bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preclinical Basis of the Efficacy and Pharmacodynamics of Finotonlimab, a Humanized Anti-PD-1 Monoclonal Antibody with Potent Implications for Clinical Benefit
Authors: Yang Xiaoning , Li Jing , Guo Erhong , Sun Chunyun , Zhang Xiao , Jia Jilei , Wang Rui , Ma Juan , Dai Yaqi , Deng Mingjing , Yu Chulin , Sun Lingling , Li Shuang , Xie Liangzhi 
Published: January 2023

AbstractBackgroundThe antibodies of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have dramatically changed the treatment landscapes for patients with cancer. Clinical uses of PD-1 antibodies have greatly improved the overall survival and durable responses in patients across selected tumor types.MethodsWe describe the preclinical characterization of Finotonlimab, a humanized anti-PD-1 antibody, by head to head comparison with Nivolumab or Pembrolizumab. Herein, we characterized the in vitro and in vivo efficacy, PK, PD and Fc mediated effector function of Finotonlimab. The single-agent anti-tumor activity of Finotonlimab was evaluated using humanized mouse models and a human PBMC reconstituted mouse model. Furthermore, in cynomolgus monkeys, comparative PK measurements confirmed better PK profiles of Finotonlimab than that of Pembrolizumab and Nivolumab.ResultsOur data showed Finotonlimab bind to human PD-1 with significantly high affinity and effectively inhibited its interaction with its ligands, PD-L1 and PD-L2, and thus could effectively stimulate the human T cell functionsin vitroand exhibited significant antitumor efficacyin vivo. In addition, Finotonlimab showed minimal impact on Fc receptor dependent effector cell activation, which may contribute to the killing of PD-1+T cells. In cynomolgus monkeys, Finotonlimab exhibited a non-linear pharmacokinetics (PK) profile in a dose-dependent manner, and approximately 90% of consistent receptor occupancy period was observed at 168 h after a single administration of 1 mg/kg. Following a 13-week successive administration of Finotonlimab, a pharmacodynamics study indicated a sustained mean receptor occupancy of ≥ 93% of PD-1 molecules on circulating T cells in cynomolgus monkeys up to 8 weeks even at 3 mg/kg.ConclusionsTaken together, these preclinical data are encouraging and provide a basis for the efficacy and pharmacodynamics of Finotonlimab in clinical trials.
A macroevolutionary role for chromosomal fusion and fission inErebiabutterflies
Authors: Augustijnen Hannah , Bätscher Livio , Cesanek Martin , Chkhartishvili Tinatin , Dincă Vlad , Iankoshvili Giorgi , Ogawa Kota , Vila Roger , Klopfstein Seraina , de Vos Jurriaan M. , Lucek Kay 
Published: January 2023

AbstractThe impact of large-scale chromosomal rearrangements, such as fusions and fissions, on speciation is a long-standing conundrum. We assessed whether bursts of change in chromosome numbers resulting from chromosomal fusion and fission are related to increased speciation rates inErebia, one of the most species-rich and karyotypically variable butterfly groups. We established a genome-based phylogeny and employed state-dependent birth-death models to infer trajectories of karyotype evolution across this genus. We demonstrated that rates of anagenetic chromosomal changes (i.e. along phylogenetic branches) exceed cladogenetic changes (i. e. at speciation events), but when cladogenetic changes occur, they are mostly associated with chromosomal fissions rather than fusions. Moreover, we found that the relative importance of fusion and fission differs amongErebiaclades of different ages, where especially in younger, more karyotypically diverse clades, speciation is more frequently associated with chromosomal changes. Overall, our results imply that chromosomal fusions and fissions have contrasting macroevolutionary roles and that large-scale chromosomal rearrangements are associated with bursts of species diversification.
Functional specialization and structured representations for space and time in prefrontal cortex
Authors: Böhm Claudia , Lee Albert K. 
Published: January 2023

ABSTRACTIndividual neurons in prefrontal cortex – a key brain area involved in cognitive functions – are selective for variables such as space or time, as well as more cognitive aspects of tasks, such as learned categories. Many neurons exhibit mixed selectivity, that is, they show selectivity for multiple variables. A fundamental question is whether neurons are functionally specialized for particular variables and how selectivity for different variables intersects across the population. Here, we analyzed neural correlates of space and time in rats performing a navigational task with two behaviorally important categories – starts and goals. Using simultaneous recordings of many medial prefrontal cortex (mPFC) neurons during behavior, we found that population codes for elapsed time were invariant to different locations within categories, and subsets of neurons had functional preferences for time or space across categories. Thus, mPFC exhibits structured selectivity, which may facilitate complex behaviors by efficiently generating informative representations of multiple variables.
Gaze patterns and brain activations in humans and marmosets in the Frith-Happé theory-of-mind animation task
Authors: Dureux Audrey , Zanini Alessandro , Selvanayagam Janahan , Menon Ravi S. , Everling Stefan 
Published: January 2023

AbstractTheory of Mind (ToM) refers to the ability to ascribe mental states to other individuals. This process is so strong that it extends even to the attribution of mental states to animations depicting interacting simple geometric shapes, such as in the Frith-Happé animations in which two triangles move either purposelessly (Random condition), or as if one triangle is reacting to the other triangle’s mental state (ToM condition). Currently, there is no evidence that nonhuman primates attribute mental states to moving abstract shapes. Here we investigated whether highly social marmosets (Callithrix jacchus) process ToM and Random Frith-Happé animations differently. Our results show that marmosets and humans (1) follow more closely one of the triangles during the observation of ToM compared to Random animations, and (2) activate large and comparable brain networks when viewing ToM compared to Random animations. These findings indicate that marmosets, like humans, process ToM animations differently from Random animations.
FROM FOREST TO SAVANNA AND BACK TO FOREST: EVOLUTIONARY HISTORY OF THE GENUSDimorphandra(LEGUMINOSAE)
Authors: Rocha Vinicius Delgado da , Dal’Sasso Thaís Carolina da Silva , Williams Christina Cleo Vinson , Simon Marcelo Fragomeni , Bueno Marcelo Leandro , Oliveira Luiz Orlando de 
Published: January 2023

AbstractThe tree genusDimorphandracomprises 26 species, which are circumscribed into three subgenera. The subgenusDimorphandrais associated with both rainforests (Amazon and Atlantic Forest) and savanna-like vegetation (Cerrado); whereas the subgeneraPocillumandPhaneropsiaare restricted to the Amazon. We obtained DNA sequence data from six gene regions of the chloroplast genome (cpDNA) and the nuclear internal transcribed spacer (ITS) from 17 species ofDimorphandraand 12 closely related species. Bayesian phylogeny and haplotype network analyses together with both ancestral area reconstructions and ecological niche modeling allowed for exploring the late evolutionary history of the genusDimorphandra. Species within the subgenusPhaneropsiawere more closely related to species of the genusMorathan to the remaining congeners in the plastid tree (but not in the ITS tree), casting doubts on the monophyly ofDimorphandra. Such incongruence may be the result of incomplete lineage sorting of ancient polymorphisms. Amazonian lineages (subgeneraPocillumandPhaneropsia) were highly polymorphic and divergent; whereas lineages from either the Cerrado or the Atlantic Forest were genetically depauperate. The Amazon seems to be the likely source of the lineage that gave rise to the extant species ofDimorphandraof the Cerrado. In turn, a lineage that occupied the Cerrado likely gave rise to the extant species that occur in the Atlantic Forest. Habitat shifts may have been a key driving force that shaped the late evolutionary history ofDimorphandra.
Dichotomy in TCR V-domain dynamics binding the opposed inclined planes of pMHC-II and pMHC-I α-helices
Authors: Murray Joseph S. 
Published: January 2023

AbstractLigand recognition by the human α/β T-cell antigen receptor (TCR) heterodimer protein, unlike the surface immunoglobulin (sIg) B-cell receptor, is not governed by relative binding affinity. Its interaction with the peptide (p) plus major histocompatibility complex (MHC) protein (abbrev. pMHC) likely involves some different molecular mechanism linking pMHC binding to T-cell functions. Recent analytical geometry of TCR:pMHC-II solved crystallographic structures (n= 40) revealed that each variable (V)-domain is bound in similar, yet mathematically unique orientations to its target pMHC groove. The relative position of the central cysteine of each V-domain was examined by multivariable calculus in spherical coordinates, where a simple volume element (dV) was found to describe clonotypic geometry with pMHC-II. Here, the study was expanded to include TCR:pMHC-I structures, and to model a physical mechanism, specifically involving the two directionally opposedinclined planes(IP) manifest by the two major α-helices prominent in both MHC-I and MHC-II proteins. Calculations for rotational torque of each V-domain, together with acceleration up and down the slopes of both MHC α-helices were used to estimate the time a given V-domain spends sliding down its cognate MHC IP. This V-domain rotation/sliding mechanism appears to be quantitatively unique for each TCR:pMHC V-domain (n= 40). However, there is an apparent and common dichotomy between the mobility of each V-domain with respect to the two classes of MHC proteins. Evolutionary motifs in the MHC helices support that the V-domains negotiate the opposed inclined planes of pMHC ligands in clonotypic fashion. Thus, this model is useful in understanding how mechanical forces are linked to TCR function.
3D Chromatin Dynamics during Innate and Adaptive Immune Memory Acquisition
Authors: Santosa Endi K. , Lau Colleen M. , Sahin Merve , Leslie Christina S. , Sun Joseph C. 
Published: January 2023

ABSTRACTImmune cells responding to pathogens undergo molecular changes that are intimately linked to genome organization. Recent work has demonstrated that natural killer (NK) and CD8+T cells experience substantial transcriptomic and epigenetic rewiring during their differentiation from naïve to effector to memory cells. Whether these molecular adaptations are accompanied by changes in three-dimensional (3D) chromatin architecture is unknown. In this study, we combine histone profiling, ATAC-seq, RNA-seq and high-throughput chromatin capture (HiC) assay to investigate the dynamics of one-dimensional (1D) and 3D chromatin during the differentiation of innate and adaptive lymphocytes. To this end, we discovered a coordinated 1D and 3D epigenetic remodeling during innate immune memory differentiation, and demonstrate that effector CD8+T cells adopt an NK-like architectural program that is maintained in memory cells. Altogether, our study reveals the dynamic nature of the 1D and 3D genome during the formation of innate and adaptive immunological memory.
Efficiency enhancement of microparticles seeding density on the inner surface of polymer hollow microfibers using microfluidics
Authors: Aykar Saurabh S. , Hashemi Nicole N. 
Published: January 2023

AbstractLateral displacement of microparticles suspended in a viscoelastic fluid flowing through a microfluidic channel occurs due to an imbalance in the first (N1) and second (N2) normal stress differences. Here, we studied the lateral displacement of fluorescent microparticles suspended in a polyethylene glycol (PEG) solution in a two-phase flow with aqueous sodium alginate, flowing through a unique microfluidic device that manufactures microparticles seeded alginate-based hollow microfibers. Parameters such as concentration of the aqueous sodium alginate and flow rate ratios were optimized to enhance microparticle seeding density and minimize their loss to the collection bath. 4 % w/v aqueous sodium alginate was observed to confine the suspended microparticles within the hollow region of microfibers as compared to 2 % w/v. Moreover, the higher flow rate ratio of the core fluid, 250μL min−1resulted in about 192 % increase in the microparticle seeding density as compared to its lower flow rate of 100μL min−1. The shear thinning index (m) was measured to be 0.91 for 2 % w/v and 0.75 for 4 % w/v sodium alginate solutions. These results help gain insights into understanding the microparticle displacement within a viscoelastic polymer solution flowing through a microfluidic channel and motivate further studies to investigate the cellular response with the optimized parameters.
Active Gαi/o mutants accelerate breast tumor metastasis via the c-Src pathway
Authors: Lyu Cancan , Bhimani Aarzoo K , Draus William T , Weigel Ronald , Chen Songhai 
Published: January 2023

AbstractConstitutively active mutations in the Gαi2and GαoAsubunits of heterotrimeric G proteins have been identified in several human cancers including breast cancer, but their functional significance in tumorigenesis and metastasis has not been well characterized. In this study, we show that expression of the constitutively active GαoAR243H and Gαi2R179C mutants alone was insufficient to induce mammary tumor formation in mice. However, in transgenic mouse models of breast cancer induced by Neu expression or PTEN loss, we found that the Gαi2R179C mutant enhanced spontaneous lung metastasis while having no effect on primary tumor initiation and growth. Additionally, we observed that ectopic expression of the GαoAR243H and Gαi2R179C mutants in tumor cells promote cell migrationin vitroas well as dissemination into multiple organsin vivoby activating c-Src signaling. Thus, our study uncovers a critical function of Gαi/osignaling in accelerating breast cancer metastasis via the c-Src pathway. This work is clinically significant, as it can potentially pave the way to personalized therapies for patients who present with active Gαi/omutations or elevated Gαi/osignaling by targeting c-Src to inhibit breast cancer metastasis.
Reintroducing genetic diversity in populations from cryopreserved material: The case of Abondance, a French local dairy cattle breed
Authors: Jacques Alicia , Leroy Grégoire , Rognon Xavier , Verrier Etienne , Tixier-Boichard Michèle , Restoux Gwendal 
Published: January 2023

AbstractBackgroundGenetic diversity is a necessary condition for populations to evolve under adaptation, selection or both. However, genetic diversity is often threatened, in particular in domestic animal populations where artificial selection, genetic drift and inbreeding are strong. In this context, cryopreserved genetic resources appear as a promising option to reintroduce lost variants and to limit inbreeding. However, while more common in plant breeding, the use of cryopreserved resources is less documented in animals due to a longer generation interval making it difficult to fill the performance gap due to continuous selection. Thus, this study investigates one of the only concrete cases presenting the results of the use of cryopreserved semen of a bull born in 1977 and belonging to a disappeared lineage, into the breeding scheme of a French local dairy cattle breed, the Abondance breed, more than 20 years later.ResultsWe found that this re-used bull was very original relative to the current population and thus allowed to restore genetic diversity lost over time. The expected negative gap in milk production due to continuous selection has been absorbed in a few years by preferential mating with elite cows. Moreover, the re-use of this old bull did not increase the level of inbreeding, it even tended to reduce it by avoiding mating with relatives. Finally, the reintroduction of an old bull in the breeding scheme allowed for increased performance for reproductive abilities, a trait that was less subject to selection in the past.ConclusionsThe use of cryopreserved material was efficient to manage the genetic diversity of an animal population, by mitigating the effects of both inbreeding and strong selection. However, attention should be paid toward mating in order to limit the disadvantages associated with the provision of genetic originality, notably a discrepancy in the breeding values for selected traits or an increase in inbreeding. Therefore, a careful characterization of the genetic resources available in cryobanks could help to ensure the sustainable management of populations and of local or small ones in particular. These results could also be transferred to the conservation of wild populations.
Structural basis of peptide recognition and activation of endothelin receptors
Authors: Ji Yujie , Duan Jia , Yuan Qingning , He Xinheng , Yang Gong , Zhu Shengnan , Wu Kai , Hu Wen , Gao Tianyu , Cheng Xi , Jiang Hualiang , Xu H. Eric , Jiang Yi 
Published: January 2023

AbstractEndothelin system comprises three endogenous 21-amino-acid peptide ligands endothelin-1, -2, and -3 (ET-1/2/3), and two G protein-coupled receptor (GPCR) subtypes—endothelin receptor A (ETAR) and B (ETBR). Since ET-1, the first endothelin, was identified in 1988 as one of the most potent endothelial cell-derived vasoconstrictor peptides with long-lasting actions, the endothelin system has attracted extensive attention due to its critical role in vasoregulation and close relevance in cardiovascular-related diseases. Here we present three cryo-electron microscopy structures of ETAR and ETBR bound to ET-1 and ETBR bound to the selective peptide IRL1620. These structures reveal a highly conserved recognition mode of ET-1 and characterize the ligand selectivity by ETRs. They also present several conformation features of the active ETRs, thus revealing a specific activation mechanism. Together, these findings deepen our understanding of endothelin system regulation and offer an opportunity to design selective drugs targeting specific ETR subtypes.
Globoside and the mucosal pH mediate parvovirus B19 entry through the epithelial barrier
Authors: Suter Corinne , Colakovic Minela , Bieri Jan , Gultom Mitra , Dijkman Ronald , Ros Carlos 
Published: January 2023

AbstractParvovirus B19 (B19V) is transmitted primarily via the respiratory route, however, the mechanism involved remains unknown. B19V targets a restricted receptor expressed in erythroid progenitor cells in the bone marrow. However, B19V shifts the receptor under acidic conditions and targets the widely expressed globoside. The pH-dependent interaction with globoside may allow virus entry through the naturally acidic nasal mucosa. To test this hypothesis, MDCK II cells and well-differentiated human airway epithelial cell (hAEC) cultures were grown on porous membranes and used as models to study the interaction of B19V with the epithelial barrier. Globoside expression was detected in polarized MDCK II cells and the ciliated cell population of well-differentiated hAEC cultures. Under the acidic conditions of the nasal mucosa, virus attachment and transcytosis occurred without productive infection. Neither virus attachment nor transcytosis was observed under neutral pH conditions or in globoside knockout cells, demonstrating the concerted role of globoside and acidic pH in the transcellular transport of B19V. Globoside-dependent virus uptake involved VP2 and occurred by a clathrin-independent pathway that is cholesterol and dynamin-dependent. This study provides mechanistic insight into the transmission of B19V through the respiratory route and reveals novel vulnerability factors of the epithelial barrier to viruses.Author summaryThe mechanism of entry of parvovirus B19 through the respiratory epithelium remains elusive. By using polarized MDCK II and well-differentiated primary human airway epithelial cell cultures, we revealed that the virus exploits the natural acidic environment of the nasal mucosa and the expression of globoside in the ciliated cell population of the airway to breach the respiratory epithelium by transcytosis. Mechanistically, virus entry and intracellular trafficking in the epithelial cells differ substantially from that in the permissive erythroid progenitor cells.
PLOD2, a key factor for MRL MSC metabolism and chondroprotective properties
Authors: Bahraoui Sarah , Tejedor Gautier , Mausset-Bonnefont Anne-Laure , Autelitano François , Jorgensen Christian , Wei Mingxing , Djouad Farida 
Published: January 2023

AbstractBackgroundInitially discovered for its ability to regenerate ear holes, the MRL mouse has been the subject of multiple research studies aimed at evaluating its ability to regenerate other body tissues and at deciphering the mechanisms underlying it. These enhanced abilities to regenerate, retained in the adult, protect the MRL mouse from degenerative diseases such as osteoarthritis (OA). Here, we hypothesized that MSC derived from the regenerative MRL mouse could be involved in their regenerative potential through the release of pro-regenerative mediators.MethodTo address this hypothesis, we compared the secretome of MRL and BL6 MSC and identified several candidate molecules produced at significantly higher levels by MRL MSC than by BL6 MSC. We selected one candidate and performed functionalin vitroassays to evaluate its role on MRL MSC properties including metabolic profile, migration, and chondroprotective effects. Using an experimental model for osteoarthritis (OA) induced by collagenase (CiOA), we assessed its contribution to MRL MSC protection from OA.ResultsAmong the candidate molecules highly expressed by MRL MSC, we focused our attention on procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2), coding for the lysyl hydrolase LH2 in charge of post-translational modifications of collagen for its stability and stiffness. PLOD2 is induced by hypoxia-inducible factor 1-alpha (HIF-1a) involved in the regeneration process of adult MRL mice.Plod2silencing induced a decrease in the glycolytic function of MRL MSC, resulting in the alteration of their migratory and chondroprotective abilitiesin vitro. In vivo, we showed thatplod2silencing in MRL MSC significantly impaired their capacity to protect mouse from developing OA.ConclusionOur results demonstrate that the chondroprotective and therapeutic properties of MRL MSC in the CiOA experimental model are in part mediated by PLOD2.