bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of Differentially Expressed Genes and associated pathways common to Eyelid and Non-Ocular Basal Cell Carcinoma to understand the Molecular Biology of BCC
Authors: Vats Pranjal , Jayaraj Perumal , Sen Seema , Dahiya Shefali , Mohindroo Vanshika 
Published: May 2021

SummaryBackgroundEyelid BCC accounts for more than 90% of Eyelid malignant neoplasms. Various aberrant signalling pathways and genes in Non-Ocular BCC have been found whereas Eyelid bcc remains elusive.ObjectiveThis study aims to find the common DEGs of Eyelid and Non-Ocular BCC using bioinformatic analysis and text mining to gain more insights into the molecular aspects common to both BCC non-ocular and Eyelid BCC and to identify common potential prognostic markers.Material and methodThe Gene Expression profiles of Eyelid BCC (GSE103439) and Non-Ocular BCC (GSE53462) were obtained from the NCBI GEO database followed by identification of common DEGs. Protein-Protein interaction and Pathway Enrichment analysis of these screened genes was done using bioinformatic tools like STRING, Cytoscape and BiNGO, DAVID, KEGG respectively.ResultsA total of 181 genes were found common in both datasets. A PPI network was formed for the screened genes and 20 HUB genes were sorted which included CTNNB1, MAPK14, BTRC, EGFR, ADAM17. Pathway enrichment of HUB genes showed that they were dysregulated in carcinogenic and apoptotic pathways that seem to play a role in the progression of both the BCC.ConclusionThe result and findings of bioinformatic analysis highlighted the molecular pathways and genes enriched in both Eyelid BCC as well as Non-Ocular BCC. The identified pathways should be studied further to recognise common molecular events that would lead to the progression of BCC. This may provide a window to explore the prognostic and therapeutic strategies common to both BCC.
3D confinement regulates stem cell fate
Authors: Dudaryeva Oksana Y. , Bucciarelli Aurelia , Bovone Giovanni , Jaydev Shibashish , Broguiere Nicolas , al-Bayati Marwa , Lütolf Marco , Tibbitt Mark W. 
Published: May 2021

AbstractBiophysical properties of the cellular microenvironment, including stiffness and geometry, influence cell fate. Recent findings have implicated geometric confinement as an important regulator of cell fate determination. Our understanding of how mechanical signals direct cell fate is based primarily on two-dimensional (2D) studies. To investigate the role of confinement on stem cell fate in three-dimensional (3D) culture, we fabricated a single cell microwell culture platform and used it to investigate how niche volume and stiffness affect human mesenchymal stem cell (hMSC) fate. The viability and proliferation of hMSCs in confined 3D microniches were compared with the fate of unconfined cells in 2D culture. Physical confinement biased hMSC fate, and this influence was modulated by the niche volume and stiffness. The rate of cell death increased, and proliferation markedly decreased upon 3D confinement. We correlated the observed differences in hMSC fate to YES-associated protein (YAP) localization. In 3D microniches, hMSCs displayed primarily cytoplasmic YAP localization, indicating reduced mechanical activation upon confinement. These results demonstrate that 3D geometric confinement can be an important regulator of cell fate, and that confinement sensing is linked to canonical mechanotransduction pathways.
NOVA2 regulates neural circRNA biogenesis
Authors: Knupp David , Cooper Daphne A. , Saito Yuhki , Darnell Robert B. , Miura Pedro 
Published: May 2021

ABSTRACTCircular RNAs (circRNAs) are highly expressed in the brain and their expression increases during neuronal differentiation. The factors regulating circRNAs in the developing mouse brain are unknown. NOVA1 and NOVA2 are neural-enriched RNA-binding proteins with well-characterized roles in alternative splicing. Profiling of circRNAs from RNA-seq data revealed that global circRNA levels were reduced in embryonic cortex ofNova2but notNova1knockout mice. Analysis of isolated inhibitory and excitatory cortical neurons lacking NOVA2 revealed an even more dramatic reduction of circRNAs and establish a widespread role for NOVA2 in enhancing circRNA biogenesis. To investigate thecis-elements controlling NOVA2-regulation of circRNA biogenesis, we generated a backsplicing reporter based on theEfnb2gene. We found that NOVA2-mediated backsplicing of circ-Efnb2was impaired when YCAY clusters located in flanking introns were removed. CLIP and additional reporter analysis demonstrated the importance of NOVA2 binding sites located in both flanking introns of circRNA loci. NOVA2 is the first RNA-binding protein identified to globally promote circRNA biogenesis in the developing brain.
Pyk2 in dorsal hippocampus plays a selective role in spatial memory and synaptic plasticity
Authors: Mastrolia Vincenzo , Massadi Omar al , de Pins Benoit , Girault Jean-Antoine 
Published: May 2021

AbstractPyk2 is a Ca2+-activated non-receptor tyrosine kinase enriched in the forebrain, especially in pyramidal neurons of the hippocampus. Previous reports suggested its role in hippocampal synaptic plasticity and spatial memory but with contradictory findings possibly due to experimental conditions. Here we address this issue and show that novel object location, a simple test of spatial memory induced by a single training session, is altered in Pyk2 KO mice and that re-expression of Pyk2 in the dorsal hippocampus corrects this deficit. Bilateral targeted deletion of Pyk2 in dorsal hippocampus CA1 region also alters novel object location. Long term potentiation (LTP) in CA1 is impaired in Pyk2 KO mice using a high frequency stimulation induction protocol nut not with a theta burst protocol, explaining differences between previous reports. The same selective LTP alteration is observed in mice with Pyk2 deletion in dorsal hippocampus CA1 region. Thus, our results establish the role of Pyk2 in specific aspects of spatial memory and synaptic plasticity and show the dependence of the phenotype on the type of experiments used to reveal it. In combination with other studies they provide evidence for a selective role of non-receptor tyrosine kinases in specific aspects of hippocampal neurons synaptic plasticity.
Cytosolic aggregation of mitochondrial proteins disrupts cellular homeostasis by stimulating the aggregation of other proteins
Authors: Nowicka Urszula , Chroscicki Piotr , Stroobants Karen , Sladowska Maria , Turek Michal , Uszczynska-Ratajczak Barbara , Kundra Rishika , Goral Tomasz , Perni Michele , Dobson Christopher M. , Vendruscolo Michele , Chacinska Agnieszka 
Published: May 2021

AbstractMitochondria are organelles with their own genomes, but they rely on the import of nuclear-encoded proteins that are translated by cytosolic ribosomes. Therefore, it is important to understand whether failures in the mitochondrial uptake of these nuclear-encoded proteins can cause proteotoxic stress and identify response mechanisms that may counteract it. Here, we report that upon impairments in mitochondrial protein import, high-risk precursor and immature forms of mitochondrial proteins form aberrant deposits in the cytosol. These deposits then cause further cytosolic accumulation and consequently aggregation of other mitochondrial proteins and disease-related proteins, including α-synuclein and amyloid β. This aggregation triggers a cytosolic protein homeostasis imbalance that is accompanied by specific molecular chaperone responses at both the transcriptomic and protein levels. Altogether, our results provide evidence that mitochondrial dysfunction, specifically protein import defects, contributes to impairments in protein homeostasis, thus revealing a possible molecular mechanism by which mitochondria are involved in neurodegenerative diseases.
Negative Urgency as a Risk Factor for Hazardous Alcohol Use: Dual Influences of Cognitive Control and Reinforcement Processing
Authors: Rawls Eric , Wolkowicz Noah R. , Ham Lindsay S. , Lamm Connie 
Published: May 2021

AbstractNegative Urgency (NU) is a prominent risk factor for hazardous alcohol use. While research has helped elucidate how NU relates to neurobiological functioning with respect to alcohol use, no known work has contextualized such functioning within existing neurobiological theories in addiction. Therefore, we elucidated mechanisms contributing to the NU–hazardous alcohol use relationship by combining NU theories with neurobiological dual models of addiction, which posit addiction is related to cognitive control and reinforcement processing. Fifty-five undergraduates self-reported NU and hazardous alcohol use. We recorded EEG while participants performed a reinforced flanker task. We measured cognitive control using N2 activation time-locked to the incongruent flanker stimulus, and we measured reinforcement processing using the feedback-related negativity (FRN) time-locked to better-than-expected negative reinforcement feedback. We modeled hazardous drinking using hierarchical regression, with NU, N2, and FRN plus their interactions as predictors. The regression model significantly predicted hazardous alcohol use, and the three-way interaction (NU×N2×FRN) significantly improved model fit. In the context of inefficient processing (i.e., larger N2s and FRNs), NU demonstrated a strong relationship with hazardous alcohol use. In the context of efficient processing (i.e., smaller N2s and FRNs), NU was unrelated to hazardous alcohol use. This analysis provides preliminary evidence that brain mechanisms of cognitive control and reinforcement processing influence the relationship between NU and hazardous alcohol use, and confirms a specific influence of negative reinforcement processing. Future clinical research could leverage these neurobiological moderators for substance misuse treatment.
Dorsal premammillary projection to periaqueductal gray controls escape vigor from innate and conditioned threats
Authors: Wang Weisheng , Schuette Peter J. , La-Vu Mimi Q. , Tobias Brooke Christine , Čeko Marta , Kragel Philip A. , Reis Fernando Midea Cuccovia V. , Ji Shiyu , Sehgal Megha , Maesta-Pereira Sandra , Chakerian Meghmik , Silva Alcino J , Canteras Newton S. , Wager Tor D. , Kao Jonathan C. , Adhikari Avishek 
Published: May 2021

AbstractEscape from threats has paramount importance for survival. However, it is unknown if a single circuit controls escape from innate and conditioned threats. The hypothalamic dorsal premammillary nucleus (PMd) may control escape, as it is activated by escape-inducing threats and projects to the region most implicated in flight, the dorsolateral periaqueductal gray (dlPAG). We show that in mice cholecystokinin (cck)-expressing PMd cells are activated during escape, but not other defensive behaviors. PMd-cck ensemble activity can also predict future escape. Furthermore, PMd inhibition decreases escape speed from both innate and conditioned threats. Inhibition of the PMd-cck projection to the dlPAG also decreased escape speed. Lastly, human fMRI data show that a posterior hypothalamic-to-dlPAG pathway increased activity during exposure to aversive images, indicating that a similar pathway may possibly have a related role in humans. Our data identify the PMd as a central node of the escape network.
METTL8 is required for 3-methylcytosine modification in human mitochondrial tRNAs
Authors: Lentini Jenna M. , Bargabos Rachel , Chen Chen , Fu Dragony 
Published: May 2021

AbstractA subset of eukaryotic tRNAs is methylated in the anticodon loop to form the 3-methylcytosine (m3C) modification. In mammals, the number of tRNAs containing m3C has expanded to include mitochondrial (mt) tRNA-Ser-UGA and mt-tRNA-Thr-UGU. Whereas the enzymes catalyzing m3C formation in nuclear-encoded cytoplasmic tRNAs have been identified, the proteins responsible for m3C modification in mt-tRNAs are unknown. Here, we show that m3C formation in human mt-tRNAs is dependent upon the Methyltransferase-Like 8 (METTL8) enzyme. We find that METTL8 is a mitochondria-associated protein that interacts with mitochondrial seryl-tRNA synthetase along with mt-tRNAs containing m3C. Human cells deficient in METTL8 exhibit loss of m3C modification in mt-tRNAs but not nuclear-encoded tRNAs. Consistent with the mitochondrial import of METTL8, the formation of m3C in METTL8-deficient cells can be rescued by re-expression of wildtype METTL8 but not by a METTL8 variant lacking the N-terminal mitochondrial localization signal. Notably, METTL8-deficiency in human cells causes alterations in the native migration pattern of mt-tRNA-Ser-UGA suggesting a role for m3C in tRNA folding. Altogether, these findings demonstrate that METTL8 is required for m3C formation in mitochondrial tRNAs and uncover a potential role for m3C modification in mitochondrial tRNA structure.
Myosins generate contractile force and maintain organization in the cytokinetic contractile ring
Authors: McDargh Zachary , Wang Shuyuan , Chin Harvey F. , Thiyagarajan Sathish , Karatekin Erdem , Pollard Thomas D. , O’Shaughnessy Ben 
Published: May 2021

AbstractDuring cytokinesis cells assemble an actomyosin contractile ring whose tension constricts and divides cells, but the ring tension was rarely measured. Actomyosin force generation is well understood for the regular sarcomeric architecture of striated muscle, but recent super-resolution studies of fission yeast contractile rings revealed organizational building blocks that are not sarcomeres but irregularly positioned plasma membrane-anchored protein complexes called nodes. Here we measured contractile ring tensions in fission yeast protoplast cells. The myosin II isoforms Myo2 and Myp2 generated the tension, with a ~2-fold greater contribution from Myo2. Simulations of a molecularly detailed ring model revealed a sliding node mechanism for tension, where nodes hosting tense actin filaments were pulled bidirectionally around the ring. Myo2 and Myp2 chaperoned self-assembling components into the ring organization, and anchored the ring against bridging instabilities. Thus, beyond force production, Myo2 and Myp2 are the principal organizers, bundlers and anchors of the contractile ring.
Basal forebrain cholinergic neurons are part of the threat memory engram
Authors: Rajebhosale Prithviraj , Ananth Mala , Crouse Richard , Jiang Li , Hernández Gretchen López- , Arty Christian , Wang Shaohua , Jone Alice , Zhong Chongbo , Desai Niraj S. , Li Yulong , Picciotto Marina R. , Role Lorna W. , Talmage David A. 
Published: May 2021

SummaryAlthough the engagement of cholinergic signaling in threat memory is well established (Knox, 2016a), our finding that specific cholinergic neurons are requisite partners in a threat memory engram is likely to surprise many. Neurons of the basal forebrain nucleus basalis and substantia innominata (NBM/SIp) comprise the major source of cholinergic input to the basolateral amygdala (BLA), whose activation are required for both the acquisition and retrieval of cued threat memory and innate threat response behavior. The retrieval of threat memory by the presentation of the conditioning tone alone elicits acetylcholine (ACh) release in the BLA and the BLA-projecting cholinergic neurons manifest immediate early gene responses and display increased intrinsic excitability for 2-5 hours following the cue-elicited memory response to the conditioned stimulus. Silencing cue-associated engram-enrolled cholinergic neurons prevents the expression of the defensive response and the subset of cholinergic neurons activated by cue is distinct from those engaged by innate threat. Taken together we find that distinct populations of cholinergic neurons are recruited to signal distinct aversive stimuli via the BLA, demonstrating exquisite, functionally refined organization of specific types of memory within the cholinergic basal forebrain.
Hypermethylation and small RNA expression are associated with increased age in almond (Prunus dulcis[Mill.] D.A. Webb) accessions
Authors: D’Amico-Willman Katherine M. , Niederhuth Chad E. , Sovic Michael , Anderson Elizabeth S. , Gradziel Thomas M. , Fresnedo Ramírez Jonathan 
Published: May 2021

SummaryThe focus of this study is to profile changes in DNA methylation and small RNA expression occurring with increased age in almond breeding germplasm to identify possible biomarkers of age that can be used to assess the potential of individuals to develop aging-related disorders.To profile DNA methylation in almond germplasm, 70 methylomes were generated from almond individuals representing three age cohorts (11, 7, and 2 years old) using an enzymatic methyl-seq approach followed by analysis to call differentially methylated regions (DMRs) within these cohorts. Small RNA (sRNA) expression was profiled in three breeding selections, each from two age cohorts (1 and 6 years old) using sRNA-Seq followed by differential expression analysis.Weighted chromosome-level methylation analysis reveals hypermethylation in 11-year old almond breeding selections when compared to 2-year-old selections in the CG and CHH contexts. Seventeen consensus DMRs were identified in all age contrasts. sRNA expression differed significantly between the two age cohorts tested, with significantly decreased expression in sRNAs in the 6-year-old selections compared to the 1-year-old.Almond shows a pattern of hypermethylation and decreased sRNA expression with increased age. Identified DMRs and differentially expressed sRNAs could function as putative biomarkers of age following validation in additional age groups.
Evidence for the equilibrium between monomers and dimers of the death domain of the p75 neurotrophin receptor
Authors: Li Zhen , Lin Zhi , Ibáñez Carlos F. 
Published: May 2021

AbstractThe p75 neurotrophin receptor (p75NTR) is an important mediator of synaptic depression and neuronal cell death, and its expression increases upon nerve injury and in neurodegenerative diseases. However, the molecular mechanisms leading to the activation of this receptor are still a matter of debate. The oligomerization properties of the death domain (DD) of p75NTRare critical for our understanding of the activation mechanisms of the receptor. In this paper, we present additional evidence supporting the existence of an equilibrium between monomeric and dimeric forms of the p75NTRDD in solution and in the absence of any other protein. Dynamic light scattering (DLS) measurements of native, untagged human p75NTRDD at room temperature yielded Rh=2.11 for this domain in 20mM phosphate buffer, corresponding to a molecular weight (MW) of approximately 19kDa, much closer to the theoretical MW of the homodimer (i.e. 21kDa) than the monomer. MWs deduced from the Rh of different control proteins used as standards were all congruent with their theoretical MWs. In addition, size-exclusion FPLC profiles of un-tagged human p75NTRDD in both HEPES and phosphate buffers revealed elution volumes corresponding to a MW of about 15kDa, which is intermediate between monomer and dimer, and indicative of dynamic monomer/dimer interconversion during the run. Together with our previous NMR studies, as well as biophysical data for other investigators, these results support the notion that the DD of p75NTRexists in equilibrium between monomers and dimers in solution, a notion that is in agreement with the oligomerization properties of all members of the DD superfamily.
Preventing disproportionate mortality in ICU overload situations: Empirical evidence from the first COVID-19 wave in Europe
Authors: Buijs Paul , Catena Rodolfo , Holweg Matthias , van der Vaart Taco 
Published: May 2021

AbstractAvoiding overloading the healthcare system remains a central issue during the COVID-19 pandemic. The logic of preventing such overload situations is intuitive since the level and quality of critical care is a function of the available capacity to provide it. Where this capacity is no longer available due to a surge in admissions, patient outcomes will invariably deteriorate in the long run – ultimately leading to disproportionate mortality. In this paper, we study the three worst affected regions in Italy, the Netherlands, and Germany during the first COVID-19 wave in the spring of 2020. We report on quantitative analyses that show how mortality rises non-linearly as the proportion of COVID-19 patients in the ICU increases. We identify changes to the patient-staff ratio, increasing exhaustion and infection levels amongst staff, as well as equipment shortages, as likely causes driving this rise in mortality. We explore these findings further with interviews of key stakeholders in the respective healthcare systems. Our results demonstrate that the common approach of managing COVID-19 surges by stretching ICU capacity in hotspot regions may be detrimental to patient outcomes. Instead, we posit that transferring patients proactively out of developing hotspots to less affected regions, well before high ICU workload situations emerge, will improve overall patient outcomes.
Use of Induced Pluripotent Stem Cells to Build Isogenic Systems and Investigate Type 1 Diabetes
Authors: Armitage Lucas H. , Stimpson Scott E. , Santostefano Katherine E. , Sui Lina , Ogundare Similoluwa O. , Newby Brittney N. , Castro-Gutierrez Roberto , Huber Mollie K. , Taylor Jared P. , Sharma Prerana , Radichev Ilian , Perry Daniel J. , Fredette Natalie C. , Savinov Alexei , Wallet Mark A. , Terada Naohiro , Brusko Todd M. , Russ Holger A. , Chen Jing , Egli Dieter , Mathews Clayton. E 
Published: May 2021

AbstractType 1 diabetes is a disease that arises due to complex immunogenetic mechanisms. Key cell-cell interactions involved in the pathogenesis of T1D are activation of autoreactive T cells by dendritic cells (DC), migration of T cells across endothelial cells (EC) lining capillary walls into the islets of Langerhans, interaction of T cells with macrophages in the islets, and killing of β-cells by autoreactive CD8+T cells. Overall, pathogenic cell-cell interactions are likely regulated by the individual’s collection of genetic T1D-risk variants. To accurately model the role of genetics, it is essential to build systems to interrogate single candidate genes in isolation during the interactions of cells that are essential for disease development. However, obtaining single-donor matched cells relevant to T1D is a challenge. Sourcing these genetic variants from human induced pluripotent stem cells (iPSC) avoids this limitation. Herein, we have differentiated iPSC from one donor into DC, macrophages, EC, and β-cells. Additionally, we also engineered T cell avatars from the same donor to provide anin vitroplatform to study genetic influences on these critical cellular interactions. This proof of concept demonstrates the ability to derive an isogenic system from a single donor to study these relevant cell-cell interactions. Our system constitutes an interdisciplinary approach with a controlled environment that provides a proof-of-concept for future studies to determine the role of disease alleles (e.g.IFIH1, PTPN22, SH2B3, TYK2)in regulating cell-cell interactions and cell-specific contributions to the pathogenesis of T1D.