bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gene expression profiling of lymph node sub-capsular sinus macrophages in cancer
Authors: Pellin Danilo , Claudio Natalie , Pucci Ferdinando 
Published: January 2021

AbstractLymph nodes are key lymphoid organs collecting lymph fluid and migratory cells from the tissue area they survey. When cancerous cells arise within a tissue, the sentinel lymph node is the first immunological organ to mount an immune response. Sub-capsular sinus macrophages (SSMs) are specialized macrophages residing in the lymph nodes that play important roles as gatekeepers against particulate antigenic material. In the context of cancer, SSMs capture tumor-derived extracellular vesicles (tEVs), a form of particulate antigen released in high amounts by tumor cells. We have recently demonstrated that SSMs possess anti-tumor activity because in their absence tumors grow faster. A comprehensive profiling of SSMs represents an important first step to identify the cellular and molecular mechanisms responsible for SSM anti-tumor activity. Unfortunately, the isolation of SSMs for molecular analyses is very challenging. Here, we combined an optimized dissociation protocol, careful marker selection and stringent gating strategies to highly purify SSMs. We provide evidence of decreased T and B cell contamination, which allowed us to reveal the gene expression profile of this elusive macrophage subset. Squamous cell carcinomas induced an increase in the expression of Fc receptors, lysosomal and proteasomal enzymes in SSMs. These results suggest that SSMs may be able to capture immune complexes for antigen processing and presentation to B and T cells on both MHC class I and II.
A convergent structure-function substrate of cognitive imbalances in autism
Authors: Hong Seok-Jun , Mottron Laurent , Park Bo-yong , Benkarim Oualid , Valk Sofie L. , Paquola Casey , Larivière Sara , Vos de Wael Reinder , Degré-Pelletier Janie , Soulieres Isabelle , Ramphal Bruce , Margolis Amy , Milham Michael , Di Martino Adriana , Bernhardt Boris C. 
Published: January 2021

AbstractAutism is a common neurodevelopmental condition characterized by substantial phenotypic heterogeneity, which hinders diagnosis, research, and intervention. A leading example can be found in marked imbalances in language and perceptual skills, where deficits in one domain often co-exist with normal or even superior performance in the other domain. The current work capitalized on multiple data analytics including data-driven subtyping and dimensional approaches to quantify cognitive imbalances in multi-site datasets of individuals diagnosed with autism spectrum disorder (ASD) and neurotypical controls, and assessed structural and functional brain network substrates. Studying cognitive dimensions as well as multimodal neuroimaging signatures in 155 ASD and 151 neurotypical individuals, we observed robust evidence for a structure-function substrate of cognitive imbalances in ASD. Specifically, ASD presented with marked imbalances in cognitive profiles relative to neurotypical controls, characterized by verbal to non-verbal intelligence discrepancy. Different analytical approaches including subtyping and dimensional regression methods converged in showing that these imbalances were reflected in atypical cortical thickening and functional integration of language networks, alongside with sensory and higher cognitive networks. Phenotypic findings could be replicated in an independent sample of 325 ASD and 569 neurotypical controls. Although verbal and non-verbal intelligence are currently considered as specifiers unrelated to the categorical diagnosis of autism, our results show that intelligence disparities are accentuated in ASD and relate to a consistent structure-function substrate affecting multiple brain networks. Our findings motivate the incorporation of cognitive imbalances in future autism research, which may help to parse the phenotypic heterogeneity of autism and potentially inform intervention-oriented subtyping.
Improving integrative 3D modeling into low- to medium- resolution EM structures with evolutionary couplings
Authors: McCafferty Caitlyn L. , Taylor David W. , Marcotte Edward M. 
Published: January 2021

AbstractElectron microscopy (EM) continues to provide near-atomic resolution structures for well-behaved proteins and protein complexes. Unfortunately, structures of some complexes are limited to low- to medium-resolution due to biochemical or conformational heterogeneity. Thus, the application of unbiased systematic methods for fitting individual structures into EM maps is important. A method that employs co-evolutionary information obtained solely from sequence data could prove invaluable for quick, confident localization of subunits within these structures. Here, we incorporate the co-evolution of intermolecular amino acids as a new type of distance restraint in the Integrative Modeling Platform (IMP) in order to build three-dimensional models of atomic structures into EM maps ranging from 10-14 Å in resolution. We validate this method using four complexes of known structure, where we highlight the conservation of intermolecular couplings despite dynamic conformational changes using the BAM complex. Finally, we use this method to assemble the subunits of the bacterial holo-translocon into a model that agrees with previous biochemical data. The use of evolutionary couplings in integrative modeling improves systematic, unbiased fitting of atomic models into medium- to low-resolution EM maps, providing additional information to integrative models lacking in spatial data.
Exonic Disruption Facilitates Antiviral CRISPR-Cas9 Activity for Multistrain HIV-1 Elimination
Authors: Herskovitz Jonathan , Hasan Mahmudul , Patel Milankumar , Blomberg Wilson R. , Cohen Jacob D. , Machhi Jatin , Stein Daniel , Schroder Evan A. , McMillan JoEllyn , Gurumurthy Channabasavaiah B. , Kevadiya Bhavesh D. , Gendelman Howard E. 
Published: January 2021

AbstractA barrier to HIV-1 cure rests in the persistence of proviral DNA in infected CD4+ leukocytes. The high mutation rate of HIV-1 gives rise to numerous circulating strains with increased capacity for immune evasion and antiretroviral drug resistance. To facilitate viral elimination while accounting for this diversity, we propose genetic inactivation of proviral DNA with CRISPR-spCas9. We designed a library of “mosaic gRNAs” against a HIV-1 consensus sequence constructed from 4004 clinical strains, targeting the viral transcriptional regulator tat. Testing in 7 HIV-1 transmitted founder strains led, on average, to viral reductions of 82% with tandem TatD and TatE (TatDE) treatment. No off-target cleavages were recorded. Lentiviral transduction of TatDE attenuated latency reversal by 94% in HIV-infected, transcriptionally silent ACH2 T cells. In all, TatDE guide RNAs successfully disrupted 5 separate HIV-1 exons (tat1-2/rev1-2/gp41) providing a pathway for CRISPR-directed HIV-1 cure therapies.Significance StatementOver 38 million individuals worldwide are infected with HIV-1, which necessitates lifelong dependence on antiretroviral therapy (ART) to prevent viral replication that leads to AIDS. Efforts to rid hosts of HIV-1 are limited by the virus’ abilities to integrate proviral DNA in nuclei, mutate their genomes, and lay dormant for decades during ART treatment. We developed mosaic guide RNAs, TatD and TatE, for CRISPR-Cas9 that recognize the majority of known HIV-1 strains and inactivate 94% of proviral DNA in latently infected cells. Tandem TatDE-CRISPR inactivation of 5 viral exons (tat1-2,rev1-2, andgp41), which blocked HIV-1 replication for 28 days in CD4+ T cells without unwanted editing to the host genome, may serve as a viable strategy for HIV cure.
Crosstalk between H2A variant-specific modifications impacts vital cell functions
Authors: Schmücker Anna , Lei Bingkun , Lorković Zdravko J. , Capella Matías , Braun Sigurd , Bourguet Pierre , Mathieu Olivier , Mechtler Karl , Berger Frédéric 
Published: January 2021

AbstractHistone variants are distinguished by specific substitutions and motifs that might be subject to post-translational modifications (PTMs). Compared with the high conservation of H3 variants, the N- and C-terminal tails of H2A variants are more divergent and are potential substrates for a more complex array of PTMs, which have remained largely unexplored. We used mass spectrometry to inventory the PTMs of the two heterochromatin-enriched variants H2A.W.6 and H2A.W.7 ofArabidopsis, which harbor the C-terminal motif KSPK. This motif is also found in macroH2A variants in animals and confers specific properties to the nucleosome. We showed that H2A.W.6 is phosphorylated by the cell cycle-dependent kinase CDKA specifically at KSPK. In contrast, this modification is absent on H2A.W.7, which also harbors the SQ motif associated with the variant H2A.X. Phosphorylation of the SQ motif is critical for the DNA damage response but is suppressed in H2A.W.7 by phosphorylation of KSPK. To identify factors involved in this suppression mechanism, we performed a synthetic screen in fission yeast expressing a mimic of theArabidopsisH2A.W.7. Among those factors was the BRCT-domain protein Mdb1. We showed that phosphorylation of KSPK prevents binding of the BRCT-domain protein Mdb1 to phosphorylated SQ and as a result hampers response to DNA damage. Hence, cross-talks between motif-specific PTMs interfere with the vital functions of H2A variants. Such interference could be responsible for the mutual exclusion of specific motifs between distinct H2A variants. We conclude that sequence innovations in H2A variants have potentiated the acquisition of many specific PTMs with still unknown functions. These add a layer of complexity to the nucleosome properties and their impact in chromatin regulation.
The Amot/Integrin protein complex transmits mechanical forces required for vascular expansion
Authors: Zhang Yuanyuan , Zhang Yumeng , Kameishi Sumako , Barutello Giuseppina , Zheng Yujuan , Tobin Nicholas P. , Nicosia John , Hennig Katharina , Chiu David Kung-Chun , Balland Martial , Barker Thomas H. , Cavallo Federica , Holmgren Lars 
Published: January 2021

SummaryVascular development is a complex multistep process involving the coordination of cellular functions such as migration, proliferation and differentiation. Understanding the underlying mechanisms of these processes is of importance due to involvement of vessel expansion in various pathologies. How mechanical forces generated by cells and transmission of these physical forces control vascular development is poorly understood. Using an endothelial-specific genetic model in mice, we show that deletion of the scaffold protein, Angiomotin (Amot), inhibits migration and expansion of physical and pathological vascular network. We further show that Amot is required for tip cell migration and the extension of cellular filopodia. Exploitingin vivoandin vitromolecular approaches, we show that Amot binds talin and is essential for relaying forces between fibronectin and the cytoskeleton. Finally, we provide evidence that Amot is a novel component of the endothelial integrin adhesome and propose that Amot integrates spatial cues from the extra-cellular matrix in order to form a functional vascular network.
Adiponectin Preserves Metabolic Fitness During Aging
Authors: Li Na , Zhang Zhuzhen , Zhao Shangang , Zhu Yi , Gliniak Christy M. , Vishvanath Lavanya , An Yu A. , Wang May-yun , Deng Yingfeng , Zhu Qingzhang , Onodera Toshiharu , Oz Orhan K , Gordillo Ruth , Gupta Rana K. , Liu Ming , Horvath Tamas L. , Dixit Vishwa Deep , Scherer Philipp E. 
Published: January 2021

AbstractAdiponectin is essential for the regulation of tissue substrate utilization and systemic insulin sensitivity. Clinical studies have suggested a positive association of circulating adiponectin with healthspan and lifespan. However, the direct effects of adiponectin on promoting healthspan and lifespan remain unexplored. Here, we are using an adiponectin null mouse and a transgenic adiponectin overexpression model. We directly assessed the effects of circulating adiponectin on the aging process and found that adiponectin null mice display exacerbated age-related glucose and lipid metabolism disorders. Moreover, adiponectin null mice have a significantly shortened lifespan on both chow and high-fat diet (HFD). In contrast, a transgenic mouse model with elevated circulating adiponectin levels has a dramatically improved systemic insulin sensitivity, reduced age-related tissue inflammation and fibrosis, and a prolonged healthspan and median lifespan. These results support a role of adiponectin as an essential regulator for healthspan and lifespan.
Parallel evolution between genomic segments of seasonal human influenza viruses reveals RNA-RNA relationships
Authors: Jones Jennifer E. , Sage Valerie Le , Padovani Gabriella H. , Calderon Michael , Wright Erik S. , Lakdawala Seema S. 
Published: January 2021

AbstractThe influenza A virus (IAV) genome consists of eight negative-sense viral RNA (vRNA) segments that are selectively assembled into progeny virus particles through RNA-RNA interactions. To identify relationships between vRNA segments, we examined parallel evolution between vRNA segments of seasonal human IAV, finding that evolutionary relationships between vRNA segments differ between subtypes and antigenically-shifted strains. Intersegmental relationships were distinct between H3N2 and H1N1 viruses, but largely conserved over time in H3N2 viruses. However, parallel evolution of vRNA segments diverged between H1N1 strains isolated before and after the 2009 pandemic. Surprisingly, intersegmental relationships were not driven solely by protein sequence, which is potentially indicative of RNA-RNA driven coevolution. Colocalization of highly coevolved vRNA segments was enriched over other pairs at the nuclear periphery during a productive viral infection. This study illustrates how phylogenetics can be applied to interrogate putative RNA interactions underlying selective assembly of IAV.
Enhanced preference for delayed rewards requires the basolateral amygdala and retrosplenial cortex
Authors: Lefner Merridee J. , Magnon Alexa P. , Gutierrez James M. , Lopez Matthew R. , Wanat Matthew J. 
Published: January 2021

Abstract‘Sunk’ or irrecoverable costs imposed on a subject can impact reward-based decisions. However, it is not known if these incurred costs elicit a sustained change in reward value. To address this, we examined if sunk temporal costs subsequently alter reward consumption and reward preference in rats. We first identified the relative preference between different flavored food pellets during a free-feeding consumption test. Animals were then trained to experience the initial less preferred reward after long delays and the initial preferred reward after short delays. This training regimen enhanced the consumption and preference for the initial less desirable food reward. We probed whether this change in reward preference involved neural systems that contribute to reward valuation. Pharmacological manipulations and site-specific lesions were performed to examine the potential involvement of the dopamine system, the orbitofrontal cortex (OFC), the basolateral amygdala (BLA), and the retrosplenial cortex (RSC). The change in reward preference was unaffected by systemic dopamine receptor antagonism or OFC lesions. In contrast, lesions of the BLA or the RSC prevented the enhanced consumption and preference for the initial less desirable reward. These findings demonstrate that both the BLA and RSC participate in how sunk temporal costs alter reward value and reward preference.Significance StatementFrom an economic standpoint, only future costs should factor into one’s decisions. However, behavioral evidence across species illustrates thatpastcosts can alter decisions. The goal of this study was to identify the neural systems responsible for past costs influencing subsequent actions. We demonstrate that delivering an initially less desirable reward after long delays (high temporal costs) subsequently increases the consumption and preference for that reward. Furthermore, we identified the basolateral amygdala and the retrosplenial cortex as essential nuclei for mediating change in reward preference elicited by past temporal costs.
20-hydroxyecdysone (20E) signaling regulates amnioserosa morphogenesis duringDrosophiladorsal closure: Ecdysone receptor modulates gene expression in a complex with the AP-1 component, Jun
Authors: Yoo Byoungjoo , Kim Hae-yoon , Chen Xi , Shen Weiping , Jang Ji Sun , Cormier Olga , Krieger Charles , Reed Bruce , Harden Nicholas , Wang Simon Ji Hau 
Published: January 2021

ABSTRACTSteroid hormones influence diverse biological processes throughout the animal life cycle, including metabolism, stress resistance, reproduction, and lifespan. In insects, the steroid hormone, 20-hydroxyecdysone (20E), is the central regulator of molting and metamorphosis, and has been shown to play roles in tissue morphogenesis. For example, amnioserosa contraction, which is a major driving force inDrosophiladorsal closure (DC), is defective in embryos mutant for 20E biosynthesis. Here, we show that 20E signaling modulates the transcription of several DC participants in the amnioserosa and other dorsal tissues during late embryonic development, including thezipperlocus, which encodes for non-muscle myosin II heavy chain. Canonical 20E signaling typically involves the binding of Ecdysone receptor (EcR) and Ultraspiracle heterodimers to ecdysone-response elements (EcREs) within the promoters of ecdysone-responsive genes to drive their expression. During DC, we provide evidence that 20E signaling instead acts in parallel to the JNK cascade via a direct interaction between EcR and the AP-1 component, Jun, which together binds to genomic regions containing AP-1 binding sites but no EcREs to control gene expression. Our work demonstrates a novel mode of action for 20E signaling inDrosophilathat likely functions beyond DC, and may provide further insights into mammalian steroid hormone receptor interactions with AP-1.
A global overview of genetically interpretable comorbidities among common diseases in UK Biobank
Authors: Dong Guiying , Feng Jianfeng , Sun Fengzhu , Chen Jingqi , Zhao Xing-Ming 
Published: January 2021

AbstractBackgroundComorbidities greatly increase global health burdens, but the landscapes of their genetic factors have not been systematically investigated.MethodsWe used the hospital inpatient data of 385,335 patients in UK Biobank to investigate the comorbid relations among 439 common diseases. Post-GWAS analyses were performed to identify comorbidity shared genetic risks at the genomic loci, network, as well as overall genetic architecture levels. We conducted network decomposition for interpretable comorbidity networks to detect the hub diseases and the involved molecules in comorbidity modules.Results11,285 comorbidities among 439 common diseases were identified, and 46% of them were genetically interpretable at the loci, network, or overall genetic architecture level. The comorbidities affecting the same and different physiological systems showed different patterns at the shared genetic components, with the former more likely to share loci-level genetic components while the latter more likely to share network-level genetic components. Moreover, both the loci- and network-level genetic components shared by comorbidities mainly converged on cell immunity, protein metabolism, and gene silencing. Furthermore, we found that the genetically interpretable comorbidities tend to form network modules, mediated by hub diseases and featuring physiological categories. Finally, we showcased how hub diseases mediating the comorbidity modules could help provide useful insights into the genetic contributors for comorbiditities.ConclusionsOur results provide a systematic resource for understanding the genetic predispositions of comorbidity, and indicate that hub diseases and converged molecules and functions may be the key for treating comorbidity. We have created an online database to facilitate researchers and physicians to browse, search or download these comorbidities (https://comorbidity.comp-sysbio.org).
SARS-CoV-2 reinfection in a cohort of 43,000 antibody-positive individuals followed for up to 35 weeks
Authors: Abu-Raddad Laith J. , Chemaitelly Hiam , Coyle Peter , Malek Joel A. , Ahmed Ayeda A. , Mohamoud Yasmin A. , Younuskunju Shameem , Ayoub Houssein H. , Kanaani Zaina Al , Kuwari Einas Al , Butt Adeel A. , Jeremijenko Andrew , Kaleeckal Anvar Hassan , Latif Ali Nizar , Shaik Riyazuddin Mohammad , Rahim Hanan F. Abdul , Nasrallah Gheyath K. , Yassine Hadi M. , Al Kuwari Mohamed G. , Romaihi Hamad Eid Al , Al-Thani Mohamed H. , Khal Abdullatif Al , Bertollini Roberto 
Published: January 2021

ABSTRACTBackgroundReinfection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been documented, raising public health concerns. Risk and incidence rate of SARS-CoV-2 reinfection were assessed in a large cohort of antibody-positive persons in Qatar.MethodsAll SARS-CoV-2 antibody-positive persons with a PCR-positive swab ≥14 days after the first-positive antibody test were individually investigated for evidence of reinfection. Viral genome sequencing was conducted for paired viral specimens to confirm reinfection. Incidence of reinfection was compared to incidence of infection in the complement cohort of those antibody-negative.ResultsAmong 43,044 anti-SARS-CoV-2 positive persons who were followed for a median of 16.3 weeks (range: 0-34.6), 314 individuals (0.7%) had at least one PCR positive swab ≥14 days after the first-positive antibody test. Of these individuals, 129 (41.1%) had supporting epidemiological evidence for reinfection. Reinfection was next investigated using viral genome sequencing. Applying the viral-genome-sequencing confirmation rate, the risk of reinfection was estimated at 0.10% (95% CI: 0.08-0.11%). The incidence rate of reinfection was estimated at 0.66 per 10,000 person-weeks (95% CI: 0.56-0.78). Incidence rate of reinfection versus month of follow-up did not show any evidence of waning of immunity for over seven months of follow-up. Meanwhile, in the complement cohort of 149,923 antibody-negative persons followed for a median of 17.0 weeks (range: 0-45.6), risk of infection was estimated at 2.15% (95% CI: 2.08-2.22%) and incidence rate of infection was estimated at 13.69 per 10,000 person-weeks (95% CI: 13.22-14.14). Efficacy of natural infection against reinfection was estimated at 95.2% (95% CI: 94.1-96.0%). Reinfections were less severe than primary infections. Only one reinfection was severe, two were moderate, and none were critical or fatal. Most reinfections (66.7%) were diagnosed incidentally through random or routine testing, or through contact tracing.ConclusionsReinfection is rare. Natural infection appears to elicit strong protection against reinfection with an efficacy ∼95% for at least seven months.