bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does Residual Invasive Disease in Wide Local Excision after Diagnosis with Partial Biopsy Technique Influence Survival in Melanoma? Matched-Pair Analysis of Multicenter Selective Lymphadenectomy Trial I and II
Authors: Ramiscal Judi Anne B , Stern Stacey L , Wilson Ana K , Lorimer Patrick D , Lee Nathaniel A , Goldfarb Melanie R , Foshag Leland J , Fischer Trevan D 
Published: June 2022

BACKGROUND:
Current guidelines recommend excisional/complete biopsy for melanoma diagnosis, owing to high rates of residual disease found at wide local excision (WLE) after partial biopsy techniques. We sought to determine any survival disadvantage associated with the presence of residual invasive melanoma in the WLE after diagnosis with a partial biopsy technique.

STUDY DESIGN:
Data were examined from Multicenter Selective Lymphadenectomy Trials I and II (MSLT-I and -II), 2 large melanoma trials. Patients diagnosed with excisional/complete biopsy were excluded. Clinicopathologic characteristics, melanoma-specific survival (MSS), distant disease-free survival (DDFS), and disease-free survival (DFS) of those with residual invasive melanoma in the definitive WLE and those with no residual melanoma were compared. Matched pairing was used to reduce variability between groups.

RESULTS:
From 1994 through 2014, 3,939 patients were enrolled in these trials and 874 (22%) were diagnosed using partial biopsy techniques. Of these, 399 (46%) had residual tumor in the WLE. Only 6 patients had residual tumor in their WLE resulting in T-upstaging of their tumor. Match-pairing formed two cohorts (1:1) of patients with and without residual invasive tumor after WLE. A total of 514 patients were paired; 288 (56%) males, 148 (28.8%) aged 60 or older, 192 (37.4%) with truncal melanomas, 214 (41.6%) had Breslow thickness 2 mm or greater, and 376 (73.2%) had positive sentinel nodes. Kaplan-Meier analysis showed no statistical difference in 10-year MSS (73.6% ± 3.3% vs 73.9% ± 3.7%, p = 0.891), DDFS (68.7% ± 3.4% vs 65.3% ± 4.0%, p = 0.548), or DFS (59.6% ± 3.7% vs 59.4% ± 3.9%, p = 0.783).

CONCLUSIONS:
Survival in patients with primary melanoma does not appear to be worse in patients who undergo a partial biopsy technique and are later found to have residual invasive tumor in the WLE specimen.
Surgical Guidance of Head and Neck Squamous Cell Carcinoma Enabled by a c-MET-Targeting Fluorescent Probe cMBP-ICG
Authors: Wang Jingbo , Li Siyi , Wang Kun , Zhu Ling , Yang Lin , Zhu Yunjing , Zhang Zhen , Hu Longwei , Yuan Yuan , Fan Qi , Ren Jiliang , Yang Gongxin , Ding Weilong , Zhou Xiaoyu , Huang Ruimin , Cui Junqi , Zhang Chunye , Yuan Ying , Tian Jie , Tao Xiaofeng 
Published: June 2022

AbstractImportanceHead and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy which is associated with subtle local invasion and metastasis. Near-infrared (NIR) fluorescence-guided surgical precise resection of the tumor margin and potential metastasis has been appealing.ObjectiveTo determine whether a peptide-based NIR fluorescence dye, which can be administered via topical application and target tumor tissue via c-MET binding, can improve discrimination of HNSCC from normal tissue.DesignA nonrandomized controlled trial was conducted between March 2021 and February 2022 at Shanghai Ninth Peoples’ Hospital, China. Study participants were blinded for subjective measurements.SettingExploratory, single-center, open-label, dose-escalationParticipantsConsecutive Asian individuals with clinically suspicious, primary or recurrent HNSCC, who were scheduled for standard-of-care surgery with curative intent, were enrolled.InterventionsEnrolled patients underwent in vivo fluorescence imaging before surgery, and ex vivo fluorescence imaging was performed on intraoperative specimens using 2.5 μM or 5.0 μM topical applicated fluorescent probes.Main Outcomes and MeasuresPrimary analysis compared mean fluorescence intensity (MFI, total fluorescence signal divided by the total number of pixels within the region of interest) of tumor and peritumoral normal tissue. Possible tumor-to-background ratios (TBR, ratio of MFI of tumor over peritumoral normal tissues) may range from 2 to 4.ResultsTen patients (1 female [10%], age = 59.4 ± 12.6 years old) were enrolled. Ex vivo imaging with 5.0 μM fluorescence prob demonstrated TBR of 2.71 ± 0.7, with 2.5 μM fluorescence prob demonstrated TBR of 3.11 ±1.2. To discriminate tumor from normal tissue with MFI, the area under the curve (AUC) was 0.88 (95% CI-0.88 to 1.0) for the 5.0 μM group, and 0.65 (95% CI 0.53 to 0.83) for the 2.5 μM group.Conclusions and RelevanceThis trial demonstrates that topical application of tumor targeting fluorescence probe can differentiate tumor and outlining tumor margins. Further research is currently underway to estimate whether this probe is potent in guiding biopsy and surgical procedure, and assisting long-term follow-up postoperatively.Trial RegistrationChinese Clinical Trial Registry Identifier: ChiCTR2200058058
RNA-sequencing improves diagnosis for neurodevelopmental disorders by identifying pathogenic non-coding variants and reinterpretation of coding variants
Authors: Dekker Jordy , Schot Rachel , Bongaerts Michiel , de Valk Walter G. , van Veghel-Plandsoen Monique M. , Monfils Kathryn , Douben Hannie , Elfferich Peter , Kasteleijn Esmee , van Unen Leontine M.A. , Geeven Geert , Saris Jasper J. , van Ierland Yvette , Verheijen Frans W. , van der Sterre Marianne L.T. , Niaraki Farah Sadeghi , Huidekoper Hidde H. , Williams Monique , Wilke Martina , Verhoeven Virginie J.M. , Joosten Marieke , Kievit Anneke J.A. , van de Laar Ingrid M.B.H. , Hoefsloot Lies H. , Hoogeveen-Westerveld Marianne , Nellist Mark , Mancini Grazia M.S. , van Ham Tjakko J. 
Published: June 2022

AbstractBackgroundFor neurodevelopmental disorders (NDD), a molecular diagnosis is key for predicting outcome, treatment and genetic counseling. Currently, in about half of NDD cases, routine DNA-based testing fails to establish a genetic diagnosis. Transcriptome analysis (RNA-seq) improves the diagnostic yield for some groups of diseases, but has not been applied to NDD in a routine diagnostic setting.MethodsHere, we explored the diagnostic potential of RNA-seq in a cohort of 96 individuals including 67 undiagnosed NDD subjects. We created a user-friendly web-application to analyze RNA-seq data from single individuals’ cultured skin fibroblasts for genic, exonic and intronic expression outliers, based on modified OUTRIDER Z-scores. Candidate pathogenic events were complemented/matched with genomic data and, if required, confirmed with additional functional assays.ResultsWe identified pathogenic small genomic deletions, mono-allelic expression, aberrant splicing events, deep intronic variants resulting in pseudo-exon insertion, but also synonymous and nonsynonymous variants with deleterious effects on transcription. This approach increased the diagnostic yield for NDD by 12%. Diagnostic pitfalls during transcriptome analysis include detection of splice abnormalities in putative disease genes caused by benign polymorphisms and/or absence of expression of the responsible gene in the tissue of choice. This was misleading in one case and could have led to the wrong diagnosis in the absence of appropriate phenotyping.ConclusionsNonetheless, our results demonstrate the utility of RNA-seq in molecular diagnostics and stress the importance of multidisciplinary team consultation. In particular, the approach is useful for the identification and interpretation of unexpected pathogenic changes in mRNA processing and expression in NDD.
Differential D1 and D2 receptor internalization and recycling induced by amphetamine in vivo
Authors: Hansen Hanne D. , Schain Martin , Deng Helen P. , Mandeville Joseph B. , Rosen Bruce R. , Sander Christin Y. 
Published: June 2022

AbstractThe dopamine system plays a significant role in drug reward and the pathogenesis of addiction. Psychostimulant drugs acutely increase dopamine levels, triggering receptor internalization. In vitro data suggest that dopamine D1 receptors (D1R) recycle, whereas D2 receptors (D2R) degrade in response to activation. Yet, receptor fates in vivo remain unclear. This study bridges in vitro mechanisms and in vivo measurements of stimulant-induced modulation of receptor states using longitudinal multi-modal imaging combined with neuropharmacology. We demonstrate how repeated amphetamine administration differentially modulates D1R vs. D2R signaling in nonhuman primates over 24 hours using simultaneous positron emission tomography and functional magnetic resonance imaging. In contrast to predominantly inhibitory D2R signaling due to an initial amphetamine challenge, excitatory D1R functional signaling prevails three hours later, while D2Rs stay internalized. These results demonstrate differential externalization mechanisms of the D1R and D2R in vivo and a shift in receptor subtype activation after a dopamine surge.
Linking histology and molecular state across human tissues
Authors: Jones Andrew , Gundersen Gregory W. , Engelhardt Barbara E. 
Published: June 2022

AbstractHistological imaging and molecular profiling of human tissues both offer information-rich characterizations of biological structure and function. Each of these modalities has been used to characterize the organization and dysregulation of a variety of tissues and cell types. While large-scale studies of each modality in isolation have been conducted, it remains largely unknown the extent to which these two views of a tissue relate to one another. Understanding how cellular states are encoded in cellular morphology would increase the utility and interpretability of imaging data; conversely, understanding the state of the cells within histology images would give deeper insights into the types and states of cells that constitute these tissue samples. To this end, we jointly analyzed 13, 360 human tissue samples with paired bulk gene expression profiles and histology images across 935 donors from the Genotype and Tissue Expression (GTEx) Consortium v8 study. This analysis reveals relationships among gene expression and cellular morphology through shared sources of expression and morphological heterogeneity both within and between tissue types. We describe shared sources of variation including cell-type heterogeneity, sample ischemic time, and donor health and demographics. We find specific correlated effects in both morphology and transcription linked to specific donor characteristics, such as their use of mechanical ventilation. This paired understanding adds value to each data modality on their own by enabling a more precise characterization of the alternative modality in the absence of those data.
Spatial distribution of metabolites in primate retina and its relevance to studies of human metabolic retinal disorders
Authors: Bonelli Roberto , Ansell Brendan R E , Woods Sasha M , Lockwood Sarah , Bishop Paul N , Khan Kamron N , Bahlo Melanie , Fruttiger Marcus 
Published: June 2022

AbstractThe primate retina has evolved regional specialisations for specific visual functions. The macula is specialised towards high acuity vision and is an area that contains an increased density of cone photoreceptors and signal processing neurons. Different regions in the retina display unique susceptibility to pathology, with many retinal diseases primarily affecting the macula. To better understand the properties of different retinal areas we conducted an untargeted metabolomics analysis on full thickness punches from three different regions (macula, temporal peri-macula and periphery) of primate retina. Half of all metabolites identified showed differential abundance in at least one comparison between the three regions. The unique metabolic phenotype of different retinal regions is likely due to the differential distribution of different cell types in these regions reflecting the specific metabolic requirements of each cell type. Furthermore, mapping metabolomics results from macula-specific eye diseases onto the region-specific distributions of healthy primate retina revealed differential abundance defining systemic metabolic dysregulations that were region specific, highlighting how our results may help to better understand the pathobiology of retinal diseases with region specificity.
Securing algal endosymbiont communities for reef-building corals
Authors: Bouwmeester Jessica , Daly Jonathan , Quinn Mariko , Henley E. Michael , Lager Claire , Perry Riley , Page Christopher A. , Hagedorn Mary 
Published: June 2022

AbstractPhotosynthetic dinoflagellates that live in symbiosis with corals (family Symbiodiniaceae) are fundamental for the survival of coral reef ecosystems. During coral bleaching events, it is assumed that these symbionts remain available in the water column, in sediments, or are seeded from unbleached coral colonies. Yet, this hypothesis has not been verified and it remains unclear whether some diversity of Symbiodiniaceae may be lost in the process. Culture methods have been developed for some Symbiodiniaceae, but for the vast majority of these photosynthetic symbionts, known culture methods are not successful at maintaining them for extensive periods. For these unculturable symbionts, cryopreservation, which places cells and tissues in suspended animation for days to decades, offers the best hope for saving the biodiversity of these crucial coral partners. Some cryopreservation processes use slow freezing, but if the cells are sensitive to low temperatures, as is the case for Symbiodiniaceae, then rapid freezing, called vitrification, is needed. We here, tested two published vitrification protocols that had been designed for algal symbionts extracted from Hawaiian corals, but we were unable to recover living symbionts after vitrification and warming. Therefore, we report a successful optimisation of the former vitrification protocols, which we tested on algal symbionts freshly extracted from three Hawaiian coral species, the development of ultra-rapid laser-warming cryopreservation techniques for symbionts, and banking procedures for algal symbionts. We also present some successful uptake of cryopreserved algal symbionts by coral larvae, although at a low rate. It is unclear why the former vitrification protocols failed but we propose that it may have been related to thermal stress and bleaching events that occurred on several occasions throughout the Hawaiian Islands. Maintenance of biodiversity is essential for sustaining functional, productive ecosystems with the adaptability to effectively recover from disturbances. By successfully cryopreserving and banking coral symbionts, we provide a critically needed component for securing Symbiodiniaceae biodiversity into the future.
Maturational networks of human fetal brain activity reveal emerging connectivity patterns prior to ex-utero exposure
Authors: Karolis Vyacheslav R. , Fitzgibbon Sean P. , Cordero-Grande Lucilio , Farahibozorg Seyedeh-Rezvan , Price Anthony N. , Hughes Emer J. , Fetit Ahmed E. , Kyriakopoulou Vanessa , Pietsch Maximilian , Rutherford Mary A. , Rueckert Daniel , Hajnal Joseph V. , Edwards A. David , O’Muircheartaigh Jonathan , Duff Eugene P. , Arichi Tomoki 
Published: June 2022

ABSTRACTA key feature of the fetal period is the rapid emergence of organised patterns of spontaneous brain activity. However, characterising this process in utero using functional MRI is inherently challenging and requires analytical methods which can capture the constituent developmental transformations. Here, we introduce a novel analytical framework, termed “maturational networks” (matnets), that achieves this by modelling functional networks as an emerging property of the developing brain. Compared to standard network analysis methods that assume consistent patterns of connectivity across development, our method incorporates age-related changes in connectivity directly into network estimation. We test its performance in a large neonatal sample, finding that the matnets approach characterises adult-like features of functional network architecture with a greater specificity than a standard group-ICA approach; for example, our approach is able to identify a nearly complete default mode network. In the in-utero brain, matnets enables us to reveal the richness of emerging functional connections and the hierarchy of their maturational relationships with remarkable anatomical specificity. We show that the associative areas play a central role within prenatal functional architecture, therefore indicating that functional connections of high-level associative areas start emerging prior to exposure to the extra-utero environment.
The F-box cofactor UFO redirects the LEAFY floral regulator to novel cis-elements
Authors: Rieu Philippe , Turchi Laura , Thévenon Emmanuel , Zarkadas Eleftherios , Nanao Max , Chahtane Hicham , Tichtinsky Gabrielle , Lucas Jérémy , Blanc-Mathieu Romain , Zubieta Chloe , Schoehn Guy , Parcy François 
Published: June 2022

SUMMARYIn angiosperms, flower patterning requires the localized expression of the APETALA3 (AP3) floral homeotic gene involved in petal and stamen development. AP3 is synergistically induced by the master transcription factor (TF) LEAFY (LFY) and the F-box protein UNUSUAL FLORAL ORGANS (UFO), but the molecular mechanism underlying this synergy has remained unknown. Here we show that the connection to ubiquitination pathways suggested by the F-box domain of UFO is mostly dispensable for its function and that UFO instead acts by forming a transcriptional complex with LFY and binds to newly discovered regulatory elements. Cryo-electron microscopy explains how a LFY-UFO complex forms on these novel DNA sites due to direct interaction of UFO with LFY and DNA. Finally, we show that this complex has a deep evolutionary origin, largely predating flowering plants. This work reveals a novel mechanism of an F-box protein in directly modulating the DNA-binding specificity of a master TF.
Structural features stabilized by divalent cation coordination within hepatitis E virus ORF1 are critical for viral replication
Authors: LeDesma Robert , Biswas Abhishek , Maya Stephanie , Gili Stefania , Higgins John , Ploss Alexander 
Published: June 2022

AbstractHepatitis E virus (HEV) is an RNA virus responsible for over 20 million infections annually. HEV’s open reading frame (ORF)1 polyprotein is essential for genome replication, though it is unknown how the different subdomains function within a structural context. Our data show that ORF1 operates as a multifunctional protein, which is not subject to proteolytic processing. Supporting this model, scanning mutagenesis performed on the putative papain-like cysteine protease (pPCP) domain revealed six cysteines essential for viral replication. Our data are consistent with their role in divalent metal ion coordination, which governs local and interdomain interactions that are critical for the overall structure of ORF1; further, the “pPCP” domain can only rescue viral genome replication in trans when expressed in the context of the full-length ORF1 protein but not as an individual subdomain. Taken together our work provides a comprehensive model of the structure and function of HEV ORF1.Significance StatementThe development of non-teratogenic and potent antiviral therapies against HEV have been hindered by an incomplete understanding of the viral replication cycle. Our work provides a mechanistic insight into the complex replicative cycle of this understudied human pathogen and identifies a novel domain-domain interaction that is vital for replicative fitness.
Characterization of the Rhizophagus irregularis multicopper oxidase family indicates that the iron transporter RiFTR1 does not require a ferroxidase partner
Authors: Tamayo E , Shim C , Castillo AG , Benz JP , Ferrol N 
Published: June 2022

AbstractThe contribution of arbuscular mycorrhizal fungi (AM fungi) to plant iron (Fe) acquisition has been demonstrated in several studies. Recently, it has been shown that AM fungi use a high-affinity reductive pathway for Fe uptake. In the AM fungus Rhizophagus irregularis the ferric reductase RiFRE1 and the Fe permeases RiFTR1 and RiFTR2 have already been characterized. In an attempt to identify the third component of the reductive iron uptake pathway, a genome-wide approach has been used in R. irregularis to find genes encoding ferroxidases of the multicopper oxidase (MCO) gene family. Nine genes putatively encoding MCOs (RiMCO1-9) were identified. A phylogenetic analysis of MCO sequences of fungi from different taxonomic groups revealed that all RiMCOs clustered together in the ferroxidase/laccase group, and none with the Fet3-type ferroxidases. RiMCO1 and RiMCO3 were the only MCO genes displaying a detectable gene expression pattern typical of a high-affinity Fe transport system, indicating that RiMCO1 and RiMCO3 might have a role in the reductive high-affinity Fe uptake system. Moreover, yeast mutant complementation assays showed that the iron permease RiFTR1 can operate without the presence of a ferroxidase, indicating that it is able to transport also ferrous (II) iron.
Development of Top-Down Cortical Propagations in Youth
Authors: Pines Adam , Keller Arielle S. , Larsen Bart , Bertolero Maxwell , Ashourvan Arian , Bassett Dani S. , Cieslak Matthew , Covitz Sydney , Fan Yong , Feczko Eric , Houghton Audrey , Rueter Amanda R. , Tapera Tinashe , Vogel Jacob , Weinstein Sarah M. , Shinohara Russell T. , Fair Damien , Satterthwaite Theodore 
Published: June 2022

AbstractHierarchical processing requires activity propagating between higher and lower-order cortical areas. However, studies of brain development have chiefly quantified fluctuations within regions over time rather than propagations occurring over space. Here, we leveraged advances in neuroimaging and computer vision to track cortical activity propagations in a large sample of youth (n=388). We found that propagations robustly ascend and descend the cortical hierarchy, and that top-down propagations become both more prevalent with cognitive control demands and with development in youth.
Structural basis for CDC42 and RAC activation by the dual specificity GEF DOCK10
Authors: Fan Danni , Yang Jing , Cronin Nora , Barford David 
Published: June 2022

ABSTRACTDedicator of cytokinesis 10 (DOCK10) is a guanine nucleotide exchange factor (GEF) belonging to the DOCK family that activate RHO GTPases. DOCK10 controls amoeboid migration and IL-4 induced B cell activation. Recent structural studies of the catalytic DHR2 domains of DOCK-family GEFs DOCK2 and DOCK9 in the presence of nucleotide-free RAC and CDC42 respectively, have revealed a conserved mechanism of nucleotide exchange distinct from the large family of Dbl homology (DH) GEFs. Less is known from a biochemical and structural perspective, about DOCK10. We have determined the crystal structure of the apo-state of the DHR2 domain of DOCK10 (DOCK10DHR2), which provides the first structural model for the apo-state of a DHR2 domain for the entire DOCK family. It demonstrates the conformational changes within DOCK10DHR2on engaging the GTPase, and associated induced conformational changes of the GTPase required to stimulate nucleotide release. We also report on the unexpected dual specificity of DOCK10DHR2which directly interacts with RAC and CDC42 and induces the nucleotide exchange of bothin vitro. This dual specificity is unique to DOCK10 within its evolutionarily related D subfamily. Structural studies of DOCK10DHR2in complex with RAC revealed an intriguing 2:1 stoichiometry between DOCK10DHR2and the GTPase, that differs from the canonical 1:1 stoichiometry for all other known DOCK-GTPase complexes. This was confirmed in solution using a variety of biophysical techniques. The identification of a novel mode of interaction between DOCK10DHR2and the RAC GTPase provides new insights into how DOCK family GEFs discriminate between CDC42, RAC and RHOA.