bluuebunny/crossref_metadata_2025_split huggingface dataset:
Integrative multi-omics data elucidating the biosynthesis and regulatory mechanisms of furanocoumarins inAngelica dahurica
Authors: Ji Jiaojiao , Han Xiaoxu , Zang Lanlan , Li Yushan , Lin Liqun , Hu Donghua , Sun Shichao , Ren Yonglin , Maker Garth , Lu Zefu , Wang Li 
Published: July 2024

AbstractFurocoumarins (FCs) are crucial natural products playing a dual role as plant defense molecules and pharmacologically active substances.Angelica dahuricais a renowned herb with diverse and abundant FCs. However, the accumulation pattern over developmental stages, biosynthesis pathway and regulatory mechanisms of FCs inA. dahuricaremain elusive, hindering the production of FCs via synthetic biology approaches. Here, we constructed a chromosome-level reference genome forA. dahuricaand quantified the content dynamics of 17 coumarins across six developmental stages of its medicinal organ, root. It showed a gradual decrease in FC concentration with root enlargement. The combined analyses of transcriptomic and metabolomic data, together with in vivo enzymatic assay, confirmed that CYP71AZ18 was involved in the biosynthesis of bergaptol, whereas CYP71AZ19 and CYP83F95 contributed to the biosynthesis of xanthotoxol. Notably, CYP71AZ19 originated from a proximal duplication event of CYP71AZ18, specific toA. dahurica, subsequently undergoing neofunctionalization. Accessible chromatin regions (ACRs), especially proximal ACRs, are correlated with higher gene expression levels, including the three validated genes involved in FC biosynthesis, showing potential to regulate metabolite biosynthesis. Our findings provide new insights into the biosynthetic pathway of FCs and the epigenetic regulation of metabolite biosynthesis.
Noradrenergic and Dopaminergic Neural Correlates of Trait Anxiety: Unveiling the Impact of Maladaptive Emotion Regulation
Authors: Zareba Michal Rafal , Ariño-Braña Paula , Picó-Pérez Maria , Visser Maya 
Published: July 2024

AbstractBackgroundMaladaptive emotion regulation plays a crucial role in the development and maintenance of elevated anxiety levels, both in patients and in individuals with subclinical symptomatology. While pharmacological treatments for anxiety target the emotion dysregulation through dopaminergic, noradrenergic and serotonergic systems, little is known about the underlying mechanisms. Therefore, the current study depicts the association of these neuromodulatory systems’ resting-state functioning with trait-anxiety, investigating the role of maladaptive emotion regulation.MethodsAmplitude of low-frequency fluctuations (ALFF), fractional amplitude of low-frequency fluctuations (fALFF), and whole-brain resting-state functional connectivity (rs-FC) were obtained from the ventral tegmental area (VTA), locus coeruleus (LC) and dorsal raphe, and correlated with trait-anxiety and self-reported maladaptive emotion regulation (N = 60).ResultsTrait-anxiety was positively associated with LC’s fALFF and negatively with VTA’s whole-brain rs-FC with the left inferior parietal lobule (L-IPL) and the left superior frontal gyrus (L-SFG). Maladaptive emotion regulation was negatively associated with VTA’s rs-FC with these regions, with trait-anxiety fully mediating this association. VTA connectivity with the frontal region, but not parietal, positively predicted its amplitude of neural oscillations, an effect that was paralleled by stronger frontal dopaminergic innervation.LimitationsUse of external molecular datasets and need for replication in patients.ConclusionsNoradrenergic and dopaminergic systems appear to contribute differently to subclinical anxiety. While noradrenaline likely acts through a more general mechanism, the dopaminergic dysconnectivity with the frontoparietal control network may act as one of the mechanisms of maladaptive emotion regulation, informing the models on the disorder development.HighlightsTrait-anxiety shows a positive association with the activity of locus coeruleusTrait-anxiety and emotional regulation are linked to VTA-frontoparietal connectivityTrait-anxiety fully mediates emotion regulation’s effect on VTA’s connectivityStrength of connectivity with VTA is positively linked to the frontal ALFF and fALFF
DNA polymerase λ-driven targeted mutagenesis for directed evolution in human cells
Authors: Aiello Davide , Ciciani Matteo , Marelli Federica , Stancampiano Marta , De Sanctis Veronica , Bertorelli Roberto , Kheir Eyemen Gafar Ali , Maule Giulia , Cereseto Anna , Arosio Daniele 
Published: July 2024

AbstractDirected evolution is an efficient strategy to steer protein function to either understand specific biological properties or develop new biotechnology tools. Currently available methods for targeted mutagenesis in human cells rely on deaminases which can only modify specific bases, limiting the region of sequence space explored during evolution. By leveraging CRISPR-Cas9 coupled with an error-prone variant of human DNA polymerase λ, here we developed CRISPR-λ, an unbiased mutagenesis tool for directed evolution in human cells. We evaluated CRISPR-λ by reverting the fluorescence of a mutated EGFP and characterized it using ultra-deep sequencing. The mutagenic activity of CRISPR-λ spans 36-46 nucleotides from the target site, with a mutation frequency as high as 1.4e-4 substitutions per base and with no bias for specific nucleotide substitutions. The versatility of CRISPR-λ extends beyond base substitution, enabling modifications of the target gene through insertions and deletions, thereby broadening its potential for genetic diversification. We validated the efficacy of CRISPR-λ in directed evolution approaches by functionally reverting a mutated blasticidin resistance gene. Furthermore, we demonstrated the sequence diversification power of CRISPR-λ by steering the syncytia formation activity of the SARS-CoV-2 Spike envelope protein in cultured cells.
In vivo–Active Soluble Epoxide Hydrolase–targeting PROTACs with Improved Potency and Stability
Authors: Nakane Keita , Morisseau Christophe , Dowker-Key Presley D. , Benitez Gabrielle , Aguilan Jennifer T. , Nagai Emiko , Sidoli Simone , Hammock Bruce D. , Bettaieb Ahmed , Shinoda Kosaku , Kitamura Seiya 
Published: July 2024

ABSTRACTSoluble epoxide hydrolase (sEH) is a bifunctional enzyme involved in fatty acid metabolism and promising drug target. We previously reported first-generation sEH proteolysis–targeting chimeras (PROTACs) with limited degradation potency and low aqueous and metabolic stability. Herein, we report the development of next-generation sEH PROTAC molecules with improved stability and degradation potency. One of the most potent molecules (compound8) exhibits a half-maximal degradation concentration in the sub-nM range, is stablein vivo, and effectively degrades sEH in mouse livers and brown adipose tissues. Given the role played by sEH in many metabolic and nonmetabolic diseases, the presented molecules provide useful chemical probes for the study of sEH biology. They also hold potential for therapeutic development against a range of disease conditions, including diabetes, inflammation, and metabolic disorders.
Solid state NMR spectral editing of histidine, arginine and lysine using Hadamard encoding
Authors: Gopinath Tata , Kraft Alyssa , Shin Kyungsoo , Wood Nicholas A. , Marassi Francesca M. 
Published: July 2024

AbstractThe NMR signals from protein sidechains are rich in information about intra- and inter-molecular interactions, but their detection can be complicated due to spectral overlap as well as conformational and hydrogen exchange. In this work, we demonstrate a protocol for multi-dimensional solid-state NMR spectral editing of signals from basic sidechains based on Hadamard matrix encoding. The Hadamard method acquires multi-dimensional experiments in such a way that both the backbone and under-sampled sidechain signals can be decoded for unambiguous editing in the15N spectral frequency dimension. All multi-dimensional15N-edited solid-state NMR experiments can be acquired using this strategy, thereby accelerating the acquisition of spectra spanning broad frequency bandwidth. Application of these methods to the ferritin nanocage, reveals signals from N atoms from His, Arg, Lys and Trp sidechains, as well as their tightly bound, ordered water molecules. The Hadamard approach adds to the arsenal of spectroscopic approaches for protein NMR signal detection.
Waning immunity drives respiratory virus evolution and reinfection
Authors: Bull James J , Koelle Katia , Antia Rustom 
Published: July 2024

AbstractReinfections with respiratory viruses such as influenza viruses and coronaviruses are thought to be driven by ongoing antigenic immune escape in the viral population. However, this does not explain why antigenic variation is frequently observed in these viruses relative to viruses such as measles that undergo systemic replication. Here, we suggest that the rapid rate of waning immunity in the respiratory tract is the key driver of antigenic evolution in respiratory viruses. Waning immunity results in hosts with immunity levels that protect against homologous reinfection but are insufficient to protect against infection with a heterologous, antigenically different strain. As such, when partially immune hosts are present at a high enough density, an immune escape variant can invade the viral population even though that variant cannot infect fully immune hosts. Invasion can occur even when the variant’s immune escape mutation incurs a fitness cost, and we expect the expanding mutant population will evolve compensatory mutations that mitigate this cost. Thus the mutant lineage should replace the wild-type, and as immunity to it builds, the process will repeat. Our model provides a new explanation for the pattern of successive emergence and replacement of antigenic variants that has been observed in many respiratory viruses. We discuss our model relative to others for understanding the drivers of antigenic evolution in these and other respiratory viruses.
Sirt5 regulates chondrocyte metabolism and osteoarthritis development through protein lysine malonylation
Authors: Liu Huanhuan , Binoy Anupama , Ren Siqi , Martino Thomas C. , Miller Anna E. , Willis Craig R. G. , Veerabhadraiah Shivakumar R. , Sukul Abhijit , Bons Joanna , Rose Jacob P. , Schilling Birgit , Jurynec Michael J. , Zhu Shouan 
Published: July 2024

AbstractObjectivesChondrocyte metabolic dysfunction plays an important role in osteoarthritis (OA) development during aging and obesity. Protein post-translational modifications (PTMs) have recently emerged as an important regulator of cellular metabolism. We aim to study one type of PTM, lysine malonylation (MaK) and its regulator Sirt5 in OA development.MethodsHuman and mouse cartilage tissues were used to measure SIRT5 and MaK levels. Both systemic and cartilage-specific conditional knockout mouse models were subject to high-fat diet (HFD) treatment to induce obesity and OA. Proteomics analysis was performed inSirt5-/-and WT chondrocytes. SIRT5 mutation was identified in the Utah Population Database (UPDB).ResultsWe found that SIRT5 decreases while MAK increases in the cartilage during aging. A combination of Sirt5 deficiency and obesity exacerbates joint degeneration in a sex dependent manner in mice. We further delineate the malonylome in chondrocytes, pinpointing MaK’s predominant impact on various metabolic pathways such as carbon metabolism and glycolysis. Lastly, we identified a rare coding mutation inSIRT5that dominantly segregates in a family with OA. The mutation results in substitution of an evolutionally invariant phenylalanine (Phe–F) to leucine (Leu–L) (F101L) in the catalytic domain. The mutant protein results in higher MaK level and decreased expression of cartilage ECM genes and upregulation of inflammation associated genes.ConclusionsWe found that Sirt5 mediated MaK is an important regulator of chondrocyte cellular metabolism and dysregulation of Sirt5-MaK could be an important mechanism underlying aging and obesity associated OA development.
Longevity or Well-being? A Dual-Dimension Structure of Neuroticism
Authors: He Yini , Xiao Jing , Hu Ke , Gao Tian , Yan Yan , Wang Lei , Li Kaixin , Lei Wenkun , Zhao Kun , Dong Changsheng , Tian Xiaohan , Ding Chaoyue , Peng Yingjie , Xian Junxing , Huang Shangzheng , Liu Xiya , Li Long , Zhang Peng , Zhang Zhanjun , He Sheng , Li Ang , Liu Bing 
Published: July 2024

AbstractThe development of personality traits is often viewed as evolutionarily adaptive. Current neuroticism research, however, predominantly highlights its negative health impacts, neglecting its potential evolutionary advantages. We propose that neuroticism’s inter-individual variability can be structured into two distinct geometric dimensions. One, named the Emotional Reactivity-Instability/Distress Spectrum (ERIS), correlates strongly with longevity and is associated with chronic diseases and risk-averse lifestyle. This dimension is underpinned by evolutionarily conserved subcortical brain regions and genes. The other, resembling the overall neuroticism score, is primarily linked to mental and stress-related disorders, as well as life satisfaction. It involves higher-order emotional brain regions and is genetically enriched in human-accelerated regions. Collectively, these dimensions represent a dual-strategy personality framework that optimizes survival and well-being, with the former being evolutionarily conservative and the latter potentially a unique human adaptation.
Bidimensional Perfectionism and Psychological Distress: The Roles of Self-Esteem and Self-Compassion
Authors: Chung Cheuk Hei Peony , Lee Antoinette Marie 
Published: July 2024

AbstractPerfectionism as a personality trait can be seen as having both adaptive and maladaptive dimensions. Nevertheless, their relationships with psychological distress remain mixed in the current literature. Previous studies were also limited by the use of impure measurements and the failure to statistically control for the effects of the other dimension. By addressing these major limitations and exploring the mediating and moderating roles of self-esteem and self-compassion, the current study provides an in-depth examination of the relationships between bidimensional perfectionism and psychological distress. In a community sample of 503 adults, results supported a bidimensional view of perfectionism, with maladaptive perfectionism positively predicting psychological distress and adaptive perfectionism being unrelated to psychological distress. Self-esteem was found to mediate the relationships between both dimensions of perfectionism and psychological distress. Self-compassion was only found to moderate the relationship between maladaptive perfectionism and self-esteem. Whilst the maladaptive nature of maladaptive perfectionism was supported in this study, findings suggested that adaptive perfectionism remains a more complicated construct. Future studies should aim at clarifying the nature and psychological outcomes of adaptive perfectionism.
The cellular hierarchy of acute myeloid leukemia informs personalized treatment
Authors: Severin Yannik , Festl Yasmin , Benoit Tobias M. , Wegmann Rebekka , Hale Benjamin D. , Roiss Michael , Kienzler Anne-Kathrin , Pabst Thomas , Scharl Michael , Sunagawa Shinichi , Manz Markus G. , Müller Antonia M.S. , Snijder Berend 
Published: July 2024

AbstractAcute myeloid leukemia (AML) is characterized by malignant myeloid precursors that span a cellular hierarchy from dedifferentiated leukemic stem cells to mature blasts. While the diagnostic and prognostic importance of AML blast maturation is increasingly recognized, personalized therapies are currently not tailored to a patients individual makeup of this cellular hierarchy. In this study, we use multiplexed image-basedex vivodrug screening (pharmacoscopy) to systematically quantify the drug sensitivity across the cellular hierarchy of AML patients. We analyzed 174 prospective and longitudinal patient samples from 44 newly diagnosed AML patients, which indicated that differences in the AML hierarchy significantly identified poor responses to first-line therapy, outperforming European LeukemiaNet (ELN) criteria. Critically, drug response profiling across the AML hierarchy of each patient improved the accuracy of predicting patient response to first-line therapy (AUC 0.91), and revealed alternative individualized treatment options targeting the complete AML hierarchy of non-responding patients. We confirmed these findings in an independent cohort of 26 relapsed/refractory AML patients, for whom pan-hierarchy response profiling improved response predictionspost hoc. Overall, our results quantify the clinical importance of therapeutically targeting the complete cellular hierarchy of newly diagnosed AML, and identify multiplexed image-basedex vivodrug screening to enable quantification and targeting of the AML maturation hierarchy for improved personalized treatment.
Application of Urinary Peptide-Biomarkers in Trauma Patients as a Predictive Tool for Prognostic Assessment, Treatment Interventions, and Intervention Timing: Prospective Nonrandomized Pilot Study
Authors: Aktas Gökmen , Keller Felix , Siwy Justyna , Latosinska Agnieszka , Mischak Harald , Mayor Jorge , Clausen Jan , Wilhelmi Michaela , Brauckmann Vesta , Sehmisch Stephan , Omar Pacha Tarek 
Published: July 2024

AbstractBackgroundTreatment of severely injured patients represents a major challenge, in part due to the unpredictable risk of major adverse events, including death. Preemptive personalized treatment aimed at preventing these events is a key objective of patient management; however, the currently available scoring systems provide only moderate guidance. Molecular biomarkers from proteomics/peptidomics studies hold promise for improving the current situation, ultimately enabling precision medicine based on individual molecular profiles.MethodsTo test the hypothesis that proteomics biomarkers could predict patient outcomes in severely injured patients, we initiated a pilot study involving consecutive urine sampling (on days 0, 2, 5, 10, and 14) and subsequent peptidome analysis using capillary electrophoresis coupled to mass spectrometry (CE-MS) of 14 severely injured patients and two additional ICU patients. The urine peptidomes of these patients were compared to the urine peptidomes of age- and sex-matched controls. Previously established urinary peptide-based classifiers, CKD274, AKI204, and CoV50, were applied to the obtained peptidome data, and the association of the scores with a combined endpoint (death and/or kidney failure and/or respiratory insufficiency) was investigated.ResultsCE-MS peptidome analysis identified 281 peptides that were significantly altered in severely injured patients. Consistent upregulation was observed for peptides from A1AT, FETUA, and MYG, while peptides derived from CD99, PIGR and UROM were consistently reduced. Most of the significant peptides were from different collagens, and the majority were reduced in abundance. Two of the predefined peptidomic classifiers, CKD273 and AKI204, showed significant associations with the combined endpoint, which was not observed for the routine scores generally applied in the clinics.ConclusionsThis prospective pilot study confirmed the hypothesis that urinary peptides provide information on patient outcomes and may guide personalized interventions based on individual molecular changes. The results obtained allow the planning of a well-powered prospective trial investigating the value of urinary peptides in this context in more detail.
Resource Considerations for Acute Ischemic Stroke Intervention in Nonagenarians
Authors: Gandhi Sani , Hollender Kimberly , Chukwuneke Florence , Mehta Deviyani , Cheng Roger 
Published: July 2024

ABSTRACTBackgroundWhile there is evidence to support the viability of intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) as treatments for acute ischemic stroke (AIS) even in the very elderly, there are practical considerations to be made regarding triage and resource allocation, particularly in a hub-and-spoke system of stroke intervention.MethodsThis is a cross-sectional study using stroke quality registry data from 2017-2021 at a comprehensive stroke center serving as the primary hub for an associated healthcare system. We identified patients aged 90 or above who received acute stroke treatment with IVT and/or MT. NIHSS, modified Rankin Score (mRS), transfer status, length of stay (LOS), and discharge disposition were examined.ResultsOut of 268 total nonagenarians admitted for AIS, 60 received an acute intervention (37 IVT, 14 MT, 9 both). All MT attempts resulted in successful reperfusion (>TICI2b). Median initial and discharge mRS were 2 and 5 respectively; only 3.3% were discharged home, with 46.7% of patients either deceased or discharged to hospice. Median LOS was 5 days (range 0-77), but prolonged LOS was common, with 11 patients having LOS >14 days. Comparing the groups who received MT vs. IVT alone, the median initial NIHSS was 17 vs. 15 (p=0.23); the MT group had better baseline mRS (1 vs 3, p=0.005), but despite this, there were no significant differences in mortality (57% vs 41%) or discharge mRS (5 vs. 5). Median LOS was not significantly different (6 vs. 5 days). Mortality in MT was 75% for transfers vs. 53% for local arrivals (p=0.36).ConclusionDespite safe and technically successful treatment, outcomes were poor overall in the nonagenarian population after both MT +/- IVT, with very high morbidity and mortality.
RetroTest unravels LINE-1 retrotransposition in Head and Neck Squamous Cell Carcinoma
Authors: Brea-Iglesias Jenifer , Oitabén Ana , Zumalave Sonia , Rodriguez-Martin Bernardo , Gallardo-Gómez María , Santamarina Martín , Pequeño-Valtierra Ana , Juaneda-Magdalena Laura , García-Escudero Ramón , López-Cedrún José Luis , Fraga Máximo , Tubio José MC , Martínez-Fernández Mónica 
Published: July 2024

AbstractThe relevant role of LINE-1 (L1) retrotransposition in cancer has been recurrently demonstrated in recent years. However, their repetitive nature hampers their identification and detection, hence remaining inaccessible for clinical practice. Also, its clinical relevance for cancer patients is still limited. Here, we develop a new method to quantify L1 activation, called RetroTest, based on targeted sequencing and a sophisticated bioinformatic pipeline, allowing its application in tumor biopsies. First, we performed the benchmarking of the method and confirmed its high specificity and reliability. Then, we unravel the L1 activation in HNSCC according to a more extensive cohort including all the HNSCC tumor stages. Our results confirm that RetroTest is remarkably efficient for L1 detection in tumor biopsies, reaching a high sensitivity and specificity. In addition, L1 retrotransposition estimation reveals a surprisingly early activation in HNSCC progression, contrary to its classical association with advanced tumor stages. This early activation together with the genomic mutational profiling of normal adjacent tissues supports field cancerization process in this tumor. These results underline the importance of estimating L1 retrotransposition in clinical practice towards an earlier and more efficient diagnosis in HNSCC.HighlightsRetroTest represents the first method to determine LINE-1 retrotransposition from tumor biopsies in real clinical settings.RetroTest not only offers global LINE-1 retrotransposition ratios but also identifies the active LINE-1 source elements.RetroTest elucidates a really early LINE-1 activation in early tumor stages of Head and Neck Squamous Cell Carcinoma.Whole Genome Analysis and LINE-1 retrotransposition demonstrates processes of field cancerization in Head and Neck Squamous Cell Carcinoma.LINE-1 retrotransposition favors an earlier and more efficient Head and Neck Squamous Cell Carcinoma diagnosis.