bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small molecule splicing modifiers with systemic HTT-lowering activity
Authors: Bhattacharyya Anuradha , Trotta Christopher R. , Narasimhan Jana , Wiedinger Kari J. , Li Wencheng , Effenberger Kerstin A. , Woll Matthew G. , Jani Minakshi B. , Risher Nicole , Yeh Shirley , Cheng Yaofeng , Sydorenko Nadiya , Moon Young-Choon , Karp Gary M. , Weetall Marla , Dakka Amal , Gabbeta Vijayalakshmi , Naryshkin Nikolai A. , Graci Jason D. , Tripodi Thomas , Southwell Amber , Hayden Michael , Colacino Joseph M. , Peltz Stuart W. 
Published: December 2021

AbstractHuntington’s disease (HD) is a hereditary neurodegenerative disorder caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin (HTT) gene. Consequently, the mutant protein is ubiquitously expressed and drives pathogenesis of HD through a toxic gain-of-function mechanism. Animal models of HD have demonstrated that reducing huntingtin (HTT) protein levels alleviates motor and neuropathological abnormalities. Investigational drugs aim to reduce HTT levels by repressingHTTtranscription, stability or translation. These drugs require invasive procedures to reach the central nervous system (CNS) and do not achieve broad CNS distribution. Here, we describe the identification of orally bioavailable small molecules with broad distribution throughout the CNS, which lowerHTTexpression consistently throughout the CNS and periphery through selective modulation of pre-messenger RNA splicing. These compounds act by promoting the inclusion of a pseudoexon containing a premature termination codon (stop-codon psiExon), leading toHTTmRNA degradation and reduction of HTT levels.
Single-cell transcriptomics captures features of human midbrain development and dopamine neuron diversity in brain organoids
Authors: Fiorenzano Alessandro , Sozzi Edoardo , Birtele Marcella , Kajtez Janko , Giacomoni Jessica , Nilsson Fredrik , Bruzelius Andreas , Sharma Yogita , Zhang Yu , Mattsson Bengt , Emnéus Jenny , Ottosson Daniella Rylander , Storm Petter , Parmar Malin 
Published: December 2021

AbstractThree-dimensional brain organoids have emerged as a valuable model system for studies of human brain development and pathology. Here we establish a midbrain organoid culture system to study the developmental trajectory from pluripotent stem cells to mature dopamine neurons. Using single cell RNA sequencing, we identify the presence of three molecularly distinct subtypes of human dopamine neurons with high similarity to those in developing and adult human midbrain. However, despite significant advancements in the field, the use of brain organoids can be limited by issues of reproducibility and incomplete maturation which was also observed in this study. We therefore designed bioengineered ventral midbrain organoids supported by recombinant spider-silk microfibers functionalized with full-length human laminin. We show that silk organoids reproduce key molecular aspects of dopamine neurogenesis and reduce inter-organoid variability in terms of cell type composition and dopamine neuron formation.
Epithelial phenotype restoring drugs suppress macular degeneration phenotypes in an iPSC model
Authors: Sharma Ruchi , George Aman , Nimmagadda Malika , Ortolan Davide , Karla Barbosa-Sabanero , Qureshy Zoya , Bose Devika , Dejene Roba , Liang Genqing , Wan Qin , Chang Justin , Jha Balendu Shekhar , Memon Omar , Miyagishima Kiyoharu Joshua , Rising Aaron , Lal Madhu , Hanson Eric , King Rebecca , Campos Mercedes Maria , Ferrer Marc , Amaral Juan , McGaughey David , Bharti Kapil 
Published: December 2021

AbstractAge-related Macular Degeneration (AMD), a blinding eye disease, is characterized by pathological protein- and lipid-rich drusen deposits underneath the retinal pigment epithelium (RPE) and atrophy of the RPE monolayer in advanced disease stages - leading to photoreceptor cell death and vision loss. Currently, there are no drugs that stop drusen formation or RPE atrophy in AMD. Here we provide an iPSC-RPE AMD model that recapitulates drusen and RPE atrophy. Drusen deposition is dependent on AMD-risk-allele CFH(H/H) and anaphylatoxin triggered alternate complement signaling via the activation of NF-κB and downregulation of autophagy pathways. Through high-throughput screening we identify two drugs, L-745,870, a dopamine receptor antagonist, and aminocaproic acid, a protease inhibitor that reduce drusen deposits and restore RPE epithelial phenotype in anaphylatoxin challenged iPSC-RPE with or without the CFH(H/H) genotype. This comprehensive iPSC-RPE model replicates key AMD phenotypes, provides molecular insight into the role of CFH(H/H) risk-allele in AMD, and discovers two candidate drugs to treat AMD.
Oxicam-type non-steroidal anti-inflammatory drugs inhibit NPR1-mediated salicylic acid pathway
Authors: Ishihama Nobuaki , Choi Seung-won , Noutoshi Yoshiteru , Saska Ivana , Asai Shuta , Takizawa Kaori , He Sheng Yang , Osada Hiroyuki , Shirasu Ken 
Published: December 2021

AbstractNonsteroidal anti-inflammatory drugs (NSAIDs), including salicylic acid (SA), target mammalian cyclooxygenases. In plants, SA is a defense hormone that regulates NON-EXPRESSOR OF PATHOGENESIS RELATED GENES 1 (NPR1), the master transcriptional regulator of immunity-related genes. We identify that the oxicam-type NSAIDs tenoxicam (TNX), meloxicam, and piroxicam, but not other types of NSAIDs, exhibit an inhibitory effect on immunity to bacteria and SA-dependent plant immune response. TNX treatment decreases NPR1 levels, independently from the proposed SA receptors NPR3 and NPR4. Instead, TNX induces oxidation of cytosolic redox status, which is also affected by SA and regulates NPR1 homeostasis. A cysteine labeling assay reveals that cysteine residues in NPR1 can be oxidized in vitro, leading to disulfide-bridged oligomerization of NPR1, but not in vivo regardless of SA or TNX treatment. Therefore, this study indicates that oxicam inhibits NPR1-mediated SA signaling without affecting the redox status of NPR1.
Network-driven anomalous transport is a fundamental component of brain microvascular dysfunction
Authors: Goirand Florian , Le Borgne Tanguy , Lorthois Sylvie 
Published: December 2021

AbstractBlood microcirculation supplies neurons with oxygen and nutrients, and contributes to clearing their neurotoxic waste, through a dense capillary network connected to larger tree-like vessels. This complex microvascular architecture results in highly heterogeneous blood flow and travel time distributions, whose origin and consequences on brain pathophysiology are poorly understood. Here, we analyze highly-resolved intracortical blood flow and transport simulations to establish the physical laws governing the macroscopic transport properties in the brain micro-circulation. We show that network-driven anomalous transport leads to the emergence of critical regions, whether hypoxic or with high concentrations of amyloid-β, a waste product centrally involved in Alzheimer’s Disease. We develop a Continuous-Time Random Walk theory capturing these dynamics and predicting that such critical regions appear much earlier than anticipated by current empirical models under mild hypoperfusion. These findings provide a framework for understanding and modelling the impact of microvascular dysfunction in brain diseases, including Alzheimer’s Disease.
Decoding non-canonical mRNA decay by the endoplasmic-reticulum stress sensor IRE1α
Authors: Le Thomas Adrien , Ferri Elena , Marsters Scot , Harnoss Jonathan M. , Lawrence David A. , Zuazo-Gaztelu Iratxe , Modrusan Zora , Chan Sara , Solon Margaret , Chalouni Cécile , Li Weihan , Koeppen Hartmut , Rudolph Joachim , Wang Weiru , Wu Thomas D. , Walter Peter , Ashkenazi Avi 
Published: December 2021

AbstractInositol requiring enzyme 1 (IRE1) mitigates endoplasmic-reticulum (ER) stress by orchestrating the unfolded-protein response (UPR). IRE1 spans the ER membrane, and signals through a cytosolic kinase-endoribonuclease module. The endoribonuclease generates the transcription factor XBP1s by intron excision between similar RNA stem-loop endomotifs, and depletes select cellular mRNAs through regulated IRE1-dependent decay (RIDD). Paradoxically, in mammals RIDD seems to target only mRNAs with XBP1-like endomotifs, while in flies RIDD exhibits little sequence restriction. By comparing nascent and total IRE1α-controlled mRNAs in human cells, we identify not only canonical endomotif-containing RIDD substrates, but also targets without such motifs—degraded by a process we coin RIDDLE, for RIDD lacking endomotif. IRE1α displays two basic endoribonuclease modalities: highly specific, endomotif-directed cleavage, minimally requiring dimers; and more promiscuous, endomotif-independent processing, requiring phospho-oligomers. An oligomer-deficient IRE1α mutant fails to support RIDDLE in vitro and in cells. Our results advance current mechanistic understanding of the UPR.
The global loss of floristic uniqueness
Authors: Yang Qiang , Weigelt Patrick , Fristoe Trevor S. , Zhang Zhijie , Kreft Holger , Stein Anke , Seebens Hanno , Dawson Wayne , Essl Franz , König Christian , Lenzner Bernd , Pergl Jan , Pouteau Robin , Pyšek Petr , Winter Marten , Ebel Aleksandr L. , Fuentes Nicol , Giehl Eduardo L. H. , Kartesz John , Krestov Pavel , Kukk Toomas , Nishino Misako , Kupriyanov Andrey , Villaseñor Jose Luis , Wieringa Jan J. , Zeddam Abida , Zykova Elena , van Kleunen Mark 
Published: December 2021

AbstractRegional species assemblages have been shaped by colonization, speciation and extinction over millions of years. Humans have altered biogeography by introducing species to new ranges. However, an analysis of how strongly naturalized plant species (i.e. alien plants that have established self-sustaining populations) affect the taxonomic and phylogenetic uniqueness of regional floras globally is still missing. Here, we present such an analysis with data from native and naturalized alien floras in 658 regions around the world. We find strong taxonomic and phylogenetic floristic homogenization overall, and that the natural decline in floristic similarity with increasing geographic distance is weakened by naturalized species. Floristic homogenization increases with climatic similarity, which emphasizes the importance of climate matching in plant naturalization. Moreover, floristic homogenization is greater between regions with current or past administrative relationships, indicating that being part of the same country as well as historical colonial ties facilitate floristic exchange, most likely due to more intensive trade and transport between such regions. Our findings show that naturalization of alien plants threatens taxonomic and phylogenetic uniqueness of regional floras globally. Unless more effective biosecurity measures are implemented, it is likely that with ongoing globalization, even the most distant regions will lose their floristic uniqueness.
CD137 (4-1BB) costimulation of CD8+ T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation
Authors: Otano Itziar , Azpilikueta Arantza , Glez-Vaz Javier , Alvarez Maite , Medina-Echeverz José , Cortés-Domínguez Ivan , Ortiz-de-Solorzano Carlos , Ellmark Peter , Fritzell Sara , Hernandez-Hoyos Gabriela , Nelson Michelle Hase , Ochoa María Carmen , Bolaños Elixabet , Cuculescu Doina , Jaúregui Patricia , Sanchez-Gregorio Sandra , Etxeberria Iñaki , Rodriguez-Ruiz María E. , Sanmamed Miguel F. , Teijeira Álvaro , Berraondo Pedro , Melero Ignacio 
Published: December 2021

AbstractCD137 (4-1BB; TNFSR9) is an activation-induced surface receptor that through costimulation effects provide antigen-primed T cells with augmented survival, proliferation and effector functions as well as metabolic advantages. These immunobiological mechanisms are being utilised for cancer immunotherapy with agonist CD137-binding and crosslinking-inducing agents that elicit CD137 intracellular signaling. In this study, side-by-side comparisons show that provision of CD137 costimulation in-cis with regard to the TCR-CD3-ligating cell is superior to that provided in-trans in terms of T cell activation, proliferation, survival, cytokine secretion and mitochondrial fitness in mouse and human. Cis ligation of CD137 relative to the TCR-CD3 complex results in more intense canonical and non-canonical NF-κB signaling and provides a more robust induction of cell cycle and DNA damage repair gene expression programs. Here we report that the superiority of cis versus trans CD137-costimulation is readily observed in vivo and is relevant for understanding the immunotherapeutic effects of CAR T cells and CD137 agonistic therapies currently undergoing clinical trials, which may provide costimulation either in cis or in trans.
Epigenetic loss of heterogeneity from low to high grade localized prostate tumours
Authors: Eksi Sebnem Ece , Chitsazan Alex , Sayar Zeynep , Thomas George V. , Fields Andrew J. , Kopp Ryan P. , Spellman Paul T. , Adey Andrew C. 
Published: December 2021

AbstractIdentifying precise molecular subtypes attributable to specific stages of localized prostate cancer has proven difficult due to high levels of heterogeneity. Bulk assays represent a population-average, which mask the heterogeneity that exists at the single-cell level. In this work, we sequence the accessible chromatin regions of 14,424 single-cells from 18 flash-frozen prostate tumours. We observe shared chromatin features among low-grade prostate cancer cells are lost in high-grade tumours. Despite this loss, high-grade tumours exhibit an enrichment for FOXA1, HOXB13 and CDX2 transcription factor binding sites, indicating a shared trans-regulatory programme. We identify two unique genes encoding neuronal adhesion molecules that are highly accessible in high-grade prostate tumours. We show NRXN1 and NLGN1 expression in epithelial, endothelial, immune and neuronal cells in prostate cancer using cyclic immunofluorescence. Our results provide a deeper understanding of the active gene regulatory networks in primary prostate tumours, critical for molecular stratification of the disease.
Genomic signatures of pre-resistance in Mycobacterium tuberculosis
Authors: Torres Ortiz Arturo , Coronel Jorge , Vidal Julia Rios , Bonilla Cesar , Moore David A. J. , Gilman Robert H. , Balloux Francois , Kon Onn Min , Didelot Xavier , Grandjean Louis 
Published: December 2021

AbstractRecent advances in bacterial whole-genome sequencing have resulted in a comprehensive catalog of antibiotic resistance genomic signatures in Mycobacterium tuberculosis. With a view to pre-empt the emergence of resistance, we hypothesized that pre-existing polymorphisms in susceptible genotypes (pre-resistance mutations) could increase the risk of becoming resistant in the future. We sequenced whole genomes from 3135 isolates sampled over a 17-year period. After reconstructing ancestral genomes on time-calibrated phylogenetic trees, we developed and applied a genome-wide survival analysis to determine the hazard of resistance acquisition. We demonstrate that M. tuberculosis lineage 2 has a higher risk of acquiring resistance than lineage 4, and estimate a higher hazard of rifampicin resistance evolution following isoniazid mono-resistance. Furthermore, we describe loci and genomic polymorphisms associated with a higher risk of resistance acquisition. Identifying markers of future antibiotic resistance could enable targeted therapy to prevent resistance emergence in M. tuberculosis and other pathogens.
Unraveling the origin of ferroelectric resistance switching through the interfacial engineering of layered ferroelectric-metal junctions
Authors: Xue Fei , He Xin , Ma Yinchang , Zheng Dongxing , Zhang Chenhui , Li Lain-Jong , He Jr-Hau , Yu Bin , Zhang Xixiang 
Published: December 2021

AbstractFerroelectric memristors have found extensive applications as a type of nonvolatile resistance switching memories in information storage, neuromorphic computing, and image recognition. Their resistance switching mechanisms are phenomenally postulated as the modulation of carrier transport by polarization control over Schottky barriers. However, for over a decade, obtaining direct, comprehensive experimental evidence has remained scarce. Here, we report an approach to experimentally demonstrate the origin of ferroelectric resistance switching using planar van der Waals ferroelectric α-In2Se3 memristors. Through rational interfacial engineering, their initial Schottky barrier heights and polarization screening charges at both terminals can be delicately manipulated. This enables us to find that ferroelectric resistance switching is determined by three independent variables: ferroelectric polarization, Schottky barrier variation, and initial barrier height, as opposed to the generally reported explanation. Inspired by these findings, we demonstrate volatile and nonvolatile ferroelectric memristors with large on/off ratios above 104. Our work can be extended to other planar long-channel and vertical ultrashort-channel ferroelectric memristors to reveal their ferroelectric resistance switching regimes and improve their performances.
Protein phosphatase 2A inactivation induces microsatellite instability, neoantigen production and immune response
Authors: Yen Yu-Ting , Chien May , Wu Pei-Yi , Ho Chi-Chang , Ho Chun-Te , Huang Kevin Chih-Yang , Chiang Shu-Fen , Chao K. S. Clifford , Chen William Tzu-Liang , Hung Shih-Chieh 
Published: December 2021

AbstractMicrosatellite-instable (MSI), a predictive biomarker for immune checkpoint blockade (ICB) response, is caused by mismatch repair deficiency (MMRd) that occurs through genetic or epigenetic silencing of MMR genes. Here, we report a mechanism of MMRd and demonstrate that protein phosphatase 2A (PP2A) deletion or inactivation converts cold microsatellite-stable (MSS) into MSI tumours through two orthogonal pathways: (i) by increasing retinoblastoma protein phosphorylation that leads to E2F and DNMT3A/3B expression with subsequent DNA methylation, and (ii) by increasing histone deacetylase (HDAC)2 phosphorylation that subsequently decreases H3K9ac levels and histone acetylation, which induces epigenetic silencing of MLH1. In mouse models of MSS and MSI colorectal cancers, triple-negative breast cancer and pancreatic cancer, PP2A inhibition triggers neoantigen production, cytotoxic T cell infiltration and ICB sensitization. Human cancer cell lines and tissue array effectively confirm these signaling pathways. These data indicate the dual involvement of PP2A inactivation in silencing MLH1 and inducing MSI.
ER proteins decipher the tubulin code to regulate organelle distribution
Authors: Zheng Pengli , Obara Christopher J. , Szczesna Ewa , Nixon-Abell Jonathon , Mahalingan Kishore K. , Roll-Mecak Antonina , Lippincott-Schwartz Jennifer , Blackstone Craig 
Published: December 2021

AbstractOrganelles move along differentially modified microtubules to establish and maintain their proper distributions and functions1,2. However, how cells interpret these post-translational microtubule modification codes to selectively regulate organelle positioning remains largely unknown. The endoplasmic reticulum (ER) is an interconnected network of diverse morphologies that extends promiscuously throughout the cytoplasm3, forming abundant contacts with other organelles4. Dysregulation of endoplasmic reticulum morphology is tightly linked to neurologic disorders and cancer5,6. Here we demonstrate that three membrane-bound endoplasmic reticulum proteins preferentially interact with different microtubule populations, with CLIMP63 binding centrosome microtubules, kinectin (KTN1) binding perinuclear polyglutamylated microtubules, and p180 binding glutamylated microtubules. Knockout of these proteins or manipulation of microtubule populations and glutamylation status results in marked changes in endoplasmic reticulum positioning, leading to similar redistributions of other organelles. During nutrient starvation, cells modulate CLIMP63 protein levels and p180–microtubule binding to bidirectionally move endoplasmic reticulum and lysosomes for proper autophagic responses.
Safety and tolerability of asunercept plus standard radiotherapy/temozolomide in Asian patients with newly-diagnosed glioblastoma: a phase I study
Authors: Wei Kuo-Chen , Hsu Peng-Wei , Tsai Hong-Chieh , Lin Ya-Jui , Chen Ko-Ting , Toh Cheng-Hong , Huang Hui-Lin , Jung Shih-Ming , Tseng Chen-Kan , Ke Yu-Xiong 
Published: December 2021

AbstractAsunercept (company code APG101 [Apogenix AG]; company code CAN008 [CANbridge Pharmaceuticals]) is a novel glycosylated fusion protein that has shown promising effectiveness in glioblastoma. This Phase I study was initiated to evaluate the tolerability and safety of asunercept in combination with standard radiotherapy and temozolomide (RT/TMZ) in Asian patients with newly diagnosed glioblastoma. This was the Phase I portion of a Phase I/II open label, multicenter trial of asunercept plus standard RT/TMZ. Adults with newly-diagnosed glioblastoma received surgical resection followed by standard RT/TMZ plus asunercept 200 mg/week (Cohort 1) or 400 mg/week (Cohort 2) by 30-min IV infusion. The primary endpoint was the safety and tolerability of asunercept during concurrent asunercept and RT/TMZ; dose-limiting toxicities were observed for each dose. Secondary endpoints included pharmacokinetics (PK) and 6-month progression-free survival (PFS6). All patients (Cohort 1, n = 3; Cohort 2, n = 7) completed ≥ 7 weeks of asunercept treatment. No DLTs were experienced. Only one possibly treatment-related treatment emergent adverse event (TEAE), Grade 1 gingival swelling, was observed. No Grade > 3 TEAEs were reported and no TEAE led to treatment discontinuation. Systemic asunercept exposure increased proportionally with dose and showed low inter-patient variability. The PFS6 rate was 33.3% and 57.1% for patients in Cohort 1 and 2, respectively. Patients in Cohort 2 maintained a PFS rate of 57.1% at Month 12. Adding asunercept to standard RT/TMZ was safe and well tolerated in patients with newly-diagnosed glioblastoma and 400 mg/week resulted in encouraging efficacy.Trial registration NCT02853565, August 3, 2016.
Circulating PIK3CA mutation detection at diagnosis in non-metastatic inflammatory breast cancer patients
Authors: Allouchery Violette , Perdrix Anne , Calbrix Céline , Berghian Anca , Lequesne Justine , Fontanilles Maxime , Leheurteur Marianne , Etancelin Pascaline , Sarafan-Vasseur Nasrin , Di Fiore Frédéric , Clatot Florian 
Published: December 2021

AbstractInflammatory breast cancer (IBC) is an aggressive BC subtype with poor outcomes. A targetable somatic PIK3CA mutation is reported in 30% of IBC, allowing for treatment by PI3Kα-specific inhibitors, such as alpelisib. The aim of this study was to evaluate the detection rate of circulating PIK3CA mutation in locally-advanced IBC (LAIBC) patients harbouring a PIK3CA mutation on initial biopsy. This monocentric retrospective study was based on available stored plasma samples and tumour biopsies at diagnosis from all LAIBC patients treated with neo-adjuvant chemotherapy (NCT) between 2008 and 2018 at the Centre Henri Becquerel. PIK3CA mutations (E542K, E545K, H1047R/L) were assessed by droplet digital PCR (ddPCR) in plasma samples and tumoral tissue at diagnosis. A total of 55 patients were included. Overall, 14/55 patients (25%) had a PIK3CA mutation identified on baseline biopsy (H1047R = 8; H1047L = 3; E545K = 2; E542K = 1). Among them, 11 (79%) patients had enough DNA for circulating DNA analyses, and corresponding circulating PIK3CA mutations were found in 6/11 (55%). Among the 41 patients without PIK3CA mutations on biopsy, 32 (78%) had enough DNA for circulating DNA analysis, and no circulating PIK3CA mutation was identified. Our results revealed no prognostic or predictive value of PIK3CA mutations at the diagnosis of non-metastatic IBC but highlighted the prognostic value of the cfDNA rate at diagnosis. Our study showed that a corresponding circulating PIK3CA mutation was identified in 55% of LAIBC patients with PIK3CA-mutated tumours, while no circulating mutation was found among patients with PI3KCA wild-type tumours.