bluuebunny/crossref_metadata_2025_split huggingface dataset:
Increased novelty-induced locomotion, sensitivity to amphetamine, and extracellular dopamine in striatum of Zdhhc15-deficient mice
Authors: Mejias Rebeca , Rodriguez-Gotor Juan J. , Niwa Minae , Krasnova Irina N. , Adamczyk Abby , Han Mei , Thomas Gareth M. , Xi Zheng-Xiong , Huganir Richard L. , Pletnikov Mikhail V. , Sawa Akira , Cadet Jean-Lud , Wang Tao 
Published: January 2021

AbstractNovelty-seeking behaviors and impulsivity are personality traits associated with several psychiatric illnesses including attention deficits hyperactivity disorders. The underlying neural mechanisms remain poorly understood. We produced and characterized a line of knockout mice for zdhhc15, which encodes a neural palmitoyltransferase. Genetic defects of zdhhc15 were implicated in intellectual disability and behavioral anomalies in humans. Zdhhc15-KO mice showed normal spatial learning and working memory but exhibited a significant increase in novelty-induced locomotion in open field. Striatal dopamine content was reduced but extracellular dopamine levels were increased during the habituation phase to a novel environment. Administration of amphetamine and methylphenidate resulted in a significant increase in locomotion and extracellular dopamine levels in the ventral striatum of mutant mice compared to controls. Number and projections of dopaminergic neurons in the nigrostriatal and mesolimbic pathways were normal. No significant change in the basal palmitoylation of known ZDHHC15 substrates including DAT was detected in striatum of zdhhc15 KO mice using an acyl-biotin exchange assay. These results support that a transient, reversible, and novelty-induced elevation of extracellular dopamine in ventral striatum contributes to novelty-seeking behaviors in rodents and implicate ZDHHC15-mediated palmitoylation as a novel regulatory mechanism of dopamine in the striatum.
Genotoxic stress-activated DNA-PK-p53 cascade and autophagy cooperatively induce ciliogenesis to maintain the DNA damage response
Authors: Chen Ting-Yu , Huang Bu-Miin , Tang Tang K. , Chao Yu-Ying , Xiao Xiao-Yi , Lee Pei-Rong , Yang Li-Yun , Wang Chia-Yih 
Published: January 2021

AbstractThe DNA-PK maintains cell survival when DNA damage occurs. In addition, aberrant activation of the DNA-PK induces centrosome amplification, suggesting additional roles for this kinase. Here, we showed that the DNA-PK-p53 cascade induced primary cilia formation (ciliogenesis), thus maintaining the DNA damage response under genotoxic stress. Treatment with genotoxic drugs (etoposide, neocarzinostatin, hydroxyurea, or cisplatin) led to ciliogenesis in human retina (RPE1), trophoblast (HTR8), lung (A459), and mouse Leydig progenitor (TM3) cell lines. Upon genotoxic stress, several DNA damage signaling were activated, but only the DNA-PK-p53 cascade contributed to ciliogenesis, as pharmacological inhibition or genetic depletion of this pathway decreased genotoxic stress-induced ciliogenesis. Interestingly, in addition to localizing to the nucleus, activated DNA-PK localized to the base of the primary cilium (mother centriole) and daughter centriole. Genotoxic stress also induced autophagy. Inhibition of autophagy initiation or lysosomal degradation or depletion of ATG7 decreased genotoxic stress-induced ciliogenesis. Besides, inhibition of ciliogenesis by depletion of IFT88 or CEP164 attenuated the genotoxic stress-induced DNA damage response. Thus, our study uncovered the interplay among genotoxic stress, the primary cilium, and the DNA damage response.
Inhibiting NLRP3 inflammasome activation prevents copper-induced neuropathology in a murine model of Wilson’s disease
Authors: Dong Jianjian , Wang Xun , Xu Chenchen , Gao Manli , Wang Shijing , Zhang Jin , Tong Haiyang , Wang Lulu , Han Yongzhu , Cheng Nan , Han Yongsheng 
Published: January 2021

AbstractWilson’s disease (WD) is an inherited disorder characterized by excessive accumulation of copper in the body, particularly in the liver and brain. In the central nervous system (CNS), extracellular copper accumulation triggers pathological microglial activation and subsequent neurotoxicity. Growing evidence suggests that levels of inflammatory cytokines are elevated in the brain of murine WD models. However, the mechanisms associated with copper deposition to neuroinflammation have not been completely elucidated. In this study, we investigated how the activation of NLR family pyrin domain containing 3 (NLRP3) inflammasome contributes to copper-mediated neuroinflammation in an animal model of WD. Elevated levels of interleukin-1β, interleukin-18, interleukin-6, and tumor necrosis factor-α were observed in the sera of WD patients and toxic milk (TX) mice. The protein levels of inflammasome adaptor molecule apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain (ASC), cleaved caspase-1, and interleukin-1β were upregulated in the brain regions of the TX mice. The NLRP3 inflammasome was activated in the TX mice brains. Furthermore, the activation of NLRP3 inflammasome was noted in primary microglia treated with CuCl2, accompanied by the increased levels of cleaved caspase-1, ASC, and interleukin-1β. Blocking NLRP3 inflammasome activation with siNlrp3 or MCC950 reduced interleukin-1β and interleukin-18 production, thereby effectively mitigating cognitive decline, locomotor behavior impairment, and neurodegeneration in TX mice. Overall, our study demonstrates the contribution of copper overload-mediated activation of NLRP3 inflammasome to progressive neuropathology in the CNS of a murine model of WD. Therefore, blockade of the NLRP3 inflammasome activation could be a potential therapeutic strategy for WD.
Glucose metabolism involved in PD-L1-mediated immune escape in the malignant kidney tumour microenvironment
Authors: Yu Yongbo , Liang Ye , Li Dan , Wang Liping , Liang Zhijuan , Chen Yuanbin , Ma Guofeng , Wu Hui , Jiao Wei , Niu Haitao 
Published: January 2021

AbstractProgrammed death receptor-ligand 1 (PD-L1) plays a crucial role in immune evasion by tumour cells. Most tumour cells exhibit energy dependency and acquire energy from glycolysis. However, the relationship between glucose metabolism and PD-L1 expression remains unclear. In this study, changes in PD-L1 expression in renal carcinoma cells were evaluated during glucose deficiency and recovery, and PD-L1 could inversely regulate glycolysis. In addition, the possible signalling pathways activated by a low level of glucose to regulate PD-L1 were tested experimentally. The results showed that glucose deficiency could upregulate PD-L1 expression in two renal cancer cell lines, 786-O and OS-RC-2. Although the native levels of PD-L1 differed in the two cell lines, the upregulated PD-L1 expression was repristinated after glucose recovery. Moreover, epidermal growth factor receptor (EGFR) expression was upregulated in both cell lines with glucose deficiency. The use of an EGFR inhibitor reversed the upregulation of PD-L1 expression induced by glucose deficiency and inhibited the phosphorylation of extracellular regulated protein kinases 1 and 2 (ERK1/2). EGFR activated by epidermal growth factor (EGF) induced PD-L1 expression and ERK1/2 phosphorylation. Furthermore, an ERK1/2 inhibitor inhibited the phosphorylation of c-Jun and decreased the elevated PD-L1 expression induced by glucose deficiency. In addition, this study also showed that 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFK-2/FBPase 3 or PFKFB3) mediated upregulation of the level of glycolysis to improve the adverse environment through PD-L1 induction. Therefore, glucose metabolism can regulate the expression of PD-L1 through the EGFR/ERK/c-Jun pathway in renal cancer, and elevated PD-L1 can also regulate glycolysis by improving the expression of PFKFB3. The findings of this study could provide a new multiple target treatment for renal cell carcinoma (RCC) therapy.
Kibble-Zurek exponent and chiral transition of the period-4 phase of Rydberg chains
Authors: Chepiga Natalia , Mila Frédéric 
Published: January 2021

AbstractChains of Rydberg atoms have emerged as an amazing playground to study quantum physics in 1D. Playing with inter-atomic distances and laser detuning, one can in particular explore the commensurate-incommensurate transition out of density waves through the Kibble-Zurek mechanism, and the possible presence of a chiral transition with dynamical exponent z > 1. Here, we address this problem theoretically with effective blockade models where the short-distance repulsions are replaced by a constraint of no double occupancy. For the period-4 phase, we show that there is an Ashkin-Teller transition point with exponent ν = 0.78 surrounded by a direct chiral transition with a dynamical exponent z = 1.11 and a Kibble-Zurek exponent μ = 0.41. For Rydberg atoms with a van der Waals potential, we suggest that the experimental value μ = 0.25 is due to a chiral transition with z ≃ 1.9 and ν ≃ 0.47 surrounding an Ashkin-Teller transition close to the 4-state Potts universality.
A clinically applicable and scalable method to regenerate T-cells from iPSCs for off-the-shelf T-cell immunotherapy
Authors: Iriguchi Shoichi , Yasui Yutaka , Kawai Yohei , Arima Suguru , Kunitomo Mihoko , Sato Takayuki , Ueda Tatsuki , Minagawa Atsutaka , Mishima Yuta , Yanagawa Nariaki , Baba Yuji , Miyake Yasuyuki , Nakayama Kazuhide , Takiguchi Maiko , Shinohara Tokuyuki , Nakatsura Tetsuya , Yasukawa Masaki , Kassai Yoshiaki , Hayashi Akira , Kaneko Shin 
Published: January 2021

AbstractClinical successes demonstrated by chimeric antigen receptor T-cell immunotherapy have facilitated further development of T-cell immunotherapy against wide variety of diseases. One approach is the development of “off-the-shelf” T-cell sources. Technologies to generate T-cells from pluripotent stem cells (PSCs) may offer platforms to produce “off-the-shelf” and synthetic allogeneic T-cells. However, low differentiation efficiency and poor scalability of current methods may compromise their utilities. Here we show improved differentiation efficiency of T-cells from induced PSCs (iPSCs) derived from an antigen-specific cytotoxic T-cell clone, or from T-cell receptor (TCR)-transduced iPSCs, as starting materials. We additionally describe feeder-free differentiation culture systems that span from iPSC maintenance to T-cell proliferation phases, enabling large-scale regenerated T-cell production. Moreover, simultaneous addition of SDF1α and a p38 inhibitor during T-cell differentiation enhances T-cell commitment. The regenerated T-cells show TCR-dependent functions in vitro and are capable of in vivo anti-tumor activity. This system provides a platform to generate a large number of regenerated T-cells for clinical application and investigate human T-cell differentiation and biology.
Loss of POMC-mediated antinociception contributes to painful diabetic neuropathy
Authors: Deshpande Divija , Agarwal Nitin , Fleming Thomas , Gaveriaux-Ruff Claire , Klose Christoph S. N. , Tappe-Theodor Anke , Kuner Rohini , Nawroth Peter 
Published: January 2021

AbstractPainful neuropathy is a frequent complication in diabetes. Proopiomelanocortin (POMC) is an endogenous opioid precursor peptide, which plays a protective role against pain. Here, we report dysfunctional POMC-mediated antinociception in sensory neurons in diabetes. In streptozotocin-induced diabetic mice the Pomc promoter is repressed due to increased binding of NF-kB p50 subunit, leading to a loss in basal POMC level in peripheral nerves. Decreased POMC levels are also observed in peripheral nervous system tissue from diabetic patients. The antinociceptive pathway mediated by POMC is further impaired due to lysosomal degradation of μ-opioid receptor (MOR). Importantly, the neuropathic phenotype of the diabetic mice is rescued upon viral overexpression of POMC and MOR in the sensory ganglia. This study identifies an antinociceptive mechanism in the sensory ganglia that paves a way for a potential therapy for diabetic neuropathic pain.
Structural analysis of cross α-helical nanotubes provides insight into the designability of filamentous peptide nanomaterials
Authors: Wang Fengbin , Gnewou Ordy , Modlin Charles , Beltran Leticia C. , Xu Chunfu , Su Zhangli , Juneja Puneet , Grigoryan Gevorg , Egelman Edward H. , Conticello Vincent P. 
Published: January 2021

AbstractThe exquisite structure-function correlations observed in filamentous protein assemblies provide a paradigm for the design of synthetic peptide-based nanomaterials. However, the plasticity of quaternary structure in sequence-space and the lability of helical symmetry present significant challenges to the de novo design and structural analysis of such filaments. Here, we describe a rational approach to design self-assembling peptide nanotubes based on controlling lateral interactions between protofilaments having an unusual cross-α supramolecular architecture. Near-atomic resolution cryo-EM structural analysis of seven designed nanotubes provides insight into the designability of interfaces within these synthetic peptide assemblies and identifies a non-native structural interaction based on a pair of arginine residues. This arginine clasp motif can robustly mediate cohesive interactions between protofilaments within the cross-α nanotubes. The structure of the resultant assemblies can be controlled through the sequence and length of the peptide subunits, which generates synthetic peptide filaments of similar dimensions to flagella and pili.
Dynamic memristor-based reservoir computing for high-efficiency temporal signal processing
Authors: Zhong Yanan , Tang Jianshi , Li Xinyi , Gao Bin , Qian He , Wu Huaqiang 
Published: January 2021

AbstractReservoir computing is a highly efficient network for processing temporal signals due to its low training cost compared to standard recurrent neural networks, and generating rich reservoir states is critical in the hardware implementation. In this work, we report a parallel dynamic memristor-based reservoir computing system by applying a controllable mask process, in which the critical parameters, including state richness, feedback strength and input scaling, can be tuned by changing the mask length and the range of input signal. Our system achieves a low word error rate of 0.4% in the spoken-digit recognition and low normalized root mean square error of 0.046 in the time-series prediction of the Hénon map, which outperforms most existing hardware-based reservoir computing systems and also software-based one in the Hénon map prediction task. Our work could pave the road towards high-efficiency memristor-based reservoir computing systems to handle more complex temporal tasks in the future.
Observation of stress corrosion cracking using real-time in situ high-speed atomic force microscopy and correlative techniques
Authors: Moore S. , Burrows R. , Kumar D. , Kloucek M. B. , Warren A. D. , Flewitt P. E. J. , Picco L. , Payton O. D. , Martin T. L. 
Published: January 2021

AbstractContact-mode high-speed atomic force microscopy (HS-AFM) has been utilised to measure in situ stress corrosion cracking (SCC) with nanometre resolution on AISI Type 304 stainless steel in an aggressive salt solution. SCC is an important failure mode in many metal systems but has a complicated mechanism that makes failure difficult to predict. Prior to the in situ experiments, the contributions of microstructure, environment and stress to SCC were independently studied using HS-AFM. During SCC measurements, uplift of grain boundaries before cracking was observed, indicating a subsurface contribution to the cracking mechanism. Focussed ion beam milling revealed a network of intergranular cracks below the surface lined with a thin oxide, indicating that the SCC process is dominated by local stress at oxide-weakened boundaries. Subsequent analysis by atom probe tomography of a crack tip showed a layered oxide composition at the surface of the crack walls. Oxide formation is posited to be mechanistically linked to grain boundary uplift. This study shows how in situ HS-AFM observations in combination with complementary techniques can give important insights into the mechanisms of SCC.
Stress and mindfulness in Parkinson’s disease – a survey in 5000 patients
Authors: van der Heide Anouk , Speckens Anne E. M. , Meinders Marjan J. , Rosenthal Liana S. , Bloem Bastiaan R. , Helmich Rick C. 
Published: January 2021

AbstractMany Parkinson’s disease (PD) patients notice that motor symptoms worsen during stress, and experience stress-related neuropsychiatric symptoms such as anxiety and depression. Here we investigated which personal and disease characteristics are associated with perceived stress in PD, which PD symptoms are sensitive to stress, and we assessed self-reported benefits of stress-reducing strategies such as mindfulness. We sent an online survey to the Fox Insight cohort (n = 28,385 PD patients, n = 11,413 healthy controls). The survey included specific questions about the influence of stress on PD symptoms, use of stress-reducing strategies, and several validated scales measuring perceived stress, anxiety, dispositional mindfulness, rumination, and self-compassion. We received completed surveys from 5000 PD patients and 1292 controls. Patients perceived more stress than controls. Among patients, stress was correlated with increased rumination (R = 0.65), lower quality of life (R = −0.56), lower self-compassion (R = −0.65), and lower dispositional mindfulness (R = −0.48). Furthermore, patients indicated that stress significantly worsened both motor symptoms – especially tremor – and non-motor symptoms. Physical exercise was most frequently used to reduce stress (83.1%). Mindfulness was practiced by 38.7% of PD respondents, who noticed improvement in both motor and non-motor symptoms. Among non-users, 43.4% were interested in gaining mindfulness skills. We conclude that PD patients experience greater levels of stress than controls, and that stress worsens both motor and non-motor symptoms. Mindfulness may improve PD symptom severity, with the strongest effects on anxiety and depressed mood. These findings justify further controlled studies to establish the merits of mindfulness and other stress-alleviating interventions.
A conjoined universal helper epitope can unveil antitumor effects of a neoantigen vaccine targeting an MHC class I-restricted neoepitope
Authors: Swartz Adam M. , Congdon Kendra L. , Nair Smita K. , Li Qi-Jing , Herndon James E. , Suryadevara Carter M. , Riccione Katherine A. , Archer Gary E. , Norberg Pamela K. , Sanchez-Perez Luis A. , Sampson John H. 
Published: January 2021

AbstractPersonalized cancer vaccines targeting neoantigens arising from somatic missense mutations are currently being evaluated for the treatment of various cancers due to their potential to elicit a multivalent, tumor-specific immune response. Several cancers express a low number of neoantigens; in these cases, ensuring the immunotherapeutic potential of each neoantigen-derived epitope (neoepitope) is crucial. In this study, we discovered that therapeutic vaccines targeting immunodominant major histocompatibility complex (MHC) I-restricted neoepitopes require a conjoined helper epitope in order to induce a cytotoxic, neoepitope-specific CD8+ T-cell response. Furthermore, we show that the universally immunogenic helper epitope P30 can fulfill this requisite helper function. Remarkably, conjoined P30 was able to unveil immune and antitumor responses to subdominant MHC I-restricted neoepitopes that were, otherwise, poorly immunogenic. Together, these data provide key insights into effective neoantigen vaccine design and demonstrate a translatable strategy using a universal helper epitope that can improve therapeutic responses to MHC I-restricted neoepitopes.
Opposing Wnt signals regulate cervical squamocolumnar homeostasis and emergence of metaplasia
Authors: Chumduri Cindrilla , Gurumurthy Rajendra Kumar , Berger Hilmar , Dietrich Oliver , Kumar Naveen , Koster Stefanie , Brinkmann Volker , Hoffmann Kirstin , Drabkina Marina , Arampatzi Panagiota , Son Dajung , Klemm Uwe , Mollenkopf Hans-Joachim , Herbst Hermann , Mangler Mandy , Vogel Jörg , Saliba Antoine-Emmanuel , Meyer Thomas F. 
Published: January 2021

AbstractThe transition zones of the squamous and columnar epithelia constitute hotspots for the emergence of cancer, often preceded by metaplasia, in which one epithelial type is replaced by another. It remains unclear how the epithelial spatial organization is maintained and how the transition zone niche is remodelled during metaplasia. Here we used single-cell RNA sequencing to characterize epithelial subpopulations and the underlying stromal compartment of endo- and ectocervix, encompassing the transition zone. Mouse lineage tracing, organoid culture and single-molecule RNA in situ hybridizations revealed that the two epithelia derive from separate cervix-resident lineage-specific stem cell populations regulated by opposing Wnt signals from the stroma. Using a mouse model of cervical metaplasia, we further show that the endocervical stroma undergoes remodelling and increases expression of the Wnt inhibitor Dickkopf-2 (DKK2), promoting the outgrowth of ectocervical stem cells. Our data indicate that homeostasis at the transition zone results from divergent stromal signals, driving the differential proliferation of resident epithelial lineages.
Prognostic signature of lung adenocarcinoma based on stem cell-related genes
Authors: Huang Zhanghao , Shi Muqi , Zhou Hao , Wang Jinjie , Zhang Hai-Jian , Shi Jia -Hai 
Published: January 2021

AbstractLung adenocarcinoma (LUAD) is characterized by high infiltration and rapid growth. The function of the stem cell population is to control and maintain cell regeneration. Therefore, it is necessary to study the prognostic value of stem cell-related genes in LUAD. Signature genes were screened out from 166 stem cell-related genes according to the least absolute shrinkage operator (LASSO) and subsequently multivariate Cox regression analysis, and then established risk model. Immune infiltration and nomogram model were used to evaluate the clinical efficacy of signature. A signature consisting of 10 genes was used to dichotomize the LUAD patients into two groups (cutoff, 1.314), and then validated in GSE20319 and GSE42127. There was a significant correlation between signature and clinical characteristics. Patients with high-risk had a shorter overall survival. Furthermore, significant differences were found in multiple immune cells between the high-risk group and low-risk group. A high correlation was also reflected between signature and immune infiltration. What’s more, the signature could effectively predict the efficacy of chemotherapy in patients with LUAD, and a nomogram based on signature might accurately predict the prognosis of patients with LUAD. The signature-based of stem cell-related genes might be contributed to predicting prognosis of patients with LUAD.