bluuebunny/crossref_metadata_2025_split huggingface dataset:
mTORC1 signaling pathway regulates tooth repair
Authors: Liu Honghong , Yue Yu , Xu Zhiyun , Guo Li , Wu Chuan , Zhang Da , Luo Lingfei , Huang Wenming , Chen Hong , Yang Deqin 
Published: March 2023

AbstractTooth germ injury can lead to abnormal tooth development and even tooth loss, affecting various aspects of the stomatognathic system including form, function, and appearance. However, the research about tooth germ injury model on cellular and molecule mechanism of tooth germ repair is still very limited. Therefore, it is of great importance for the prevention and treatment of tooth germ injury to study the important mechanism of tooth germ repair by a tooth germ injury model. Here, we constructed a Tg(dlx2b:Dendra2-NTR) transgenic line that labeled tooth germ specifically. Taking advantage of the NTR/Mtz system, the dlx2b+ tooth germ cells were depleted by Mtz effectively. The process of tooth germ repair was evaluated by antibody staining, in situ hybridization, EdU staining and alizarin red staining. The severely injured tooth germ was repaired in several days after Mtz treatment was stopped. In the early stage of tooth germ repair, the expression of phosphorylated 4E-BP1 was increased, indicating that mTORC1 is activated. Inhibition of mTORC1 signaling in vitro or knockdown of mTORC1 signaling in vivo could inhibit the repair of injured tooth germ. Normally, mouse incisors were repaired after damage, but inhibition/promotion of mTORC1 signaling inhibited/promoted this repair progress. Overall, we are the first to construct a stable and repeatable repair model of severe tooth germ injury, and our results reveal that mTORC1 signaling plays a crucial role during tooth germ repair, providing a potential target for clinical treatment of tooth germ injury.
Angular momentum holography via a minimalist metasurface for optical nested encryption
Authors: Yang Hui , He Peng , Ou Kai , Hu Yueqiang , Jiang Yuting , Ou Xiangnian , Jia Honghui , Xie Zhenwei , Yuan Xiaocong , Duan Huigao 
Published: March 2023

AbstractMetasurfaces can perform high-performance multi-functional integration by manipulating the abundant physical dimensions of light, demonstrating great potential in high-capacity information technologies. The orbital angular momentum (OAM) and spin angular momentum (SAM) dimensions have been respectively explored as the independent carrier for information multiplexing. However, fully managing these two intrinsic properties in information multiplexing remains elusive. Here, we propose the concept of angular momentum (AM) holography which can fully synergize these two fundamental dimensions to act as the information carrier, via a single-layer, non-interleaved metasurface. The underlying mechanism relies on independently controlling the two spin eigenstates and arbitrary overlaying them in each operation channel, thereby spatially modulating the resulting waveform at will. As a proof of concept, we demonstrate an AM meta-hologram allowing the reconstruction of two sets of holographic images, i.e., the spin-orbital locked and the spin-superimposed ones. Remarkably, leveraging the designed dual-functional AM meta-hologram, we demonstrate a novel optical nested encryption scheme, which is able to achieve parallel information transmission with ultra-high capacity and security. Our work opens a new avenue for optionally manipulating the AM, holding promising applications in the fields of optical communication, information security and quantum science.
Sperm quality metrics were improved by a biomimetic microfluidic selection platform compared to swim-up methods
Authors: Vasilescu Steven A. , Ding Lin , Parast Farin Yazdan , Nosrati Reza , Warkiani Majid Ebrahimi 
Published: March 2023

AbstractSperm selection is an essential component of all assisted reproductive treatments (ARTs) and is by far the most neglected step in the ART workflow in regard to technological innovation. Conventional sperm selection methodologies typically produce a higher total number of sperm with variable motilities, morphologies, and levels of DNA integrity. Gold-standard techniques, including density gradient centrifugation (DGC) and swim-up (SU), have been shown to induce DNA fragmentation through introducing reactive oxygen species (ROS) during centrifugation. Here, we demonstrate a 3D printed, biologically inspired microfluidic sperm selection device (MSSP) that utilizes multiple methods to simulate a sperms journey toward selection. Sperm are first selected based on their motility and boundary-following behavior and then on their expression of apoptotic markers, yielding over 68% more motile sperm than that of previously reported methods with a lower incidence of DNA fragmentation and apoptosis. Sperm from the MSSP also demonstrated higher motile sperm recovery after cryopreservation than that of SU or neat semen. Experiments were conducted side-by-side against conventional SU methods using human semen (n = 33) and showed over an 85% improvement in DNA integrity with an average 90% reduction in sperm apoptosis. These results that the platform is easy-to-use for sperm selection and mimics the biological function of the female reproductive tract during conception.
Dual-signal readout paper-based wearable biosensor with a 3D origami structure for multiplexed analyte detection in sweat
Authors: Cheng Yuemeng , Feng Shaoqing , Ning Qihong , Li Tangan , Xu Hao , Sun Qingwen , Cui Daxiang , Wang Kan 
Published: March 2023

AbstractIn this research, we design and implement a small, convenient, and noninvasive paper-based microfluidic sweat sensor that can simultaneously detect multiple key biomarkers in human sweat. The origami structure of the chip includes colorimetric and electrochemical sensing regions. Different colorimetric sensing regions are modified with specific chromogenic reagents to selectively identify glucose, lactate, uric acid, and magnesium ions in sweat, as well as the pH value. The regions of electrochemical sensing detect cortisol in sweat by molecular imprinting. The entire chip is composed of hydrophilically and hydrophobically treated filter paper, and 3D microfluidic channels are constructed by using folding paper. The thread-based channels formed after the hydrophilic and hydrophobic modifications are used to control the rate of sweat flow, which in turn can be used to control the sequence of reactions in the differently developing colored regions to ensure that signals of the best color can be captured simultaneously by the colorimetric sensing regions. Finally, the results of on-body experiments verify the reliability of the proposed sweat sensor and its potential for the noninvasive identification of a variety of sweat biomarkers.
HSV-1 cellular model reveals links between aggresome formation and early step of Alzheimer’s disease
Authors: Albaret Marie Alexandra , Textoris Julien , Dalzon Bastien , Lambert Jérémy , Linard Morgane , Helmer Catherine , Hacot Sabine , Ghayad Sandra E. , Ferréol Martial , Mertani Hichem C. , Diaz Jean-Jacques 
Published: March 2023

AbstractMany studies highlight the potential link between the chronic degenerative Alzheimer’s disease and the infection by the herpes simplex virus type-1 (HSV-1). However, the molecular mechanisms making possible this HSV-1-dependent process remain to be understood. Using neuronal cells expressing the wild type form of amyloid precursor protein (APP) infected by HSV-1, we characterized a representative cellular model of the early stage of the sporadic form of the disease and unraveled a molecular mechanism sustaining this HSV-1- Alzheimer’s disease interplay. Here, we show that HSV-1 induces caspase-dependent production of the 42 amino-acid long amyloid peptide (Aβ42) oligomers followed by their accumulation in neuronal cells. Aβ42 oligomers and activated caspase 3 (casp3A) concentrate into intracytoplasmic structures observed in Alzheimer’s disease neuronal cells called aggresomes. This casp3A accumulation in aggresomes during HSV-1 infection limits the execution of apoptosis until its term, similarly to an abortosis-like event occurring in Alzheimer’s disease neuronal cells patients. Indeed, this particular HSV-1 driven cellular context, representative of early stages of the disease, sustains a failed apoptosis mechanism that could explain the chronic amplification of Aβ42 production characteristic of Alzheimer’s disease patients. Finally, we show that combination of flurbiprofen, a non-steroidal anti-inflammatory drug (NSAID), with caspase inhibitor reduced drastically HSV-1-induced Aβ42 oligomers production. This provided mechanistic insights supporting the conclusion of clinical trials showing that NSAIDs reduced Alzheimer’s disease incidence in early stage of the disease. Therefore, from our study we propose that caspase-dependent production of Aβ42 oligomers together with the abortosis-like event represents a vicious circle in early Alzheimer’s disease stages leading to a chronic amplification of Aβ42 oligomers that contributes to the establishment of degenerative disorder like Alzheimer’s disease in patients infected by HSV-1. Interestingly this process could be targeted by an association of NSAID with caspase inhibitors.
Immuno-regulatory malignant B cells contribute to Chronic Lymphocytic Leukemia progression
Authors: Mékinian Arsène , Quinquenel Anne , Belkacem Koceïla Ait , Kanoun Feriel , Dondi Elisabetta , Franck Emilie , Boubaya Marouane , Mhibik Maïssa , Baran-Marszak Fanny , Letestu Rémi , Ajchenbaum-Cymbalista Florence , Lévy Vincent , Varin-Blank Nadine , Le Roy Christine 
Published: March 2023

AbstractChronic Lymphocytic Leukemia (CLL) is a heterogeneous B cell neoplasm ranging from indolent to rapidly progressive disease. Leukemic cell subsets with regulatory properties evade immune clearance; however, the contribution of such subsets during CLL progression is not completely elucidated. Here, we report that CLL B cells crosstalk with their immune counterparts, notably by promoting the regulatory T (Treg) cell compartment and shaping several helper T (Th) subsets. Among various constitutively- and BCR/CD40-mediated factors secreted, tumour subsets co-express two important immunoregulatory cytokines, IL10 and TGFβ1, both associated with a memory B cell phenotype. Neutralizing secreted IL10 or inhibiting the TGFβ signalling pathway demonstrated that these cytokines are mainly involved in Th- and Treg differentiation/maintenance. In line with the regulatory subsets, we also demonstrated that a CLL B cell population expresses FOXP3, a marker of regulatory T cells. Analysis of IL10, TGFβ1 and FOXP3 positive subpopulations frequencies in CLL samples discriminated 2 clusters of untreated CLL patients that were significantly different in Tregs frequency and time-to-treatment. Since this distinction was pertinent to disease progression, the regulatory profiling provides a new rationale for patient stratification and sheds light on immune dysfunction in CLL.
Blocking dPerk in the intestine suppresses neurodegeneration in a Drosophila model of Parkinson’s disease
Authors: Popovic Rebeka , Mukherjee Amrita , Leal Nuno Santos , Morris Lydia , Yu Yizhou , Loh Samantha H. Y. , Miguel Martins L. 
Published: March 2023

AbstractParkinson’s disease (PD) is characterised by selective death of dopaminergic (DA) neurons in the midbrain and motor function impairment. Gastrointestinal issues often precede motor deficits in PD, indicating that the gut-brain axis is involved in the pathogenesis of this disease. The features of PD include both mitochondrial dysfunction and activation of the unfolded protein response (UPR) in the endoplasmic reticulum (ER). PINK1 is a mitochondrial kinase involved in the recycling of defective mitochondria, and PINK1 mutations cause early-onset PD. Like PD patients, pink1 mutant Drosophila show degeneration of DA neurons and intestinal dysfunction. These mutant flies also lack vital proteins due to sustained activation of the kinase R-like endoplasmic reticulum kinase (dPerk), a kinase that induces the UPR. Here, we investigated the role of dPerk in intestinal dysfunction. We showed that intestinal expression of dPerk impairs mitochondrial function, induces cell death, and decreases lifespan. We found that suppressing dPerk in the intestine of pink1-mutant flies rescues intestinal cell death and is neuroprotective. We conclude that in a fly model of PD, blocking gut-brain transmission of UPR-mediated toxicity, is neuroprotective.
The translational revolution in atopic dermatitis: the paradigm shift from pathogenesis to treatment
Authors: Facheris Paola , Jeffery Jane , Del Duca Ester , Guttman-Yassky Emma 
Published: March 2023

AbstractAtopic dermatitis (AD) is the most common inflammatory skin disease, and it is considered a complex and heterogeneous condition. Different phenotypes of AD, defined according to the patient age at onset, race, and ethnic background; disease duration; and other disease characteristics, have been recently described, underlying the need for a personalized treatment approach. Recent advancements in understanding AD pathogenesis resulted in a real translational revolution and led to the exponential expansion of the therapeutic pipeline. The study of biomarkers in clinical studies of emerging treatments is helping clarify the role of each cytokine and immune pathway in AD and will allow addressing the unique immune fingerprints of each AD subset. Personalized medicine will be the ultimate goal of this targeted translational research. In this review, we discuss the changes in the concepts of both the pathogenesis of and treatment approach to AD, highlight the scientific rationale behind each targeted treatment and report the most recent clinical efficacy data.
Reference compounds for characterizing cellular injury in high-content cellular morphology assays
Authors: Dahlin Jayme L. , Hua Bruce K. , Zucconi Beth E. , Nelson Shawn D. , Singh Shantanu , Carpenter Anne E. , Shrimp Jonathan H. , Lima-Fernandes Evelyne , Wawer Mathias J. , Chung Lawrence P. W. , Agrawal Ayushi , O’Reilly Mary , Barsyte-Lovejoy Dalia , Szewczyk Magdalena , Li Fengling , Lak Parnian , Cuellar Matthew , Cole Philip A. , Meier Jordan L. , Thomas Tim , Baell Jonathan B. , Brown Peter J. , Walters Michael A. , Clemons Paul A. , Schreiber Stuart L. , Wagner Bridget K. 
Published: March 2023

AbstractRobust, generalizable approaches to identify compounds efficiently with undesirable mechanisms of action in complex cellular assays remain elusive. Such a process would be useful for hit triage during high-throughput screening and, ultimately, predictive toxicology during drug development. Here we generate cell painting and cellular health profiles for 218 prototypical cytotoxic and nuisance compounds in U-2 OS cells in a concentration-response format. A diversity of compounds that cause cellular damage produces bioactive cell painting morphologies, including cytoskeletal poisons, genotoxins, nonspecific electrophiles, and redox-active compounds. Further, we show that lower quality lysine acetyltransferase inhibitors and nonspecific electrophiles can be distinguished from more selective counterparts. We propose that the purposeful inclusion of cytotoxic and nuisance reference compounds such as those profiled in this resource will help with assay optimization and compound prioritization in complex cellular assays like cell painting.
Hypomorphic Brca2 and Rad51c double mutant mice display Fanconi anemia, cancer and polygenic replication stress
Authors: Tomaszowski Karl-Heinz , Roy Sunetra , Guerrero Carolina , Shukla Poojan , Keshvani Caezaan , Chen Yue , Ott Martina , Wu Xiaogang , Zhang Jianhua , DiNardo Courtney D. , Schindler Detlev , Schlacher Katharina 
Published: March 2023

AbstractThe prototypic cancer-predisposition disease Fanconi Anemia (FA) is identified by biallelic mutations in any one of twenty-three FANC genes. Puzzlingly, inactivation of one Fanc gene alone in mice fails to faithfully model the pleiotropic human disease without additional external stress. Here we find that FA patients frequently display FANC co-mutations. Combining exemplary homozygous hypomorphic Brca2/Fancd1 and Rad51c/Fanco mutations in mice phenocopies human FA with bone marrow failure, rapid death by cancer, cellular cancer-drug hypersensitivity and severe replication instability. These grave phenotypes contrast the unremarkable phenotypes seen in mice with single gene-function inactivation, revealing an unexpected synergism between Fanc mutations. Beyond FA, breast cancer-genome analysis confirms that polygenic FANC tumor-mutations correlate with lower survival, expanding our understanding of FANC genes beyond an epistatic FA-pathway. Collectively, the data establish a polygenic replication stress concept as a testable principle, whereby co-occurrence of a distinct second gene mutation amplifies and drives endogenous replication stress, genome instability and disease.
A generalizable nanopore sensor for highly specific protein detection at single-molecule precision
Authors: Ahmad Mohammad , Ha Jeung-Hoi , Mayse Lauren A. , Presti Maria F. , Wolfe Aaron J. , Moody Kelsey J. , Loh Stewart N. , Movileanu Liviu 
Published: March 2023

AbstractProtein detection has wide-ranging implications in molecular diagnostics. Substantial progress has been made in protein analytics using nanopores and the resistive-pulse technique. Yet, a long-standing challenge is implementing specific interfaces for detecting proteins without the steric hindrance of the pore interior. Here, we formulate a class of sensing elements made of a programmable antibody-mimetic binder fused to a monomeric protein nanopore. This way, such a modular design significantly expands the utility of nanopore sensors to numerous proteins while preserving their architecture, specificity, and sensitivity. We prove the power of this approach by developing and validating nanopore sensors for protein analytes that drastically vary in size, charge, and structural complexity. These analytes produce unique electrical signatures that depend on their identity and quantity and the binder-analyte assembly at the nanopore tip. The outcomes of this work could impact biomedical diagnostics by providing a fundamental basis for biomarker detection in biofluids.
TRAK adaptors regulate the recruitment and activation of dynein and kinesin in mitochondrial transport
Authors: Canty John T. , Hensley Andrew , Aslan Merve , Jack Amanda , Yildiz Ahmet 
Published: March 2023

AbstractMitochondrial transport along microtubules is mediated by Miro1 and TRAK adaptors that recruit kinesin-1 and dynein-dynactin. To understand how these opposing motors are regulated during mitochondrial transport, we reconstitute the bidirectional transport of Miro1/TRAK along microtubules in vitro. We show that the coiled-coil domain of TRAK activates dynein-dynactin and enhances the motility of kinesin-1 activated by its cofactor MAP7. We find that TRAK adaptors that recruit both motors move towards kinesin-1’s direction, whereas kinesin-1 is excluded from binding TRAK transported by dynein-dynactin, avoiding motor tug-of-war. We also test the predictions of the models that explain how mitochondrial transport stalls in regions with elevated Ca2+. Transport of Miro1/TRAK by kinesin-1 is not affected by Ca2+. Instead, we demonstrate that the microtubule docking protein syntaphilin induces resistive forces that stall kinesin-1 and dynein-driven motility. Our results suggest that mitochondrial transport stalls by Ca2+-mediated recruitment of syntaphilin to the mitochondrial membrane, not by disruption of the transport machinery.
Longitudinal single-cell profiling of chemotherapy response in acute myeloid leukemia
Authors: Naldini Matteo Maria , Casirati Gabriele , Barcella Matteo , Rancoita Paola Maria Vittoria , Cosentino Andrea , Caserta Carolina , Pavesi Francesca , Zonari Erika , Desantis Giacomo , Gilioli Diego , Carrabba Matteo Giovanni , Vago Luca , Bernardi Massimo , Di Micco Raffaella , Di Serio Clelia , Merelli Ivan , Volpin Monica , Montini Eugenio , Ciceri Fabio , Gentner Bernhard 
Published: March 2023

AbstractAcute myeloid leukemia may be characterized by a fraction of leukemia stem cells (LSCs) that sustain disease propagation eventually leading to relapse. Yet, the contribution of LSCs to early therapy resistance and AML regeneration remains controversial. We prospectively identify LSCs in AML patients and xenografts by single-cell RNA sequencing coupled with functional validation by a microRNA-126 reporter enriching for LSCs. Through nucleophosmin 1 (NPM1) mutation calling or chromosomal monosomy detection in single-cell transcriptomes, we discriminate LSCs from regenerating hematopoiesis, and assess their longitudinal response to chemotherapy. Chemotherapy induced a generalized inflammatory and senescence-associated response. Moreover, we observe heterogeneity within progenitor AML cells, some of which proliferate and differentiate with expression of oxidative-phosphorylation (OxPhos) signatures, while others are OxPhos (low) miR-126 (high) and display enforced stemness and quiescence features. miR-126 (high) LSCs are enriched at diagnosis in chemotherapy-refractory AML and at relapse, and their transcriptional signature robustly stratifies patients for survival in large AML cohorts.
Digital nanoreactors to control absolute stoichiometry and spatiotemporal behavior of DNA receptors within lipid bilayers
Authors: Maingi Vishal , Zhang Zhao , Thachuk Chris , Sarraf Namita , Chapman Edwin R. , Rothemund Paul W. K. 
Published: March 2023

AbstractInteractions between membrane proteins are essential for cell survival but are often poorly understood. Even the biologically functional ratio of components within a multi-subunit membrane complex—the native stoichiometry—is difficult to establish. Here we demonstrate digital nanoreactors that can control interactions between lipid-bound molecular receptors along three key dimensions: stoichiometric, spatial, and temporal. Each nanoreactor is based on a DNA origami ring, which both templates the synthesis of a liposome and provides tethering sites for DNA-based receptors (modelling membrane proteins). Receptors are released into the liposomal membrane using strand displacement and a DNA logic gate measures receptor heterodimer formation. High-efficiency tethering of receptors enables the kinetics of receptors in 1:1 and 2:2 absolute stoichiometries to be observed by bulk fluorescence, which in principle is generalizable to any ratio. Similar single-molecule-in-bulk experiments using DNA-linked membrane proteins could determine native stoichiometry and the kinetics of membrane protein interactions for applications ranging from signalling research to drug discovery.