
Published: November 2019

AbstractMajor depressive disorder (MDD) is associated with altered global brain connectivity (GBC), as assessed via resting state functional magnetic resonance imaging (rsfMRI). Previous studies found that antidepressant treatment with ketamine normalized aberrant GBC changes in the prefrontal and cingulate cortices, warranting further investigations of GBC as a putative imaging marker. However, the results were only obtained via global signal regression (GSR). This study is an independent replication of that analysis using a separate dataset. GBC was analyzed in 28 individuals with MDD and 22 healthy controls (HCs) at baseline, post-placebo, and post-ketamine. To investigate the effects of preprocessing, three distinct pipelines were used: 1) regression of white matter (WM)/cerebrospinal fluid (CSF) signals only (BASE); 2) WM/CSF+GSR (GSR); and 3) WM/CSF+physiological parameter regression (PHYSIO). Compared to PHYSIO and BASE regression, GSR reduced Fisher Z-scores (Fz-scores) in large clusters. PHYSIO did not resemble GBC preprocessed with GSR (GBCr). Reduced GBCr was observed in individuals with MDD at baseline in the anterior and medial cingulate cortices, as well as in the prefrontal cortex. Significant results were only found with GSR. Ketamine had no effect compared to baseline or placebo in either group. These results concur with several studies that used GSR to study GBC. Altered GBCr was observed in the cingulate and prefrontal cortices, but ketamine treatment had no effect. Further investigations are warranted into disease-specific components of global fMRI signals that may drive these results and of GBCr as a potential imaging marker in MDD.
DeePaN: A deep patient graph convolutional network integratingclinico-genomic evidence to stratify lung cancers benefiting from immunotherapy
Authors: Fang Chao , Xu Dong , Su Jing , Dry Jonathan R , Linghu Bolan 
Published: November 2019

AbstractImmuno-oncology (IO) therapies have transformed the therapeutic landscape of non-small cell lung cancer (NSCLC). However, patient responses to IO are variable and influenced by a heterogeneous combination of health, immune and tumor factors. There is a pressing need to discover the distinct NSCLC subgroups that influence response. We have developed a deep patient graph convolutional network, we call “DeePaN”, to discover NSCLC complexity across data modalities impacting IO benefit. DeePaN employs high-dimensional data derived from both real world evidence (RWE) based electronic health records (EHRs) and genomics across 1,937 IO treated NSCLC patients. DeePaN demonstrated effectiveness to stratify patients into subgroups with significantly different (p-value of 2.2 × 10−11) overall survival of 20.35 months and 9.42 months post-IO therapy. Significant differences in IO outcome were not seen from multiple non-graph based unsupervised methods. Furthermore, we demonstrate that patient stratification from DeePaN has the potential to augment the emerging IO biomarker of tumor mutation burden (TMB). Characterization of the subgroups discovered by DeePaN indicates potential to inform IO therapeutic insight, including the enrichment of mutated KRAS and high blood monocyte count in the IO beneficial and IO non-beneficial subgroups, respectively. To the best of our knowledge, our work for the first time has proven the concept that graph based AI is feasible and can effectively integrate high-dimensional genomic and EHR data to meaningfully stratify cancer patients on distinct clinical outcomes, with potential to inform precision oncology.
Genomic signature of accelerated evolution in a saline-alkaline lake-dwelling Schizothoracine fish
Authors: Tong Chao , Li Miao 
Published: November 2019

AbstractTibetan Plateau imposes extremely inhospitable environment on most wildlife. Besides the harsh aquatic environment including hypoxia and chronic cold, high salinity and alkalinity is an increasing threat to Tibetan endemic fishes. Previous genome-wide studies identified key genes contributed to highland fish adaptation to hypoxia and long-term cold, while our understanding of saline and alkaline adaptation in Tibetan fish remains limited. In this study, we performed a comparative genomics analysis in a saline lake-dwelling highland fish Gymnocypris przewalskii, aimed to identify candidate genes that contributed to saline and alkaline adaptation. We found elevated genome-wide rate of molecular evolution in G. przewalskii relative to lowland teleost fish species. In addition, we found nine genes encoding biological macromolecules associated with ion transport functions underwent accelerated evolution in G. przewalskii, which broadly expressed across kidney, gill, liver, spleen, brain and muscle tissues. Moreover, we found putative evidence of ion transport under selection were interacted by co-expression in G. przewalskii adaptation to high salinity and alkalinity environment of Lake Qinghai. Taken together, our comparative genomics study identified a set of rapidly evolving ion transport genes and transcriptomic signatures in Schizothoracine fish adaptation to saline and alkaline environment on the Tibetan Plateau.
The immunocytokine L19-TNF eradicates Sarcomas in combination with Chemotherapy agents or with immune check-point inhibitors
Authors: Corbellari Riccardo , Nadal Lisa , Villa Alessandra , Neri Dario , De Luca Roberto 
Published: November 2019

AbstractAntibody-cytokine fusion proteins (also called “immunocytokines”) represent an emerging class of biopharmaceutical products, which are being considered for cancer immunotherapy. When used as single agents, pro-inflammatory immunocytokines are rarely capable of induce complete and durable cancer regression in mouse models and in patients. However, the combination treatment with conventional chemotherapy or with other immune-stimulatory agents typically increases the therapeutic efficacy of immunocytokines.In this article, we describe combination treatments of a tumor-targeting antibody-cytokine fusion protein based on the L19 antibody (specific to a splice isoform of fibronectin) fused to murine tumor necrosis factor (TNF) with standard chemotherapy (dacarbazine, trabectedin or melphalan) or with an immune check-point inhibitor (anti-PD-1) in a BALB/c derived immunocompetent murine model of sarcoma (WEHI-164).All combination treatments led to improved tumor remission compared to single agent treatments, suggesting that these combination partners may be suitable for further clinical development in sarcoma patients.
Cavin1 intrinsically disordered domains are essential for fuzzy electrostatic interactions and caveola formation
Authors: Tillu Vikas A. , Rae James , Gao Ya , Ariotti Nicholas , Floetenmeyer Matthias , Kovtun Oleksiy , McMahon Kerrie-Ann , Chaudhary Natasha , Parton Robert G. , Collins Brett M. 
Published: November 2019

SummaryCaveolae are spherically shaped nanodomains of the plasma membrane, generated by cooperative assembly of caveolin and cavin proteins. Cavins are cytosolic peripheral membrane proteins with negatively charged intrinsically disordered regions (DR1-3) that flank positively charged α-helical regions (HR1 and HR2). Here we show that the three DR domains of Cavin1 are essential for caveola formation and dynamic trafficking of caveolae. Electrostatic interactions between DR and HR regions promote liquid-liquid phase separation behaviour of Cavin1 in vitro, assembly of Cavin1 oligomers in solution, generation of membrane curvature, association with caveolin-1 (CAV1), and Cavin1 recruitment to caveolae in cells. Removal of the first disordered region causes irreversible gel formation in vitro and results in aberrant caveola trafficking through the endosomal system. We propose a model for caveola assembly whereby fuzzy electrostatic interactions between Cavin1 and CAV1 proteins, combined with membrane lipid interactions, are required to generate membrane curvature and a metastable caveola coat.
An enzymatic assay to measure long-term adherence to pre-exposure prophylaxis and antiretroviral therapy
Authors: Olanrewaju Ayokunle O. , Sullivan Benjamin P. , Zhang Jane Y. , Bender Andrew T. , Sevenler Derin , Lo Tiffany J. , Fernandez-Suarez Marta , Drain Paul K. , Posner Jonathan D. 
Published: November 2019

AbstractPoor adherence to pre-exposure prophylaxis (PrEP) and antiretroviral therapy (ART) can lead to human immunodeficiency virus (HIV) acquisition and emergence of drug resistant infections, respectively. Measurement of antiviral drug levels provides objective adherence information that may help prevent adverse health outcomes. Gold standard drug-level measurement by liquid chromatography/mass spectrometry is centralized, heavily instrumented, and expensive and is thus unsuitable and unavailable for routine use in clinical settings. We developed the REverse TranscrIptase Chain Termination (RESTRICT) assay as a rapid and accessible measurement of drug levels indicative of long-term adherence to PrEP and ART. The assay uses designer single stranded DNA templates and intercalating fluorescent dyes to measure complementary DNA (cDNA) formation by reverse transcriptase in the presence of nucleotide reverse transcriptase inhibitor drugs. We developed a probabilistic model for the RESTRICT assay by calculating the likelihood of incorporation of inhibitors into cDNA as a function of the relative concentrations of inhibitors and nucleotides. We validated the model by carrying out the RESTRICT assay using aqueous solutions of tenofovir diphosphate (TFV-DP), a measure of long-term adherence to PrEP and ART. We used dilution in water as a simple sample preparation strategy to detect TFV-DP spiked into blood. The RESTRICT assay accurately distinguishes TFV-DP drug levels within the clinical range for adherence and has the potential to be a useful test to identify patients with poor adherence to ART and PrEP.
Sensory Neurons Innervate Peripheral Lymph Nodes and Locally Regulate Gene Expression in Postsynaptic Endothelium, Stromal Cells, and Innate Leukocytes
Authors: Huang Siyi , Ziegler Carly G. K. , Austin John , Mannoun Najat , Vukovic Marko , Ordovas-Montanes Jose , Shalek Alex K. , von Andrian Ulrich H. 
Published: November 2019

ABSTRACTImmune responses within barrier tissues are regulated, in part, by nociceptors, specialized peripheral sensory neurons that detect noxious stimuli. Previous work has shown that nociceptor ablation not only alters local responses to immune challenge at peripheral sites, but also within draining lymph nodes (LNs). The mechanisms and significance of nociceptor-dependent modulation of LN function are unknown. Indeed, although sympathetic innervation of LNs is well documented, it has been unclear whether the LN parenchyma itself is innervated by sensory neurons. Here, using a combination of high-resolution imaging, retrograde viral tracing, single-cell transcriptomics (scRNA-seq), and optogenetics, we identified and functionally tested a sensory neuro-immune circuit that is preferentially located in the outermost cortex of skin-draining LNs. Transcriptomic profiling revealed that there are at least four discrete subsets of sensory neurons that innervate LNs with a predominance of peptidergic nociceptors, and an innervation pattern that is distinct from that in the surrounding skin. To uncover potential LN-resident communication partners for LN-innervating sensory neurons, we employed scRNA-seq to generate a draft atlas of all murine LN cells and, based on receptor-ligand expression patterns, nominated candidate target populations among stromal and immune cells. Using selective optogenetic stimulation of LN-innervating sensory axons, we directly experimentally tested our inferred connections. Acute neuronal activation triggered rapid transcriptional changes preferentially within our top-ranked putative interacting partners, principally endothelium and other nodal stroma cells, as well as several innate leukocyte populations. Thus, LNs are monitored by a unique population of sensory neurons that possesses immunomodulatory potential.
Genetically encoded phase contrast agents for digital holographic microscopy
Authors: Farhadi Arash , Bedrossian Manuel , Lee Justin , Ho Gabrielle H. , Shapiro Mikhail G. , Nadeau Jay 
Published: November 2019

ABSTRACTQuantitative phase imaging and digital holographic microscopy have shown great promise for visualizing the motion, structure and physiology of microorganisms and mammalian cells in three dimensions. However, these imaging techniques currently lack molecular contrast agents analogous to the fluorescent dyes and proteins that have revolutionized fluorescence microscopy. Here we introduce the first genetically encodable phase contrast agents based on gas vesicles, a unique class of air-filled protein nanostructures derived from buoyant microbes. The relatively low index of refraction of the air-filled core of gas vesicles results in optical phase advancement relative to aqueous media, making them a “positive” phase contrast agent easily distinguished from organelles, dyes, or microminerals. We demonstrate this capability by identifying and tracking the motion of gas vesicles and gas vesicle-expressing bacteria using digital holographic microscopy, and by imaging the uptake of engineered gas vesicles by mammalian cells. These results give phase imaging a biomolecular contrast agent, greatly expanding the capabilities of this powerful technology for three-dimensional biological imaging.
The Consequences of Egg Adaptation in the H3N2 Component to the Immunogenicity of Live Attenuated Influenza Vaccine
Authors: Goldhill Daniel H. , Lindsey Benjamin , Kugathasan Ruthiran , Garza Zandra Felix , Jagne Ya Jankey , Sallah Hadijatou Jane , Goderski Gabriel , van Tol Sophie , Höschler Katja , Meijer Adam , Barclay Wendy S. , de Silva Thushan I. 
Published: November 2019

AbstractAdaptation in egg-passaged vaccine strains may cause reduced vaccine effectiveness due to altered antigenicity of the influenza haemagglutinin. We tested whether egg adaptation modified serum and mucosal antibody responses to the A(H3N2) component in the Live Attenuated Influenza Vaccine (LAIV). Twice as many children seroconverted to an egg-adapted H3N2 than the equivalent wildtype strain. Seroconversion to the wildtype strain was greater in children seronegative pre-LAIV, whereas higher mucosal IgA responses to wildtype antigen were observed if seropositive prior to vaccination. Sequencing of virus from nasopharyngeal swabs from 7 days post-LAIV showed low sequence diversity and no reversion of egg-adaptive mutations.
Vibrio deploys Type 2 secreted lipase to esterify cholesterol with host fatty acids and mediate cell egress
Authors: de Souza Santos Marcela , Chimalapati Suneeta , Ray Ann , Lee Wan-Ru , Rivera-Cancel Giomar , Lafrance Alexander , Vale Gonçalo , Pawłowski Krzysztof , Mitsche Matt , McDonald Jeffrey G , Liou Jen , Orth Kim 
Published: November 2019

AbstractPathogens find diverse niches for survival inside host cells where replication occurs in a relatively protected environment. Vibrio parahaemolyticus, a facultative intracellular pathogen, uses its type 3 secretion system 2 (T3SS2) to invade and replicate inside host cells. However, after extensive analysis, the T3SS2 pathogenicity island appeared to lack a mechanism for egress of this bacterium from the invaded host cell. Using a combination of cell biology, microbial genetics and lipid biochemistry, we found that VPA0226, a constitutively secreted lipase, is required for escape of Vibrio parahaemolyticus from host cells. Remarkably, this lipase must be delivered into the host cytoplasm where it preferentially uses fatty acids associated with innate immune response (i.e. arachidonic acid, 20:4) to esterify cholesterol, weakening the plasma membrane and allowing egress of the bacteria. This study reveals the resourcefulness of microbes and the interplay between virulence systems to evolve an ingenious scheme for survival and escape.Impact StatementConsidering the course of a pathogen’s evolution, there appears to be interplay between secretion systems, providing unique, synergistic mechanisms to support a successful lifestyle for possibly pathogenesis, symbiosis and/or parasitosis.
Aire-dependent genes undergo Clp1-mediated 3’UTR shortening associated with higher transcript stability in the thymus
Authors: Guyon Clotilde , Jmari Nada , Padonou Francine , Li Yen-Chin , Ucar Olga , Fujikado Noriyuki , Coulpier Fanny , Blanchet Christophe , Root David E. , Giraud Matthieu 
Published: November 2019

AbstractThe ability of the immune system to avoid autoimmune disease relies on tolerization of thymocytes to self-antigens whose expression and presentation by thymic medullary epithelial cells (mTECs) is controlled predominantly by Aire at the transcriptional level and possibly regulated at other unrecognized levels. Aire-sensitive gene expression is influenced by several molecular factors, some of which belong to the 3’end processing complex, suggesting they might impact transcript stability and levels through an effect on 3’UTR shortening. We discovered that Aire-sensitive genes display a pronounced preference for short-3’UTR transcript isoforms in mTECs, a feature preceding Aire’s expression and correlated with the preferential selection of proximal polyA sites by the 3’end processing complex. Through an RNAi screen and generation of a lentigenic mouse, we found that one factor, Clp1, promotes 3’UTR shortening associated with higher transcript stability and expression of Aire-sensitive genes, revealing a post-transcriptional level of control of Aire-activated expression in mTECs.
A deregulated stress response underlies distinct INF2 associated disease profiles
Authors: Bayraktar S. , Nehrig J. , Menis E. , Karli K. , Janning A. , Struk T. , Halbritter J. , Michgehl U. , Krahn M.P. , Schuberth C.E. , Pavenstädt H.P. , Wedlich-Söldner R. 
Published: November 2019

AbstractMonogenic diseases provide favorable opportunities to elucidate the molecular mechanisms of disease progression and improve medical diagnostics. However, the complex interplay between genetic and environmental factors in disease etiologies makes it difficult to discern the mechanistic links between different alleles of a single locus and their associated pathophysiologies. Here we systematically characterize a large panel (>50) of autosomal dominant mutants of the actin regulator inverted formin 2 (INF2) that have been reported to cause the podocytic kidney disease focal segmental glomerulosclerosis (FSGS) and the neurological disorder Charcot Marie-Tooth disease (CMT). We found that INF2 mutations lead to deregulated activation of the formin and a constitutive stress response in cultured cells, primary patient cells and Drosophila nephrocytes. Using quantitative live-cell imaging we were able to identify distinct subsets of INF2 variants that exhibit varying degrees of activation. Furthermore, we could clearly distinguish between INF2 mutations that were linked exclusively to FSGS from those that caused a combination of FSGS and CMT. Our results indicate that cellular profiling of disease-associated mutations can contribute substantially to sequence-based phenotype predictions.
Metabolic signatures of regulation by phosphorylation and acetylation
Authors: Smith Kirk , Shen Fangzhou , Lee Ho Joon , Chandrasekaran Sriram 
Published: November 2019

AbstractAcetylation and phosphorylation are highly conserved post-translational modifications (PTMs) that regulate cellular metabolism, yet how metabolic control is shared between these PTMs is unknown. Here we analyze transcriptome, proteome, acetylome, and phosphoproteome datasets inE.coli,S.cerevisiae, and mammalian cells across diverse conditions using CAROM, a new approach that uses genome-scale metabolic networks and machine-learning to classify regulation by PTMs. We built a single machine-learning model that accurately distinguished reactions controlled by each PTM in a condition across all three organisms based on reaction attributes (AUC>0.8). Our model uncovered enzymes regulated by phosphorylation during a mammalian cell-cycle, which we validate using phosphoproteomics. Interpreting the machine-learning model using game-theory uncovered enzyme properties including network connectivity, essentiality, and condition-specific factors such as maximum flux that differentiate regulation by phosphorylation from acetylation. The conserved and predictable partitioning of metabolic regulation identified here between these PTMs can enable rational engineering of regulatory circuits.Graphical Abstract
Mechanical Suppression of Breast Cancer Cell Invasion and Paracrine Signaling Requires Nucleo-Cytoskeletal Connectivity
Authors: Yi Xin , Wright Laura E. , Pagnotti Gabriel M. , Uzer Gunes , Powell Katherine M. , Wallace Joseph , Sankar Uma , Rubin Clinton T. , Mohammad Khalid , Guise Theresa A. , Thompson William R. 
Published: November 2019

SummaryExercise benefits the musculoskeletal system and reduces the effects of cancer. The beneficial effects of exercise are multifactorial, where metabolic changes and tissue adaptation influence outcomes. Mechanical signals, a principal component of exercise, are anabolic to the musculoskeletal system and restrict cancer progression. We examined the mechanisms through which cancer cells sense and respond to mechanical signals. Low-magnitude, high-frequency signals were applied to human breast cancer cells in the form of low-intensity vibration (LIV). LIV decreased invasion through matrix and impaired secretion of osteolytic factors PTHLH, IL-11, and RANKL. Furthermore, paracrine signals from mechanically stimulated cancer cells, reduced osteoclast differentiation resorptive capacity. Physically disconnecting the nucleus by knockdown of SUN1 and SUN2 impaired the ability of LIV to suppress invasion and production of osteolytic factors. LIV also increased cell stiffness; an effect dependent on an intact LINC complex. These data show that mechanical signals alter the metastatic potential of human breast cancer cells, where the nucleus serves as a mechanosensory apparatus to alter cell structure and intercellular signaling.