bluuebunny/crossref_metadata_2025_split huggingface dataset:
BAF53A drives colorectal cancer development by regulating DUSP5-mediated ERK phosphorylation
Authors: Yang Ziqing , Huang Dandan , Meng Manqi , Wang Wencong , Feng Junyan , Fang Lekun , Chen Honglei , Zou Shaomin 
Published: December 2022

AbstractBAF53A, an important subunit of the SWI/SNF epigenetic chromatin regulatory complex, has been implicated as the driver of diverse cancers. However, the role of BAF53A in colorectal cancer (CRC) remains poorly understood. Here, we examined the expression of BAF53A in CRC samples and observed that BAF53A was significantly upregulated in CRC tissues compared with paired adjacent normal tissues. In vitro and in vivo studies suggested that ectopic expression of BAF53A promoted colorectal cancer cell proliferation, colony formation, and tumorigenesis, whereas knockdown of BAF53A hindered these cellular functions. DUSP5 (dual-specificity phosphatase 5), an ERK1/2-specific endogenous phosphatase, was expressed at low levels in CRC. We found a negative correlation between BAF53A and DUSP5 expression in a set of CRC samples. Mechanistic studies revealed that P63 was a potential transcription repressor of DUSP5. BAF53A could interact with P63, decreasing the DUSP5 expression level and subsequently promoting ERK1/2 phosphorylation. Thus, our study provides insights into the applicability of the BAF53A-DUSP5-ERK1/2 axis as a potential therapeutic target in CRC.
Unconventional self-similar Hofstadter superconductivity from repulsive interactions
Authors: Shaffer Daniel , Wang Jian , Santos Luiz H. 
Published: December 2022

AbstractFractal Hofstadter bands have become widely accessible with the advent of moiré superlattices, opening the door to studies of the effect of interactions in these systems. In this work we employ a renormalization group (RG) analysis to demonstrate that the combination of repulsive interactions with the presence of a tunable manifold of Van Hove singularities provides a new mechanism for driving unconventional superconductivity in Hofstadter bands. Specifically, the number of Van Hove singularities at the Fermi energy can be controlled by varying the flux per unit cell and the electronic filling, leading to instabilities toward nodal superconductivity and chiral topological superconductivity with Chern number $${{{{{{{\mathcal{C}}}}}}}}=\pm 6$$
C
=
±
6
. The latter is characterized by a self-similar fixed trajectory of the RG flow and an emerging self-similarity symmetry of the order parameter. Our results establish Hofstadter quantum materials such as moiré heterostructures as promising platforms for realizing novel reentrant Hofstadter superconductors.
Perpendicular electric field drives Chern transitions and layer polarization changes in Hofstadter bands
Authors: Adak Pratap Chandra , Sinha Subhajit , Giri Debasmita , Mukherjee Dibya Kanti , Chandan  , Sangani L. D. Varma , Layek Surat , Mukherjee Ayshi , Watanabe Kenji , Taniguchi Takashi , Fertig H. A. , Kundu Arijit , Deshmukh Mandar M. 
Published: December 2022

AbstractMoiré superlattices engineer band properties and enable observation of fractal energy spectra of Hofstadter butterfly. Recently, correlated-electron physics hosted by flat bands in small-angle moiré systems has been at the foreground. However, the implications of moiré band topology within the single-particle framework are little explored experimentally. An outstanding problem is understanding the effect of band topology on Hofstadter physics, which does not require electron correlations. Our work experimentally studies Chern state switching in the Hofstadter regime using twisted double bilayer graphene (TDBG), which offers electric field tunable topological bands, unlike twisted bilayer graphene. Here we show that the nontrivial topology reflects in the Hofstadter spectra, in particular, by displaying a cascade of Hofstadter gaps that switch their Chern numbers sequentially while varying the perpendicular electric field. Our experiments together with theoretical calculations suggest a crucial role of charge polarization changing concomitantly with topological transitions in this system. Layer polarization is likely to play an important role in the topological states in few-layer twisted systems. Moreover, our work establishes TDBG as a novel Hofstadter platform with nontrivial magnetoelectric coupling.
Detecting and quantifying liquid–liquid phase separation in living cells by model-free calibrated half-bleaching
Authors: Muzzopappa Fernando , Hummert Johan , Anfossi Michela , Tashev Stanimir Asenov , Herten Dirk-Peter , Erdel Fabian 
Published: December 2022

AbstractCells contain numerous substructures that have been proposed to form via liquid–liquid phase separation (LLPS). It is currently debated how to reliably distinguish LLPS from other mechanisms. Here, we benchmark different methods using well-controlled model systems in vitro and in living cells. We find that 1,6-hexanediol treatment and classical FRAP fail to distinguish LLPS from the alternative scenario of molecules binding to spatially clustered binding sites without phase-separating. In contrast, the preferential internal mixing seen in half-bleach experiments robustly distinguishes both mechanisms. We introduce a workflow termed model-free calibrated half-FRAP (MOCHA-FRAP) to probe the barrier at the condensate interface that is responsible for preferential internal mixing. We use it to study components of heterochromatin foci, nucleoli, stress granules and nuage granules, and show that the strength of the interfacial barrier increases in this order. We anticipate that MOCHA-FRAP will help uncover the mechanistic basis of biomolecular condensates in living cells.
Hepatic neddylation deficiency triggers fatal liver injury via inducing NF-κB-inducing kinase in mice
Authors: Xu Cheng , Zhou Hongyi , Jin Yulan , Sahay Khushboo , Robicsek Anna , Liu Yisong , Dong Kunzhe , Zhou Jiliang , Barrett Amanda , Su Huabo , Chen Weiqin 
Published: December 2022

AbstractThe conjugation of neural precursor cell expressed, developmentally downregulated 8 (NEDD8) to target proteins, termed neddylation, participates in many cellular processes and is aberrant in various pathological diseases. Its relevance to liver function and failure remains poorly understood. Herein, we show dysregulated expression of NAE1, a regulatory subunit of the only NEDD8 E1 enzyme, in human acute liver failure. Embryonic- and adult-onset deletion of NAE1 in hepatocytes causes hepatocyte death, inflammation, and fibrosis, culminating in fatal liver injury in mice. Hepatic neddylation deficiency triggers oxidative stress, mitochondrial dysfunction, and hepatocyte reprogramming, potentiating liver injury. Importantly, NF-κB-inducing kinase (NIK), a serine/Thr kinase, is a neddylation substrate. Neddylation of NIK promotes its ubiquitination and degradation. Inhibition of neddylation conversely causes aberrant NIK activation, accentuating hepatocyte damage and inflammation. Administration of N-acetylcysteine, a glutathione surrogate and antioxidant, mitigates liver failure caused by hepatic NAE1 deletion in adult male mice. Therefore, hepatic neddylation is important in maintaining postnatal and adult liver homeostasis, and the identified neddylation targets/pathways provide insights into therapeutically intervening acute liver failure.
Multiple pathways promote microtubule stabilization in senescent intestinal epithelial cells
Authors: Chu Siwei , Moujaber Ossama , Lemay Serge , Stochaj Ursula 
Published: December 2022

AbstractIntestinal epithelial cells are critical for gastrointestinal homeostasis. However, their function declines during aging. The aging-related loss of organ performance is largely driven by the increase in senescent cells. To date, the hallmarks and molecular mechanisms related to cellular senescence are not fully understood. Microtubules control epithelial functions, and we identified microtubule stabilization as a phenotypic marker of senescent intestinal epithelial cells. The senescence inducer determined the pathway to microtubule stabilization. Specifically, enhanced microtubule stability was associated with α-tubulin hyperacetylation or increased abundance of the microtubule-binding protein tau. We show further that overexpression of MAPT, which encodes tau, augmented microtubule stability in intestinal epithelial cells. Notably, pharmacological microtubule stabilization was sufficient to induce cellular senescence. Taken together, this study provides new insights into the molecular mechanisms that control epithelial cell homeostasis. Our results support the concept that microtubule stability serves as a critical cue to trigger intestinal epithelial cell senescence.
The Wsp chemosensory system modulates c-di-GMP-dependent biofilm formation by integrating DSF quorum sensing through the WspR-RpfG complex in Lysobacter
Authors: Xu Kangwen , Wang Limin , Xiong Dan , Chen Hongjun , Tong Xinru , Shao Xiaolong , Li Tao , Qian Guoliang 
Published: December 2022

AbstractThe ubiquitous Wsp (wrinkly spreader phenotype) chemosensory system and DSF (diffusible signal factor) quorum sensing are two important chemically associated signaling systems that mediate bacterial communications between the host and environment. Although these two systems individually control biofilm formation in pathogenic bacteria via the ubiquitous second messenger c-di-GMP, their crosstalk mechanisms remain elusive. Here we present a scenario from the plant-beneficial and antifungal bacterium Lysobacter enzymogenes OH11, where biofilm formation favors the colonization of this bacterium in fungal hyphae. We found that the Wsp system regulated biofilm formation via WspR-mediated c-di-GMP signaling, whereas DSF system did not depend on the enzymatic activity of RpfG to regulate biofilm formation. We further found that WspR, a diguanylate cyclase (DGC) responsible for c-di-GMP synthesis, could directly bind to one of the DSF signaling components, RpfG, an active phosphodiesterase (PDE) responsible for c-di-GMP degradation. Thus, the WspR-RpfG complex represents a previously undiscovered molecular linker connecting the Wsp and DSF systems. Mechanistically, RpfG could function as an adaptor protein to bind and inhibit the DGC activity of unphosphorylated WspR independent of its PDE activity. Phosphorylation of WspR impaired its binding affinity to RpfG and also blocked the ability of RpfG to act as an adaptor protein, which enabled the Wsp system to regulate biofilm formation in a c-di-GMP-dependent manner by dynamically integrating the DSF system. Our findings demonstrated a previously uncharacterized mechanism of crosstalk between Wsp and DSF systems in plant-beneficial and antifungal bacteria.
Bone metabolism during strict head-down tilt bed rest and exposure to elevated levels of ambient CO2
Authors: McGrath Emily R. , Frings-Meuthen Petra , Sibonga Jean , Heer Martina , Clement Gilles R. , Mulder Edwin , Smith Scott M. , Zwart Sara R. 
Published: December 2022

AbstractAstronauts on the International Space Station are exposed to levels of atmospheric carbon dioxide (CO2) above typical terrestrial levels. We explored the possibility that increased levels of ambient CO2 further stimulate bone resorption during bed rest. We report here data from 2 ground-based spaceflight analog studies in which 12 male and 7 female subjects were placed in a strict 6° head-down tilt (HDT) position for either 30 days at 0.5% ambient CO2 or 60 days with nominal environmental exposure to CO2. Bone mineral density (BMD) and bone mineral content (BMC) were determined using dual-energy X-ray absorptiometry (DXA). Blood and urine were collected before and after HDT for biochemical analysis. No change was detected in either BMD or BMC, as expected given the study duration. Bone resorption markers increased after bed rest as expected; however, elevated CO2 had no additive effect. Elevated CO2 did not affect concentrations of minerals in serum and urine. Serum parathyroid hormone and 1,25-dihydroxyvitamin D were both reduced after bed rest, likely secondary to calcium efflux from bone. In summary, exposure to 0.5% CO2 for 30 days did not exacerbate the typical bone resorption response observed after HDT bed rest. Furthermore, results from these strict HDT studies were similar to data from previous bed rest studies, confirming that strict 30–60 days of HDT can be used to evaluate changes in bone metabolism. This is valuable in the continuing effort to develop and refine efficacious countermeasure protocols to mitigate bone loss during spaceflight in low-Earth orbit and beyond.
Identification and prediction of Parkinson’s disease subtypes and progression using machine learning in two cohorts
Authors: Dadu Anant , Satone Vipul , Kaur Rachneet , Hashemi Sayed Hadi , Leonard Hampton , Iwaki Hirotaka , Makarious Mary B. , Billingsley Kimberley J. , Bandres‐Ciga Sara , Sargent Lana J. , Noyce Alastair J. , Daneshmand Ali , Blauwendraat Cornelis , Marek Ken , Scholz Sonja W. , Singleton Andrew B. , Nalls Mike A. , Campbell Roy H. , Faghri Faraz 
Published: December 2022

AbstractThe clinical manifestations of Parkinson’s disease (PD) are characterized by heterogeneity in age at onset, disease duration, rate of progression, and the constellation of motor versus non-motor features. There is an unmet need for the characterization of distinct disease subtypes as well as improved, individualized predictions of the disease course. We used unsupervised and supervised machine learning methods on comprehensive, longitudinal clinical data from the Parkinson’s Disease Progression Marker Initiative (n = 294 cases) to identify patient subtypes and to predict disease progression. The resulting models were validated in an independent, clinically well-characterized cohort from the Parkinson’s Disease Biomarker Program (n = 263 cases). Our analysis distinguished three distinct disease subtypes with highly predictable progression rates, corresponding to slow, moderate, and fast disease progression. We achieved highly accurate projections of disease progression 5 years after initial diagnosis with an average area under the curve (AUC) of 0.92 (95% CI: 0.95 ± 0.01) for the slower progressing group (PDvec1), 0.87 ± 0.03 for moderate progressors, and 0.95 ± 0.02 for the fast-progressing group (PDvec3). We identified serum neurofilament light as a significant indicator of fast disease progression among other key biomarkers of interest. We replicated these findings in an independent cohort, released the analytical code, and developed models in an open science manner. Our data-driven study provides insights to deconstruct PD heterogeneity. This approach could have immediate implications for clinical trials by improving the detection of significant clinical outcomes. We anticipate that machine learning models will improve patient counseling, clinical trial design, and ultimately individualized patient care.
Muscle stem cells and fibro-adipogenic progenitors in female pelvic floor muscle regeneration following birth injury
Authors: Sesillo Francesca Boscolo , Rajesh Varsha , Wong Michelle , Duran Pamela , Rudell John B. , Rundio Courtney P. , Baynes Brittni B. , Laurent Louise C. , Sacco Alessandra , Christman Karen L. , Alperin Marianna 
Published: December 2022

AbstractPelvic floor muscle (PFM) injury during childbirth is a key risk factor for pelvic floor disorders that affect millions of women worldwide. Muscle stem cells (MuSCs), supported by the fibro-adipogenic progenitors (FAPs) and immune cells, are indispensable for the regeneration of injured appendicular skeletal muscles. However, almost nothing is known about their role in PFM regeneration following birth injury. To elucidate the role of MuSCs, FAPs, and immune infiltrate in this context, we used radiation to perturb cell function and followed PFM recovery in a validated simulated birth injury (SBI) rat model. Non-irradiated and irradiated rats were euthanized at 3,7,10, and 28 days post-SBI (dpi). Twenty-eight dpi, PFM fiber cross-sectional area (CSA) was significantly lower and the extracellular space occupied by immune infiltrate was larger in irradiated relative to nonirradiated injured animals. Following SBI in non-irradiated animals, MuSCs and FAPs expanded significantly at 7 and 3 dpi, respectively; this expansion did not occur in irradiated animals at the same time points. At 7 and 10 dpi, we observed persistent immune response in PFMs subjected to irradiation compared to non-irradiated injured PFMs. CSA of newly regenerated fibers was also significantly smaller following SBI in irradiated compared to non-irradiated injured PFMs. Our results demonstrate that the loss of function and decreased expansion of MuSCs and FAPs after birth injury lead to impaired PFM recovery. These findings form the basis for further studies focused on the identification of novel therapeutic targets to counteract postpartum PFM dysfunction and the associated pelvic floor disorders.
Polydactyly-derived allogeneic chondrocyte cell-sheet transplantation with high tibial osteotomy as regenerative therapy for knee osteoarthritis
Authors: Hamahashi Kosuke , Toyoda Eriko , Ishihara Miya , Mitani Genya , Takagaki Tomonori , Kaneshiro Nagatoshi , Maehara Miki , Takahashi Takumi , Okada Eri , Watanabe Ayako , Nakamura Yoshihiko , Kato Reiko , Matoba Ryo , Takagi Takehiko , Akutsu Hidenori , Umezawa Akihiro , Kobayashi Hiroyuki , Akamatsu Tadashi , Yamato Masayuki , Okano Teruo , Watanabe Masahiko , Sato Masato 
Published: December 2022

AbstractAllogeneic cell therapies are not fully effective in treating osteoarthritis of the knee (OAK). We recently reported that transplantation of autologous chondrocyte cell-sheets along with open-wedge high tibial osteotomy promoted hyaline cartilage repair in humans. Here we describe our regenerative therapy for OAK using polydactyly-derived allogeneic chondrocyte cell-sheets (PD sheets) and temperature-responsive culture inserts. Ten patients with OAK and cartilage defects categorized arthroscopically as Outerbridge grade III or IV received the therapy. Cartilage viscoelasticity and thickness were assessed before and after transplantation. Arthroscopic biopsies obtained 12 months after transplantation were analyzed histologically. Gene expression was analyzed to evaluate the PD sheets. In this small initial longitudinal series, PD sheet transplantation was effective in treating OAK, as indicated by changes in cartilage properties. Gene marker sets in PD sheets may predict outcomes after therapy and provide markers for the selection of donor cells. This combined surgery may be an ideal regenerative therapy with disease-modifying effects in OAK patients.
Serum antibody profiling identifies vaccine-induced correlates of protection against aerosolized ricin toxin in rhesus macaques
Authors: Roy Chad J. , Ehrbar Dylan , Van Slyke Greta , Doering Jennifer , Didier Peter J. , Doyle-Meyers Lara , Donini Oreola , Vitetta Ellen S. , Mantis Nicholas J. 
Published: December 2022

AbstractInhalation of the biothreat agent, ricin toxin (RT), provokes a localized inflammatory response associated with pulmonary congestion, edema, neutrophil infiltration, and severe acute respiratory distress. The extreme toxicity of RT is the result of the toxin’s B chain (RTB) promoting rapid uptake into alveolar macrophages and lung epithelial cells, coupled with the A chain’s (RTA) potent ribosome-inactivating properties. We previously reported that intramuscular vaccination of rhesus macaques with a lyophilized, alum-adsorbed recombinant RTA subunit vaccine (RiVax®) was sufficient to confer protection against a lethal dose of aerosolized RT. That study implicated RT-specific serum IgG, toxin-neutralizing activity (TNA), and epitope-specific responses as being associated with immunity. However, it was not possible to define actual correlates of protection (COP) because all vaccinated animals survived the RT challenge. We addressed the issue of COP in the current study, by vaccinating groups of rhesus macaques with RiVax® following the previously determined protective regimen (100 µg on study days 0, 30 and 60) or one of two anticipated suboptimal regimens (100 µg on study days 30 and 60; 35 µg on study days 0, 30, and 60). Two unvaccinated animals served as controls. The animals were challenged with ~5 × LD50s of aerosolized RT on study day 110. We report that all vaccinated animals seroconverted prior to RT challenge, with the majority also having measurable TNA, although neither antibody levels nor TNA reached statistical significance with regard to a correlation with protection. By contrast, survival correlated with pre-challenge, epitope-specific serum IgG levels, derived from a competitive sandwich ELISA using a panel of toxin-neutralizing monoclonal antibodies directed against distinct epitopes on RiVax®. The identification of a species-neutral, competitive ELISA that correlates with vaccine-induced protection against RT in nonhuman represents an important advance in the development of medical countermeasures (MCM) against a persistent biothreat.
A genetically modified Plasmodium berghei parasite as a surrogate for whole-sporozoite vaccination against P. vivax malaria
Authors: Moita Diana , Maia Teresa G. , Duarte Miguel , Andrade Carolina M. , Albuquerque Inês S. , Dwivedi Ankit , Silva Joana C. , González-Céron Lilia , Janse Chris J. , Mendes António M. , Prudêncio Miguel 
Published: December 2022

AbstractTwo malaria parasite species, Plasmodium falciparum (Pf) and P. vivax (Pv) are responsible for most of the disease burden caused by malaria. Vaccine development against this disease has focused mainly on Pf. Whole-sporozoite (WSp) vaccination, targeting pre-erythrocytic (PE) parasite stages, is a promising strategy for immunization against malaria and several PfWSp-based vaccine candidates are currently undergoing clinical evaluation. In contrast, no WSp candidates have been developed for Pv, mainly due to constraints in the production of Pv sporozoites in the laboratory. Recently, we developed a novel approach for WSp vaccination against Pf based on the use of transgenic rodent P. berghei (Pb) sporozoites expressing immunogens of this human-infective parasite. We showed that this platform can be used to deliver PE Pf antigens, eliciting both targeted humoral responses and cross-species cellular immune responses against Pf. Here we explored this WSp platform for the delivery of Pv antigens. As the Pv circumsporozoite protein (CSP) is a leading vaccine candidate antigen, we generated a transgenic Pb parasite, PbviVac, that, in addition to its endogenous PbCSP, expresses PvCSP under the control of a strictly PE promoter. Immunofluorescence microscopy analyses confirmed that both the PbCSP and the PvCSP antigens are expressed in PbviVac sporozoites and liver stages and that PbviVac sporozoite infectivity of hepatic cells is similar to that of its wild-type Pb counterpart. Immunization of mice with PbviVac sporozoites elicits the production of anti-PvCSP antibodies that efficiently recognize and bind to Pv sporozoites. Our results warrant further development and evaluation of PbviVac as a surrogate for WSp vaccination against Pv malaria.