bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lenalidomide derivatives and proteolysis-targeting chimeras for controlling neosubstrate degradation
Authors: Yamanaka Satoshi , Furihata Hirotake , Yanagihara Yuta , Taya Akihito , Nagasaka Takato , Usui Mai , Nagaoka Koya , Shoya Yuki , Nishino Kohei , Yoshida Shuhei , Kosako Hidetaka , Tanokura Masaru , Miyakawa Takuya , Imai Yuuki , Shibata Norio , Sawasaki Tatsuya 
Published: August 2023

AbstractLenalidomide, an immunomodulatory drug (IMiD), is commonly used as a first-line therapy in many haematological cancers, such as multiple myeloma (MM) and 5q myelodysplastic syndromes (5q MDS), and it functions as a molecular glue for the protein degradation of neosubstrates by CRL4CRBN. Proteolysis-targeting chimeras (PROTACs) using IMiDs with a target protein binder also induce the degradation of target proteins. The targeted protein degradation (TPD) of neosubstrates is crucial for IMiD therapy. However, current IMiDs and IMiD-based PROTACs also break down neosubstrates involved in embryonic development and disease progression. Here, we show that 6-position modifications of lenalidomide are essential for controlling neosubstrate selectivity; 6-fluoro lenalidomide induced the selective degradation of IKZF1, IKZF3, and CK1α, which are involved in anti-haematological cancer activity, and showed stronger anti-proliferative effects on MM and 5q MDS cell lines than lenalidomide. PROTACs using these lenalidomide derivatives for BET proteins induce the selective degradation of BET proteins with the same neosubstrate selectivity. PROTACs also exert anti-proliferative effects in all examined cell lines. Thus, 6-position-modified lenalidomide is a key molecule for selective TPD using thalidomide derivatives and PROTACs.
A brainstem to circadian system circuit links Tau pathology to sundowning-related disturbances in an Alzheimer’s disease mouse model
Authors: Warfield Andrew E. , Gupta Pooja , Ruhmann Madison M. , Jeffs Quiana L. , Guidone Genevieve C. , Rhymes Hannah W. , Thompson McKenzi I. , Todd William D. 
Published: August 2023

AbstractAlzheimer’s disease (AD) patients exhibit progressive disruption of entrained circadian rhythms and an aberrant circadian input pathway may underlie such dysfunction. Here we examine AD-related pathology and circadian dysfunction in the APPSwe-Tau (TAPP) model of AD. We show these mice exhibit phase delayed body temperature and locomotor activity with increases around the active-to-rest phase transition. Similar AD-related disruptions are associated with sundowning, characterized by late afternoon and early evening agitation and aggression, and we show TAPP mice exhibit increased aggression around this transition. We show such circadian dysfunction and aggression coincide with hyperphosphorylated Tau (pTau) development in lateral parabrachial (LPB) neurons, with these disturbances appearing earlier in females. Finally, we show LPB neurons, including those expressing dynorphin (LPBdyn), project to circadian structures and are affected by pTau, and LPBdyn ablations partially recapitulate the hyperthermia of TAPP mice. Altogether we link pTau in a brainstem circadian input pathway to AD-related disturbances relevant to sundowning.
The net electrostatic potential and hydration of ABCG2 affect substrate transport
Authors: Gose Tomoka , Aitken Heather M. , Wang Yao , Lynch John , Rampersaud Evadnie , Fukuda Yu , Wills Medb , Baril Stefanie A. , Ford Robert C. , Shelat Anang , O’Mara Megan L. , Schuetz John D. 
Published: August 2023

AbstractABCG2 is a medically important ATP-binding cassette transporter with crucial roles in the absorption and distribution of chemically-diverse toxins and drugs, reducing the cellular accumulation of chemotherapeutic drugs to facilitate multidrug resistance in cancer. ABCG2’s capacity to transport both hydrophilic and hydrophobic compounds is not well understood. Here we assess the molecular basis for substrate discrimination by the binding pocket. Substitution of a phylogenetically-conserved polar residue, N436, to alanine in the binding pocket of human ABCG2 permits only hydrophobic substrate transport, revealing the unique role of N436 as a discriminator. Molecular dynamics simulations show that this alanine substitution alters the electrostatic potential of the binding pocket favoring hydration of the transport pore. This change affects the contact with substrates and inhibitors, abrogating hydrophilic compound transport while retaining the transport of hydrophobic compounds. The N436 residue is also required for optimal transport inhibition of ABCG2, as many inhibitors are functionally impaired by this ABCG2 mutation. Overall, these findings have biomedical implications, broadly extending our understanding of substrate and inhibitor interactions.
Early-adulthood spike in protein translation drives aging via juvenile hormone/germline signaling
Authors: Kim Harper S. , Parker Danitra J. , Hardiman Madison M. , Munkácsy Erin , Jiang Nisi , Rogers Aric N. , Bai Yidong , Brent Colin , Mobley James A. , Austad Steven N. , Pickering Andrew M. 
Published: August 2023

AbstractProtein translation (PT) declines with age in invertebrates, rodents, and humans. It has been assumed that elevated PT at young ages is beneficial to health and PT ends up dropping as a passive byproduct of aging. In Drosophila, we show that a transient elevation in PT during early-adulthood exerts long-lasting negative impacts on aging trajectories and proteostasis in later-life. Blocking the early-life PT elevation robustly improves life-/health-span and prevents age-related protein aggregation, whereas transiently inducing an early-life PT surge in long-lived fly strains abolishes their longevity/proteostasis benefits. The early-life PT elevation triggers proteostatic dysfunction, silences stress responses, and drives age-related functional decline via juvenile hormone-lipid transfer protein axis and germline signaling. Our findings suggest that PT is adaptively suppressed after early-adulthood, alleviating later-life proteostatic burden, slowing down age-related functional decline, and improving lifespan. Our work provides a theoretical framework for understanding how lifetime PT dynamics shape future aging trajectories.
A genome-wide association study of blood cell morphology identifies cellular proteins implicated in disease aetiology
Authors: Akbari Parsa , Vuckovic Dragana , Stefanucci Luca , Jiang Tao , Kundu Kousik , Kreuzhuber Roman , Bao Erik L. , Collins Janine H. , Downes Kate , Grassi Luigi , Guerrero Jose A. , Kaptoge Stephen , Knight Julian C. , Meacham Stuart , Sambrook Jennifer , Seyres Denis , Stegle Oliver , Verboon Jeffrey M. , Walter Klaudia , Watkins Nicholas A. , Danesh John , Roberts David J. , Di Angelantonio Emanuele , Sankaran Vijay G. , Frontini Mattia , Burgess Stephen , Kuijpers Taco , Peters James E. , Butterworth Adam S. , Ouwehand Willem H. , Soranzo Nicole , Astle William J. 
Published: August 2023

AbstractBlood cells contain functionally important intracellular structures, such as granules, critical to immunity and thrombosis. Quantitative variation in these structures has not been subjected previously to large-scale genetic analysis. We perform genome-wide association studies of 63 flow-cytometry derived cellular phenotypes—including cell-type specific measures of granularity, nucleic acid content and reactivity—in 41,515 participants in the INTERVAL study. We identify 2172 distinct variant-trait associations, including associations near genes coding for proteins in organelles implicated in inflammatory and thrombotic diseases. By integrating with epigenetic data we show that many intracellular structures are likely to be determined in immature precursor cells. By integrating with proteomic data we identify the transcription factor FOG2 as an early regulator of platelet formation and α-granularity. Finally, we show that colocalisation of our associations with disease risk signals can suggest aetiological cell-types—variants in IL2RA and ITGA4 respectively mirror the known effects of daclizumab in multiple sclerosis and vedolizumab in inflammatory bowel disease.
Engineered NIR-II fluorophores with ultralong-distance molecular packing for high-contrast deep lesion identification
Authors: Feng Zhe , Li Yuanyuan , Chen Siyi , Li Jin , Wu Tianxiang , Ying Yanyun , Zheng Junyan , Zhang Yuhuang , Zhang Jianquan , Fan Xiaoxiao , Yu Xiaoming , Zhang Dan , Tang Ben Zhong , Qian Jun 
Published: August 2023

AbstractThe limited signal of long-wavelength near-infrared-II (NIR-II, 900–1880 nm) fluorophores and the strong background caused by the diffused photons make high-contrast fluorescence imaging in vivo with deep tissue disturbed still challenging. Here, we develop NIR-II fluorescent small molecules with aggregation-induced emission properties, high brightness, and maximal emission beyond 1200 nm by enhancing electron-donating ability and reducing the donor-acceptor (D-A) distance, to complement the scarce bright long-wavelength emissive organic dyes. The convincing single-crystal evidence of D-A-D molecular structure reveals the strong inhibition of the π-π stacking with ultralong molecular packing distance exceeding 8 Å. The delicately-designed nanofluorophores with bright fluorescent signals extending to 1900 nm match the background-suppressed imaging window, enabling the signal-to-background ratio of the tissue image to reach over 100 with the tissue thickness of ~4–6 mm. In addition, the intraluminal lesions with strong negatively stained can be identified with almost zero background. This method can provide new avenues for future long-wavelength NIR-II molecular design and biomedical imaging of deep and highly scattering tissues.
Phase I/II trial of a peptide-based COVID-19 T-cell activator in patients with B-cell deficiency
Authors: Heitmann Jonas S. , Tandler Claudia , Marconato Maddalena , Nelde Annika , Habibzada Timorshah , Rittig Susanne M. , Tegeler Christian M. , Maringer Yacine , Jaeger Simon U. , Denk Monika , Richter Marion , Oezbek Melek T. , Wiesmüller Karl-Heinz , Bauer Jens , Rieth Jonas , Wacker Marcel , Schroeder Sarah M. , Hoenisch Gravel Naomi , Scheid Jonas , Märklin Melanie , Henrich Annika , Klimovich Boris , Clar Kim L. , Lutz Martina , Holzmayer Samuel , Hörber Sebastian , Peter Andreas , Meisner Christoph , Fischer Imma , Löffler Markus W. , Peuker Caroline Anna , Habringer Stefan , Goetze Thorsten O. , Jäger Elke , Rammensee Hans-Georg , Salih Helmut R. , Walz Juliane S. 
Published: August 2023

AbstractT-cell immunity is central for control of COVID-19, particularly in patients incapable of mounting antibody responses. CoVac-1 is a peptide-based T-cell activator composed of SARS-CoV-2 epitopes with documented favorable safety profile and efficacy in terms of SARS-CoV-2-specific T-cell response. We here report a Phase I/II open-label trial (NCT04954469) in 54 patients with congenital or acquired B-cell deficiency receiving one subcutaneous CoVac-1 dose. Immunogenicity in terms of CoVac-1-induced T-cell responses and safety are the primary and secondary endpoints, respectively. No serious or grade 4 CoVac-1-related adverse events have been observed. Expected local granuloma formation has been observed in 94% of study subjects, whereas systemic reactogenicity has been mild or absent. SARS-CoV-2-specific T-cell responses have been induced in 86% of patients and are directed to multiple CoVac-1 peptides, not affected by any current Omicron variants and mediated by multifunctional T-helper 1 CD4+ T cells. CoVac-1-induced T-cell responses have exceeded those directed to the spike protein after mRNA-based vaccination of B-cell deficient patients and immunocompetent COVID-19 convalescents with and without seroconversion. Overall, our data show that CoVac-1 induces broad and potent T-cell responses in patients with B-cell/antibody deficiency with a favorable safety profile, which warrants advancement to pivotal Phase III safety and efficacy evaluation. ClinicalTrials.gov identifier NCT04954469.
Momentum-independent magnetic excitation continuum in the honeycomb iridate H3LiIr2O6
Authors: de la Torre A. , Zager B. , Bahrami F. , Upton M. H. , Kim J. , Fabbris G. , Lee G.-H. , Yang W. , Haskel D. , Tafti F. , Plumb K. W. 
Published: August 2023

AbstractUnderstanding the interplay between the inherent disorder and the correlated fluctuating-spin ground state is a key element in the search for quantum spin liquids. H3LiIr2O6 is considered to be a spin liquid that is proximate to the Kitaev-limit quantum spin liquid. Its ground state shows no magnetic order or spin freezing as expected for the spin liquid state. However, hydrogen zero-point motion and stacking faults are known to be present. The resulting bond disorder has been invoked to explain the existence of unexpected low-energy spin excitations, although data interpretation remains challenging. Here, we use resonant X-ray spectroscopies to map the collective excitations in H3LiIr2O6 and characterize its magnetic state. In the low-temperature correlated state, we reveal a broad bandwidth of magnetic excitations. The central energy and the high-energy tail of the continuum are consistent with expectations for dominant ferromagnetic Kitaev interactions between dynamically fluctuating spins. Furthermore, the absence of a momentum dependence to these excitations are consistent with disorder-induced broken translational invariance. Our low-energy data and the energy and width of the crystal field excitations support an interpretation of H3LiIr2O6 as a disordered topological spin liquid in close proximity to bond-disordered versions of the Kitaev quantum spin liquid.
Spatial patterns of vascular plant species richness in Poland - a data set
Authors: Szymura Tomasz H. , Kassa Henok , Swacha Grzegorz , Szymura Magdalena , Zając Adam , Kącki Zygmunt 
Published: August 2023

AbstractRecognition of species richness spatial patterns is important for nature conservation and theoretical studies. Inventorying species richness, especially at a larger spatial extent is challenging, thus different data sources are joined and harmonized to obtain a comprehensive data set. Here we present a new data set showing vascular plant species richness in Poland based on a grid of 10 × 10 km squares. The data set was created using data from two sources: the Atlas of Distribution of Vascular Plants in Poland and the Polish Vegetation Database. Using this data set, we analysed 2,160 species with taxonomical nomenclature according to the Euro + Med PlantBase checklist in 3,283 squares covering the entire territory of Poland (ca. 312,000 km2). The species were divided into groups according to their status and frequency of distribution, and the statistics for each square were obtained. For purposes of analysis, sampling bias was assessed. The data set promotes theoretical analysis on species richness and reinforces the planning of nature conservations.
Condensed tannins, novel compounds and sources of variation determine the antiparasitic activity of Nordic conifer bark against gastrointestinal nematodes
Authors: Chylinski Caroline , Degnes Kristin Fløgstad , Aasen Inga Marie , Ptochos Sokratis , Blomstrand Berit Marie , Mahnert Karl-Christian , Enemark Heidi Larsen , Thamsborg Stig Milan , Steinshamn Håvard , Athanasiadou Spiridoula 
Published: August 2023

AbstractThe antiparasitic potential of plants could offer a vital solution to alleviating the costs of gastrointestinal nematode (GIN) infections in ruminant production globally. Leveraging known bioactive molecules, however, is complex, where plant species, extraction processes and seasonality impact bioavailability and efficacy. This study assessed the impact of a comprehensive set of factors on the antiparasitic activity of Norwegian conifers to identify bark compounds specific against GIN. Antiparasitic activity was determined using in vitro assays targeting morphologically distinct life stages of ovine GIN: the egg hatch assay and larval motility assay. In depth characterisation of the chemical composition of the bark extracts was carried out using chromatographic separation, UV-absorbance, and molecular mass profiles to identify compounds implicated in the activity. Three key findings emerged: (1) the activity of bark extracts varied markedly from 0 to 100% antiparasitic efficacy, owing to tree species, extraction solvent and seasonality; (2) the GIN exhibited species-and stage-specific susceptibility to the bark extracts; (3) the presence of condensed tannins, amongst other compounds, was associated with anthelmintic activity. These findings add new insights into urgently needed alternative parasite control strategies in livestock.
Solving ordinary and partial differential equations using an analog computing system based on ultrasonic metasurfaces
Authors: Uy Robert Frederik , Bui Viet Phuong 
Published: August 2023

AbstractWave-based analog computing has recently emerged as a promising computing paradigm due to its potential for high computational efficiency and minimal crosstalk. Although low-frequency acoustic analog computing systems exist, their bulky size makes it difficult to integrate them into chips that are compatible with complementary metal-oxide semiconductors (CMOS). This research paper addresses this issue by introducing a compact analog computing system (ACS) that leverages the interactions between ultrasonic waves and metasurfaces to solve ordinary and partial differential equations. The results of our wave propagation simulations, conducted using MATLAB, demonstrate the high accuracy of the ACS in solving such differential equations. Our proposed device has the potential to enhance the prospects of wave-based analog computing systems as the supercomputers of tomorrow.
Differential gut microbiome in spondyloarthritis patients associated to Blastocystis colonization
Authors: Nieto-Clavijo Carlos , Morales Liliana , Marquez-Ortiz Ricaurte Alejandro , Romero-Sánchez Consuelo , Ramos-Casallas Alejandro , Escobar-Perez Javier , Bautista-Molano Wilson , Bello-Gualtero Juan Manuel , Chaparro-Olaya Jacqueline 
Published: August 2023

AbstractThe role ofBlastocystisin intestinal health is an open controversy, and little is known about the potential effect of this microorganism in autoinflammatory diseases such as spondyloarthritis (SpA). Here, we analyzed the gut microbiome of 36 SpA patients and 13 control individuals and demonstrated that the richness, diversity, and taxonomic composition between these two groups are different. We also showed that colonization byBlastocystisin control individuals increases the richness and diversity of the intestinal microbiome, whereas in SpA patients, it does not seem to have any impact. This may reflect a potential role ofBlastocystisin sculpting the gut microbiome architecture in control individuals, whereas in subjects with SpA, the modulation of the microbiome may be governed by disease-dependent factors that cannot be overcome byBlastocystis. Regarding taxonomic characterization, SpA patients colonized byBlastocystisshowed significant increases in the phylumPseudomonadota, classGammaproteobacteria, familySuccinivibrionaceae, and genusSuccinivibrio. Simultaneously, there were significant increases in the classBacilli, orderLactobacillales, familiesLactobacillaceaeandClostridiaceae,and generaLactobacillusandClostridiumin non-colonized SpA patients. On the other hand, PICRUSt analysis inBlastocystis-positive SpA patients showed elevations in pathways that may enhance antioxidant capacities and alleviate intestinal inflammation, whileBlastocystis-negative SpA patients showed significant changes in pathways that promote cell division/proliferation and can lead to larger changes in the gut microbiome. Our analyses lead us to believe that these changes in the gut microbiome of SpA patients may trigger protective mechanisms as an initial response to inflammation in an attempt to restore balance in the intestinal environment.
The interleukin-11 receptor variant p.W307R results in craniosynostosis in humans
Authors: Ahmad Ilyas , Lokau Juliane , Kespohl Birte , Malik Naveed Altaf , Baig Shahid Mahmood , Hartig Roland , Behme Daniel , Schwab Roland , Altmüller Janine , Jameel Muhammad , Mucha Sören , Thiele Holger , Tariq Muhammad , Nürnberg Peter , Erdmann Jeanette , Garbers Christoph 
Published: August 2023

AbstractCraniosynostosis is characterized by the premature fusion and ossification of one or more of the sutures of the calvaria, often resulting in abnormal features of the face and the skull. In cases in which growth of the brain supersedes available space within the skull, developmental delay or cognitive impairment can occur. A complex interplay of different cell types and multiple signaling pathways are required for correct craniofacial development. In this study, we report on two siblings with craniosynostosis and a homozygous missense pathogenic variant within the IL11RA gene (c.919 T > C; p.W307R). The patients present with craniosynostosis, exophthalmos, delayed tooth eruption, mild platybasia, and a basilar invagination. The p.W307R variant is located within the arginine-tryptophan-zipper within the D3 domain of the IL-11R, a structural element known to be important for the stability of the cytokine receptor. Expression of IL-11R-W307R in cells shows impaired maturation of the IL-11R, no transport to the cell surface and intracellular retention. Accordingly, cells stably expressing IL-11R-W307R do not respond when stimulated with IL-11, arguing for a loss-of-function mutation. In summary, the IL-11R-W307R variant, reported here for the first time to our knowledge, is most likely the causative variant underlying craniosynostosis in these patients.
Generative adversarial networks based skin lesion segmentation
Authors: Innani Shubham , Dutande Prasad , Baid Ujjwal , Pokuri Venu , Bakas Spyridon , Talbar Sanjay , Baheti Bhakti , Guntuku Sharath Chandra 
Published: August 2023

AbstractSkin cancer is a serious condition that requires accurate diagnosis and treatment. One way to assist clinicians in this task is using computer-aided diagnosis tools that automatically segment skin lesions from dermoscopic images. We propose a novel adversarial learning-based framework called Efficient-GAN (EGAN) that uses an unsupervised generative network to generate accurate lesion masks. It consists of a generator module with a top-down squeeze excitation-based compound scaled path, an asymmetric lateral connection-based bottom-up path, and a discriminator module that distinguishes between original and synthetic masks. A morphology-based smoothing loss is also implemented to encourage the network to create smooth semantic boundaries of lesions. The framework is evaluated on the International Skin Imaging Collaboration Lesion Dataset. It outperforms the current state-of-the-art skin lesion segmentation approaches with a Dice coefficient, Jaccard similarity, and accuracy of 90.1%, 83.6%, and 94.5%, respectively. We also design a lightweight segmentation framework called Mobile-GAN (MGAN) that achieves comparable performance as EGAN but with an order of magnitude lower number of training parameters, thus resulting in faster inference times for low compute resource settings.