bluuebunny/crossref_metadata_2025_split huggingface dataset:
The First Insight into the Hereditary Fusion Gene Landscape of Amyotrophic Lateral Sclerosis
Authors: Yang Jinfeng , Yuan Fenghua , Palovcak Anna , Fei Ling , Zhuo Noah ,   NYGC ALS Consortium, Zhang Yanbin , Zhuo Degen 
Published: March 2023

AbstractAmyotrophic lateral sclerosis (ALS) is a progressive nervous system disease that causes loss of muscle control. Over 30 mutated genes are associated with ASL. However, 90-95% of ASL cases have been found without a family history. Here, we have analyzed RNA-Seq data of NYGC ALS Consortium and identified fusion transcripts from ASL patients and non-neurologic controls (NNC). In this study, we combined previously-curated 1180 monozygotic (MZ) hereditary fusion genes (HFGs), and 204 HFGs discovered from NNC to analyze ASL fusion transcripts and identified 348 HFGs. Comparative analysis between ASL and GTEx shows that 139 HFGs are associated with ASL and ranged from 10.4% to 98.7% of 77 ASL patients. The most recurrent HFG isZNF528-ZNF880, detected in 98.7% of 77 ASL patients and 4.5% of 133 GTEx brain cortexes. Alignments of HFG transcripts from ASL with fusion transcripts from mesial temporal lobe epilepsy (MTLE) and Alzheimer’s disease (AD) showed that 43.9% and 11.6% of the ASL HFGs were present in MTLE and AD, respectively. The most recurrent and common HFG among ASL, MTLE, and AD wasADAMTSL3-SH3GL3, which behaves like ubiquitously-expressedSH3GL3-ADAMTSL3epigenetic fusion gene (EFG) and shows thatADAMTSL3-SH3GL3is a potential dormant or differentially-expressed HFG (dHFG), suggesting that they have common pathophysiological mechanisms. These HFGs associated with ASL have shown that HFGs are the missing genetic heritability and provide novel therapeutic targets for more efficient therapeutic drugs and methods to treat and cure many neurological diseases.
Prevalence of Elevated Blood Pressure and Left Ventricular Hypertrophy in Adolescents with Congenital Heart Disease
Authors: Walsh Aaron T. , Hor Kan N. , Eisner Mariah , Kallash Mahmoud , Spencer John David , Tran Andrew H. 
Published: March 2023

AbstractBackgroundLeft ventricular hypertrophy (LVH) associated with hypertension (HTN) is a predictor of cardiovascular (CV) events in adulthood. LVH is defined using left ventricular mass indexed to height2.7(LVMI-ht2.7) with current guidelines using the adult cutoff of 51 g/ht2.7; however, the pediatric cutoff is lower. Adults with congenital heart disease (CHD) have higher rates of HTN compared to the general adult population. Data on the prevalence of elevated blood pressure (SBP) in youths with CHD is limited. The aim of our study was to determine the prevalence of elevated BP and LVH in adolescents with CHD.MethodsWe retrospectively analyzed echocardiograms from patients with CHD from 2012-2019. Patients with biventricular CHD aged 13-17 years with documented BP, height, weight, and measurement of LVMI-ht2.7were included. We defined LVH using the pediatric cutoff of LVMI-ht2.7≥ 38.6 g/ht2.7. Patients were grouped by BP category into normotensive (NT, SBP < 120 mm Hg), Elevated BP (E-BP, 120 ≤ SBP < 130 mm Hg), Stage 1 HTN (HTN-1, 130 ≤ SBP < 140 mm Hg), and Stage 2 HTN (HTN-2, SBP ≥ 140 mm Hg). Prevalence of LVH was reported in each group defined as LVMI-HT2.7≥ 38.6 g/ht2.7.Results855 patients were included. Mean (± standard deviation, SD) age was 15.5±1.5 years with 485/855 (56.7%) male, SBP 117±13.5 mmHg, and LVMI-ht2.734.2±10.5 g/ht2.7. 493/855 (57.7%) were in the NT group, 214/855 (25%) in E-BP, 99/855 (11.6%) in HTN-1, and 49/855 (5.7%) in HTN-2. Prevalence of LVH increased with higher SBP with 96/493 (19.5%) in NT, 80/214 (37.4%) in E-BP, 32/99 (32.3%) in HTN-1, and 20/49 (40.8%) in HTN-2. Of youths with LVH, 49/228 (21.5%) met adult criteria of ≥ 51 g/ht2.7. Age, male sex, and body mass index (BMI) percentile were significantly associated with increased LVMI-ht2.7.ConclusionsYouths with CHD have a high prevalence of elevated BP, HTN, and LVH. BMI is a significant risk factor for the development of LVH in this population. These findings support early screening for HTN in this group because youths with CHD have baseline increased CV risk that may be compounded by obesity and long-term HTN.Clinical PerspectiveWhat is new?The prevalence of abnormal blood pressure and LVH in adolescents with CHD is understudied and our data show that HTN and LVH are common in this population.One-fifth of adolescents with biventricular congenital heart disease and left ventricular hypertrophy met adult criteria for left ventricular hypertrophy.What are the clinical implications?Left ventricular hypertrophy secondary to hypertension is linked to adverse cardiac events in adulthood.Early screening and detection for abnormal blood pressure in the adolescent congenital heart disease population may lead to earlier initiation of lifestyle interventions or pharmacotherapy and mitigate long-term adverse clinical and financial outcomes in an already vulnerable population.
Identifying keystone species in microbial communities using deep learning
Authors: Wang Xu-Wen , Sun Zheng , Jia Huijue , Michel-Mata Sebastian , Angulo Marco Tulio , Dai Lei , He Xuesong , Weiss Scott T. , Liu Yang-Yu 
Published: March 2023

AbstractPrevious studies suggested that microbial communities harbor keystone species whose removal can cause a dramatic shift in microbiome structure and functioning. Yet, an efficient method to systematically identify keystone species in microbial communities is still lacking. This is mainly due to our limited knowledge of microbial dynamics and the experimental and ethical difficulties of manipulating microbial communities. Here, we propose a Data-driven Keystone species Identification (DKI) framework based on deep learning to resolve this challenge. Our key idea is to implicitly learn the assembly rules of microbial communities from a particular habitat by training a deep learning model using microbiome samples collected from this habitat. The well-trained deep learning model enables us to quantify the community-specific keystoneness of each species in any microbiome sample from this habitat by conducting a thought experiment on species removal. We systematically validated this DKI framework using synthetic data generated from a classical population dynamics model in community ecology. We then applied DKI to analyze human gut, oral microbiome, soil, and coral microbiome data. We found that those taxa with high median keystoneness across different communities display strong community specificity, and many of them have been reported as keystone taxa in literature. The presented DKI framework demonstrates the power of machine learning in tackling a fundamental problem in community ecology, paving the way for the data-driven management of complex microbial communities.
Phage display uncovers a sequence motif that drives polypeptide binding to a conserved regulatory exosite of O-GlcNAc transferase
Authors: Alteen Matthew G. , Meek Richard W. , Kolappan Subramania , Busmann Jil A. , Cao Jessica , O’Gara Zoe , Derda Ratmir , Davies Gideon J. , Vocadlo David J. 
Published: March 2023

ABSTRACTThe modification of nucleocytoplasmic proteins by O-linked N-acetylglucosamine (O-GlcNAc) is an important regulator of cell physiology.O-GlcNAc is installed on over a thousand proteins by just one enzyme,O-GlcNAc transferase (OGT). How OGT is therefore regulated is therefore a topic of interest. To gain insight into these questions, we used OGT to perform phage display selection from an unbiased library of ∼108peptides of 15 amino acids in length. Following rounds of selection and deep mutational panning we identified a high-fidelity peptide consensus sequence, [Y/F]-x-P-x-Y-x-[I/M/F], that drives peptide binding to OGT. Peptides containing this sequence bind to OGT in the high nanomolar to low micromolar range and inhibit OGT in a non-competitive manner with low micromolar potencies. X-ray structural analyses of OGT in complex with a peptide containing this motif surprisingly revealed binding to an exosite proximal to the active site of OGT. This structure defines the detailed molecular basis driving peptide binding and explains the need for specific residues within the sequence motif. Analysis of the human proteome revealed this motif within 52 nuclear and cytoplasmic proteins. Collectively, these data suggest an unprecedented mode of regulation of OGT by which polypeptides can bind to this exosite to cause allosteric inhibition of OGT through steric occlusion of its active site. We expect these insights will drive improved understanding of the regulation of OGT within cells and enable the development of new chemical tools to exert fine control over OGT activity.SIGNIFICANCE STATEMENTThousands of proteins within humans are modified by the monosaccharide N-acetylglucosamine (O-GlcNAc). O-GlcNAc regulates cellular physiology and is being pursued to create therapeutics. Remarkably, only one enzyme, O-GlcNAc transferase (OGT), installs O-GlcNAc and its regulation is poorly understood. By affinity selection using a vast peptide library, we uncover an amino acid sequence motif that drives binding of polypeptides to OGT. An OGT-peptide complex shows how this motif binds to an allosteric site proximal to the active site and inhibits OGT in an unprecedented manner. Given the distribution of this sequence motif within the human proteome proteins containing this motif likely regulate the activity of OGT, outlining a new mode by which OGT is controlled and opening new avenues for research.
A qualitative exploration into the role of illness perceptions in endometriosis-related quality of life
Authors: Moore Chloe , Cogan Nicola , Williams Lynn 
Published: March 2023

AbstractObjectivesEndometriosis is linked to adverse quality of life (QoL) outcomes. In the absence of effective treatment for endometriosis-related symptoms, supporting the QoL of those experiencing endometriosis is crucial. Illness perception (IP) interventions have prompted modest increases in QoL in several chronic conditions, yet IPs have not been comprehensively studied in relation to endometriosis. It is, therefore, necessary to examine the IPs held by individuals experiencing endometriosis to establish whether IP-based interventions might be useful in supporting QoL in this population. This research aims to gain an understanding of the IPs held by people experiencing endometriosis and their impact on QoL.DesignQualitative using one-to-one online semi-structured interviews.MethodsThirty individuals with endometriosis participated. Interviews sought to gain an understanding of participants’ experiences and perceptions in relation to living with endometriosis. Reflexive thematic analysis was used to develop themes.ResultsThree major themes were developed: (1) a life disrupted; (2) lost and fragmented sense of self; and (3) complex emotional responses. Largely negative IPs were held by individuals living with the condition which, along with endometriosis-specific symptoms and reduced functioning, fuelled fears for the future and reduced QoL.ConclusionsEndometriosis-specific symptoms fuelled adverse QoL outcomes directly, and indirectly through moulding IPs. The disruption to the life trajectory associated with experiencing the condition as well as perceptions of control had a major impact on participants’ wellbeing, self-concept, and the varied emotional responses associated with experiencing endometriosis. IP-based interventions may support the wellbeing of those experiencing endometriosis whilst effective treatment is sought.
6mA-Sniper: Quantifying 6mA Sites in Eukaryotes at Single-Nucleotide Resolution
Authors: Zhang Jie , Peng Qi , Ma Chengchuan , Wang Jiaxin , Xiao Chunfu , Li Ting , Liu Xiaoge , Zhou Liankui , Zhou Wei-Zhen , Ding Wanqiu , An Ni A. , Zhang Li , Liu Ying , Li Chuan-Yun 
Published: March 2023

ABSTRACTWhileN6-methyldeoxyadenine (6mA) modification has been linked to fundamental regulatory processes in prokaryotes, its prevalence and functional implications in eukaryotes are controversial. Here, we report 6mA-Sniper to quantify 6mA sites in eukaryotes at single-nucleotide resolution. With 6mA-Sniper, we delineated an accurate 6mA profile inC. eleganswith 2,034 sites, significantly enriched on sequences of [GC]GAG motif. Twenty-six of 39 6mA events with MnlI restriction endonuclease sites were experimentally verified, demonstrating the feasibility of this method. Notably, the enrichment of these 6mA sites on a specific sequence motif, their within-population conservation and the combinatorial patterns, and the selective constrains on them jointly support an active model for the shaping of the profile by some undiscovered methyltransferases. In a joint study (Cell Research, in revision), Maet al.reported METL-9 as a new methyltransferase in shaping the basal and stress-dependent 6mA profile inC. elegans. Notably, with the 6mA profile identified by 6mA-Sniper at single-nucleotide resolution, we found that the levels of 6mAs are significantly decreased in strains with the removal of METL-9 (METL-9 KO-OP50), while generally increased afterP. aeruginosainfection, further verified the efficiency of 6mA-Sniper in accurately pinpointing 6mA sites. Moreover, for the regions marked by 998 6mA sites emerged specifically after the infection, we identified an enrichment of the upregulated genes after the infection. The gene upregulations are likely mediated through a mutual exclusive crosstalk between 6mA and H3K27me3 modification, as supported by their co-occurrence, and the signal of increased H3K27me3 at regions marked by 6mAs depleted in METL-9 KO-OP50 strains. Notably, in differentC. elegansstrains, the cross-strain genetic variants removing 6mA sites are associated with the decreased expression of their host genes, and the removal of two randomly-selected 6mA events with genome editing directly decreased the expression of their host genes. We thus highlight 6mA regulation as a previously-neglected regulator of transcriptome in eukaryotes.
Single-cell RNA sequencing across isogenicFUSandTARDBPALS lines reveals a shared early mitochondrial dysfunction unique to motor neurons
Authors: Schweingruber Christoph , Nijssen Jik , Mechtersheimer Jonas , Reber Stefan , Leboeuf Melanie , O’Brien Niamh , Mei Irene , Hedges Erin , Keuper Michaela , Aguila Benitez Julio , Radoi Vlad , Jastroch Martin , Ruepp Marc-David , Hedlund Eva 
Published: March 2023

AbstractMutations in the RNA/DNA-binding proteins FUS and TDP-43 cause the fatal disease amyotrophic lateral sclerosis (ALS). The precise mechanisms behind the selective motor neuron degeneration remain unclear and it is uncertain if ALS-causative mutations trigger motor neuron death through shared or distinct pathogenic pathways. To address these two questions, we performed single-cell RNA sequencing across neuron types derived from isogenic induced pluripotent stem cell lines, harbouring FUS P525L, FUS R495X, TARDBP M337V mutations or FUS knockout. The mutations elicited 5- to 15-fold greater transcriptional responses in motor neurons than interneurons. Approximately 20% of transcripts uniquely dysregulated in motor neurons were shared across FUS mutations, with half being driven by FUS gain-of-function. Among these, a majority pointed towards mitochondrial impairments, with attenuated pathways shared with the TARDBP M337V mutation. Meta-analysis demonstrated convergence on mitochondrial dysfunction withC9orf72-ALS patient-derived motor neurons. We observed impaired mitochondrial motility across ALS motor axons, even in isogenic FUS R244C motor neurons, which retain FUS in the nucleus, demonstrating shared toxic gain-of-function mechanisms acrossFUS- andTARDBP-ALS, uncoupled from protein mislocalization. These early signs of mitochondrial dysfunction unique to motor neurons could have profound implications for their survival and represent promising therapeutic targets across multiple ALS forms.
Single-residue mutation in protein kinase C toggles between cancer and neurodegeneration
Authors: Jones Alexander C. , Kornev Alexandr P. , Weng Jui-Hung , Manning Gerard , Taylor Susan S. , Newton Alexandra C. 
Published: March 2023

AbstractConventional protein kinase C (PKC) isozymes tune the signaling output of cells, with loss-of-function somatic mutations associated with cancer and gain-of-function germline mutations identified in neurodegeneration. PKC with impaired autoinhibition is removed from the cell by quality-control mechanisms to prevent accumulation of aberrantly active enzyme. Here, we examine how a single residue in the C1A domain of PKCβ, arginine 42 (R42), permits quality-control degradation when mutated to histidine in cancer (R42H) and blocks downregulation when mutated to proline in the neurodegenerative disease spinocerebellar ataxia (R42P). Using FRET-based biosensors, we determined that mutation of R42 to any residue, including lysine, resulted in reduced autoinhibition as indicated by higher basal activity and faster agonist-induced plasma membrane translocation. R42 is predicted to form a stabilizing salt bridge with E655 in the C-tail and mutation of E655, but not neighboring E657, also reduced autoinhibition. Western blot analysis revealed that whereas R42H had reduced stability, the R42P mutant was stable and insensitive to activator-induced ubiquitination and downregulation, an effect previously observed by deletion of the entire C1A domain. Molecular dynamics (MD) simulations and analysis of stable regions of the domain using local spatial pattern (LSP) alignment suggested that P42 interacts with Q66 to impair mobility and conformation of one of the ligand-binding loops. Additional mutation of Q66 to the smaller asparagine (R42P/Q66N), to remove conformational constraints, restored degradation sensitivity to that of WT. Our results unveil how disease-associated mutations of the same residue in the C1A domain can toggle between gain- or loss-of-function of PKC.
A prebiotic genetic alphabet as an early Darwinian ancestor for pre-RNA evolution
Authors: Sawant Anupam A. , Tripathi Sneha , Galande Sanjeev , Rajamani Sudha 
Published: March 2023

AbstractRNA-based genetic code is thought to be central to life’s emergence due to its dual ability for information transfer and catalysis. Nonetheless, the genetic code of early life was potentially not restricted to canonical genetic alphabets alone. The presence of an extensive repertoire of modified nucleobases in extant biology as ‘signatures of the past’, highlights the relevance of non-canonical alphabets, ably strengthened by experiments demonstrating their ready conversion into nucleosides and nucleotides. All these strongly support a pre-RNA World, wherein informational molecules are posited to have contained alternate genetic alphabets. Nevertheless, understanding pre-RNA molecules’ capacity to acquire emergent function has remained less prevalent. Further, the steps involved in their transition to a canonical RNA World has not been systematically studied in the origins of life framework. In this study, we report the synthesis of a prebiotically relevant genetic alphabet containing the non-canonical nucleobase, barbituric acid. We demonstrate for the first instance the enzymatic incorporation of this prebiotically plausible alphabet (BaTP) into an RNA, using proteinaceous T7 RNA polymerase. Pertinently, the incorporation of this genetic alphabet into a baby spinach aptamer did not affect its overall secondary structure, while also allowing it to retain its aptameric function. Furthermore, we demonstrate the faithful transfer of genetic information from pre-RNA-containing barbitudine nucleotides to DNA, using a high-fidelity RNA-dependent DNA polymerase. These findings allude to a putative pathway for the early molecular evolution of the genetic code of extant life.
Adaptive host responses to infection can resemble parasitic manipulation
Authors: Håkonsrud Jensen Camilla , Weidner Jacqueline , Giske Jarl , Jørgensen Christian , Eliassen Sigrunn , Mennerat Adèle 
Published: March 2023

AbstractUsing a dynamic optimisation model for juvenile fish in stochastic food environments, we investigate optimal hormonal regulation, energy allocation and foraging behaviour of a growing host infected by a parasite that only incurs an energetic cost. We find it optimal for the infected host to have higher levels of orexin, growth- and thyroid hormones, resulting in higher activity levels, increased foraging, and faster growth. This growth strategy thus displays several of the fingerprints often associated with parasite manipulation: higher levels of metabolic hormones, faster growth, higher allocation to reserves (i.e. parasite-induced gigantism), higher risk taking and eventually higher predation rate. However, there is no route for manipulation in our model, so these changes reflect adaptive host compensatory responses. Interestingly, several of these changes also increase the fitness of the parasite. Our results call for caution when interpreting observations of gigantism or risky host behaviours as parasite manipulation without further testing.
Upfront Menin-inhibitor resistance in multiply pretreated leukemias
Authors: Mahdavi Leila , Goodrow Haley , Alikarami Fatemeh , Lenard Alexandra , Riedel Simone S. , Libbrecht Clara , Bowser Isabel , Tasian Sarah K. , Falkenstein Catherine D. , Manning Bryan , Skuli Sarah , Carroll Martin P. , Wertheim Gerald , Cai Sheng F. , McGeehan Gerard , Xie Hongbo M. , Bernt Kathrin M. 
Published: March 2023

AbstractInhibitors of the Menin-KMT2A interaction are promising agents for the treatment ofKMT2A-rearranged (KMT2A-r) leukemias. We evaluated Menin inhibition in patient derived xenografts ofKMT2A-rleukemias with high-risk features. Three AMLs with high-risk fusion partners (MLLT10, MLLT4) and two infant ALL samples were sensitive to Menin inhibition. We also evaluated serial samples from two patients with multiply relapsed ALL. We found that highly pretreatedKMT2A-AFF1ALL samples were much less sensitive compared to cells obtained earlier in the same patients’ disease course. Since none of the patients had been treated with a Menin inhibitor, resistance in these highly pretreated samples was acquired in the absence to Menin inhibitor exposure. Transcriptomic analysis documented sustained on-target efficacy towards the canonical targets in the Menin-inhibitor in resistant cells. Targeted genomic analysis documented the emergence of multiple co-mutations, including RAS pathway andTP53mutations, although neither was sufficient to induce Menin-inhibitor resistance in vitro. Downregulation of KMT3D may account for resistance in one patients; inactivation of KMT2C/D had previously been reported to result in Menin inhibitor resistance. Future studies will need to clarify more broadly which genomic/epigenomic alterations drive upfront resistance. Regardless of mechanism, our data supports using Menin-inhibitors upfront or in early lines of therapy before substantial genomic or epigenomic evolution has occurred.