bluuebunny/crossref_metadata_2025 huggingface dataset:
Prenatal origins of suicide mortality: A prospective cohort study in the United States
Authors: Vidal-Ribas Pablo , Govender Theemeshni , Sundaram Rajeshwari , Perlis Roy H. , Gilman Stephen E.
Published: January 2022

Most suicide research focuses on acute precipitants and is conducted in high-risk populations. Yet, vulnerability to suicide is likely established years prior to its occurrence. In this study, we aimed to investigate the risk of suicide mortality conferred by prenatal sociodemographic and pregnancy-related factors. Offspring of participants (N = 49,853) of the Collaborative Perinatal Project, a U.S. population-based cohort of pregnancies enrolled between 1959 and 1966, were linked to the U.S. National Death Index to determine their vital status by the end 2016. We examined associations between sociodemographic factors during pregnancy, pregnancy complications, labor and delivery complications, and neonatal complications with suicide death coded according to ICD-9/10 criteria. By the end of 2016, 3,555 participants had died. Of these, 288 (214 males, 74 females) died by suicide (incidence rate = 15.6 per 100,000 person-years, 95% Confidence Interval [CI] = 13.9–17.5). In adjusted models, male sex (Hazard Ratio [HR] = 2.98, CI: 2.26–3.93), White race (HR = 2.14, CI = 1.63–2.83), low parental education (HR = 2.23, CI = 1.38–3.62), manual parental occupation (HR = 1.38, CI = 1.05–1.82), being a younger sibling (HR = 1.52, CI = 1.10–2.11), higher rates of pregnancy complications (HR = 2.36, CI = 1.08–5.16), and smoking during pregnancy (HR = 1,28, CI = 0.99–1.66) were independently associated with suicide risk, whereas birth and neonatal complications were not. Consistent with the developmental origins of psychiatric disorders, vulnerability to suicide mortality is established early in development. Both sociodemographic and pregnancy factors play a role in this risk, which underscores the importance of considering life course approaches to suicide prevention, possibly including provision of high-quality prenatal care, and alleviating the socioeconomic burdens of mothers and families.
SARS-CoV-2 non-structural protein 6 triggers NLRP3-dependent pyroptosis by targeting ATP6AP1
Authors: Sun Xiao , Liu Yingzhi , Huang Ziheng , Xu Wenye , Hu Wei , Yi Lina , Liu Zhe , Chan Hung , Zeng Judeng , Liu Xiaodong , Chen Huarong , Yu Jun , Chan Francis Ka Leung , Ng Siew Chien , Wong Sunny Hei , Wang Maggie Haitian , Gin Tony , Joynt Gavin Matthew , Hui David Shu Cheong , Zou Xuan , Shu Yuelong , Cheng Christopher Hon Ki , Fang Shisong , Luo Huanle , Lu Jing , Chan Matthew Tak Vai , Zhang Lin , Wu William Ka Kei
Published: January 2022

A recent mutation analysis suggested that Non-Structural Protein 6 (NSP6) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a key determinant of the viral pathogenicity. Here, by transcriptome analysis, we demonstrated that the inflammasome-related NOD-like receptor signaling was activated in SARS-CoV-2-infected lung epithelial cells and Coronavirus Disease 2019 (COVID-19) patients’ lung tissues. The induction of inflammasomes/pyroptosis in patients with severe COVID-19 was confirmed by serological markers. Overexpression of NSP6 triggered NLRP3/ASC-dependent caspase-1 activation, interleukin-1β/18 maturation, and pyroptosis of lung epithelial cells. Upstream, NSP6 impaired lysosome acidification to inhibit autophagic flux, whose restoration by 1α,25-dihydroxyvitamin D3, metformin or polydatin abrogated NSP6-induced pyroptosis. NSP6 directly interacted with ATP6AP1, a vacuolar ATPase proton pump component, and inhibited its cleavage-mediated activation. L37F NSP6 variant, which was associated with asymptomatic COVID-19, exhibited reduced binding to ATP6AP1 and weakened ability to impair lysosome acidification to induce pyroptosis. Consistently, infection of cultured lung epithelial cells with live SARS-CoV-2 resulted in autophagic flux stagnation, inflammasome activation, and pyroptosis. Overall, this work supports that NSP6 of SARS-CoV-2 could induce inflammatory cell death in lung epithelial cells, through which pharmacological rectification of autophagic flux might be therapeutically exploited.
Exosomal hsa_circ_0004658 derived from RBPJ overexpressed-macrophages inhibits hepatocellular carcinoma progression via miR-499b-5p/JAM3
Authors: Zhang Lei , Zhang Jing , Li Pengfei , Li Ting , Zhou Zhiqin , Wu Huiling
Published: January 2022

Macrophage-derived exosomes (Mφ-Exo) have multidimensional involvement in tumor initiation, progression, and metastasis, but their regulation in hepatocellular carcinoma (HCC) is not fully understood. RBPJ has been implicated in macrophage activation and plasticity. In this study we assess the role of exosomes derived from RBPJ-overexpressed macrophages (RBPJ+/+ Mφ-Exo) in HCC. The circular RNA (circRNA) profiles in RBPJ+/+ Mφ-Exo and THP-1-like macrophages (WT Mφ)-Exo was evaluated using circRNA microarray. CCK-8, Transwell, and flow cytometry analyses were used to evaluate the function of Mφ-Exo-circRNA on HCC cells. Luciferase reporter assays, RNA immunoprecipitation, and Pearson’s correlation analysis were used to confirm interactions. A nude mouse xenograft model was used to further analyze the functional significance of Mφ-Exo-cirRNA in vivo. Our results shown that hsa_circ_0004658 is upregulated in RBPJ+/+ Mφ-Exo compared to WT Mφ-Exo. RBPJ+/+ Mφ-Exo and hsa_circ_0004658 inhibits proliferation and promotes apoptosis in HCC cells, whereas hsa_circ_0004658 knockdown stimulated cell proliferation and migration but restrained apoptosis in vitro and promotes tumor growth in vivo. The effects of RBPJ+/+ Mφ-Exo on HCC cells can be reversed by the hsa_circ_0004658 knockdown. Mechanistic investigations revealed that hsa_circ_0004658 acts as a ceRNA of miR-499b-5p, resulting in the de-repression of JAM3. These results indicate that exosome circRNAs secreted from RBPJ+/+ Mφ inhibits tumor progression through the hsa_circ_0004658/miR-499b-5p/JAM3 pathway and hsa_circ_0004658 may be a diagnostic biomarker and potential target for HCC therapy.
Metformin prevents methylglyoxal-induced apoptosis by suppressing oxidative stress in vitro and in vivo
Authors: Wang Gang , Wang Yanan , Yang Qinzhi , Xu Chunrong , Zheng Youkun , Wang Liqun , Wu Jianbo , Zeng Min , Luo Mao
Published: January 2022

Methylglyoxal (MGO) is an active metabolite of glucose and plays a prominent role in the pathogenesis of diabetic vascular complications, including endothelial cell apoptosis induced by oxidative stress. Metformin (MET), a widely prescribed antidiabetic agent, appears to reduce excessive reactive oxygen species (ROS) generation and limit cell apoptosis. However, the molecular mechanisms underlying this process are still not fully elucidated. We reported here that MET prevents MGO-induced apoptosis by suppressing oxidative stress in vitro and in vivo. Protein expression and protein phosphorylation were investigated using western blotting, ELISA, and immunohistochemical staining, respectively. Cell viability and apoptosis were assessed by the MTT assay, TUNEL staining, and Annexin V-FITC and propidium iodide double staining. ROS generation and mitochondrial membrane potential (MMP) were measured with fluorescent probes. Our results revealed that MET prevented MGO-induced HUVEC apoptosis, inhibited apoptosis-associated biochemical changes such as loss of MMP, the elevation of the Bax/Bcl-2 ratio, and activation of cleaved caspase-3, and attenuated MGO-induced mitochondrial morphological alterations in a dose-dependent manner. MET pretreatment also significantly suppressed MGO-stimulated ROS production, increased signaling through the ROS-mediated PI3K/Akt and Nrf2/HO-1 pathways, and markedly elevated the levels of its downstream antioxidants. Finally, similar results were obtained in vivo, and we demonstrated that MET prevented MGO-induced oxidative damage, apoptosis, and inflammation. As expected, MET reversed MGO-induced downregulation of Nrf2 and p-Akt. In addition, a PI3K inhibitor (LY-294002) and a Nrf2 inhibitor (ML385) observably attenuated the protective effects of MET on MGO-induced apoptosis and ROS generation by inhibiting the Nrf2/HO-1 pathways, while a ROS scavenger (NAC) and a permeability transition pores inhibitor (CsA) completely reversed these effects. Collectively, these findings broaden our understanding of the mechanism by which MET regulates apoptosis induced by MGO under oxidative stress conditions, with important implications regarding the potential application of MET for the treatment of diabetic vascular complications.
Neurokinin-1 receptor promotes non-small cell lung cancer progression through transactivation of EGFR
Authors: Zhang Xiao-Wei , Li Lin , Hu Wen-Qian , Hu Ming-Ning , Tao Yan , Hu Hui , Miao Xiao-Kang , Yang Wen-Le , Zhu Qiong , Mou Ling-Yun
Published: January 2022

Despite the great advances in target therapy, lung cancer remains the top cause of cancer-related death worldwide. G protein-coupled receptor neurokinin-1 (NK1R) is shown to play multiple roles in various cancers; however, the pathological roles and clinical implication in lung cancer are unclarified. Here we identified NK1R as a significantly upregulated GPCR in the transcriptome and tissue array of human lung cancer samples, associated with advanced clinical stages and poor prognosis. Notably, NK1R is co-expressed with epidermal growth factor receptor (EGFR) in NSCLC patients’ tissues and co-localized in the tumor cells. NK1R can crosstalk with EGFR by interacting with EGFR, transactivating EGFR phosphorylation and regulating the intracellular signaling of ERK1/2 and Akt. Activation of NK1R promotes the proliferation, colony formation, EMT, MMP2/14 expression, and migration of lung cancer cells. The inhibition of NK1R by selective antagonist aprepitant repressed cell proliferation and migration in vitro. Knockdown of NK1R significantly slowed down the tumor growth in nude mice. The sensitivity of lung cancer cells to gefitinib/osimertinib is highly increased in the presence of the selective NK1R antagonist aprepitant. Our data suggest that NK1R plays an important role in lung cancer development through EGFR signaling and the crosstalk between NK1R and EGFR may provide a potential therapeutic target for lung cancer treatment.
Autophagy facilitates age-related cell apoptosis—a new insight from senile cataract
Authors: Huang Jiani , Yu Wangshu , He Qin , He Xiaoying , Yang Ming , Chen Wei , Han Wei
Published: January 2022

Age-related cell loss underpins many senescence-associated diseases. Apoptosis of lens epithelial cells (LECs) is the important cellular basis of senile cataract resulted from prolonged exposure to oxidative stress, although the specific mechanisms remain elusive. Our data indicated the concomitance of high autophagy activity, low SQSTM1/p62 protein level and apoptosis in the same LEC from senile cataract patients. Meanwhile, in primary cultured LECs model, more durable autophagy activation and more obvious p62 degradation under oxidative stress were observed in LECs from elder healthy donors, compared with that from young healthy donors. Using autophagy-deficiency HLE-B3 cell line, autophagy adaptor p62 was identified as the critical scaffold protein sustaining the pro-survival signaling PKCι-IKK-NF-κB cascades, which antagonized the pro-apoptotic signaling. Moreover, the pharmacological inhibitor of autophagy, 3-MA, significantly inhibited p62 degradation and rescued oxidative stress-induced apoptosis in elder LECs. Collectively, this study demonstrated that durable activation of autophagy promoted age-related cell death in LECs. Our work contributes to better understanding the pathogenesis of senescence-associated diseases.
Double-edge sword roles of iron in driving energy production versus instigating ferroptosis
Authors: Zhang Shuping , Xin Wei , Anderson Gregory J. , Li Ruibin , Gao Ling , Chen Shuguang , Zhao Jiajun , Liu Sijin
Published: January 2022

Iron is vital for many physiological functions, including energy production, and dysregulated iron homeostasis underlies a number of pathologies. Ferroptosis is a recently recognized form of regulated cell death that is characterized by iron dependency and lipid peroxidation, and this process has been reported to be involved in multiple diseases. The mechanisms underlying ferroptosis are complex, and involve both well-described pathways (including the iron-induced Fenton reaction, impaired antioxidant capacity, and mitochondrial dysfunction) and novel interactions linked to cellular energy production. In this review, we examine the contribution of iron to diverse metabolic activities and their relationship to ferroptosis. There is an emphasis on the role of iron in driving energy production and its link to ferroptosis under both physiological and pathological conditions. In conclusion, excess reactive oxygen species production driven by disordered iron metabolism, which induces Fenton reaction and/or impairs mitochondrial function and energy metabolism, is a key inducer of ferroptosis.
RSL1D1 promotes the progression of colorectal cancer through RAN-mediated autophagy suppression
Authors: Liu Xunhua , Chen Jianxiong , Long Xiaoli , Lan Jiawen , Liu Xiaoting , Zhou Miao , Zhang Sijing , Zhou Jun
Published: January 2022

RSL1D1 (ribosomal L1 domain containing 1), a member of the universal ribosomal protein uL1 family, was suggested to be a new candidate target for colorectal cancer (CRC). However, the role of RSL1D1 in cancer, including CRC, remains largely elusive. Here, we demonstrated that RSL1D1 expression was significantly elevated in tumors from CRC patients and that high expression of RSL1D1 was correlated with poorer survival of CRC patients. Functionally, RSL1D1 promoted the proliferation, invasion, and metastasis of CRC cells by suppressing autophagy. Interestingly, RSL1D1 interacted with RAN and inhibited its deacetylation by competitively binding with Sirt7. By affecting the acetylation of RAN, RSL1D1 inhibited the accumulation of nuclear STAT3 and the STAT3-regulated autophagic program. Taken together, our study uncovered the key role of the RSL1D1/RAN/STAT3 regulatory axis in autophagy and tumor progression in CRC, providing a new candidate target for CRC treatment.
Focal neural perturbations reshape low-dimensional trajectories of brain activity supporting cognitive performance
Authors: Iyer Kartik K. , Hwang Kai , Hearne Luke J. , Muller Eli , D’Esposito Mark , Shine James M. , Cocchi Luca
Published: January 2022

The emergence of distributed patterns of neural activity supporting brain functions and behavior can be understood by study of the brain’s low-dimensional topology. Functional neuroimaging demonstrates that brain activity linked to adaptive behavior is constrained to low-dimensional manifolds. In human participants, we tested whether these low-dimensional constraints preserve working memory performance following local neuronal perturbations. We combined multi-session functional magnetic resonance imaging, non-invasive transcranial magnetic stimulation (TMS), and methods translated from the fields of complex systems and computational biology to assess the functional link between changes in local neural activity and the reshaping of task-related low dimensional trajectories of brain activity. We show that specific reconfigurations of low-dimensional trajectories of brain activity sustain effective working memory performance following TMS manipulation of local activity on, but not off, the space traversed by these trajectories. We highlight an association between the multi-scale changes in brain activity underpinning cognitive function.
Megaripple mechanics: bimodal transport ingrained in bimodal sands
Authors: Tholen Katharina , Pähtz Thomas , Yizhaq Hezi , Katra Itzhak , Kroy Klaus
Published: January 2022

Aeolian sand transport is a major process shaping landscapes on Earth and on diverse celestial bodies. Conditions favoring bimodal sand transport, with fine-grain saltation driving coarse-grain reptation, give rise to the evolution of megaripples with a characteristic bimodal sand composition. Here, we derive a unified phase diagram for this special aeolian process and the ensuing nonequilibrium megaripple morphodynamics by means of a conceptually simple quantitative model, grounded in the grain-scale physics. We establish a well-preserved quantitative signature of bimodal aeolian transport in the otherwise highly variable grain size distributions, namely, the log-scale width (Krumbein phi scale) of their coarse-grain peaks. A comprehensive collection of terrestrial and extraterrestrial data, covering a wide range of geographical sources and environmental conditions, supports the accuracy and robustness of this unexpected theoretical finding. It could help to resolve ambiguities in the classification of terrestrial and extraterrestrial sedimentary bedforms.
Single-cell analysis of human primary prostate cancer reveals the heterogeneity of tumor-associated epithelial cell states
Authors: Song Hanbing , Weinstein Hannah N. W. , Allegakoen Paul , Wadsworth Marc H. , Xie Jamie , Yang Heiko , Castro Ethan A. , Lu Kevin L. , Stohr Bradley A. , Feng Felix Y. , Carroll Peter R. , Wang Bruce , Cooperberg Matthew R. , Shalek Alex K. , Huang Franklin W.
Published: January 2022

Prostate cancer is the second most common malignancy in men worldwide and consists of a mixture of tumor and non-tumor cell types. To characterize the prostate cancer tumor microenvironment, we perform single-cell RNA-sequencing on prostate biopsies, prostatectomy specimens, and patient-derived organoids from localized prostate cancer patients. We uncover heterogeneous cellular states in prostate epithelial cells marked by high androgen signaling states that are enriched in prostate cancer and identify a population of tumor-associated club cells that may be associated with prostate carcinogenesis. ERG-negative tumor cells, compared to ERG-positive cells, demonstrate shared heterogeneity with surrounding luminal epithelial cells and appear to give rise to common tumor microenvironment responses. Finally, we show that prostate epithelial organoids harbor tumor-associated epithelial cell states and are enriched with distinct cell types and states from their parent tissues. Our results provide diagnostically relevant insights and advance our understanding of the cellular states associated with prostate carcinogenesis.
Maximizing response to intratumoral immunotherapy in mice by tuning local retention
Authors: Momin Noor , Palmeri Joseph R. , Lutz Emi A. , Jailkhani Noor , Mak Howard , Tabet Anthony , Chinn Magnolia M. , Kang Byong H. , Spanoudaki Virginia , Hynes Richard O. , Wittrup K. Dane
Published: January 2022

Direct injection of therapies into tumors has emerged as an administration route capable of achieving high local drug exposure and strong anti-tumor response. A diverse array of immune agonists ranging in size and target are under development as local immunotherapies. However, due to the relatively recent adoption of intratumoral administration, the pharmacokinetics of locally-injected biologics remains poorly defined, limiting rational design of tumor-localized immunotherapies. Here we define a pharmacokinetic framework for biologics injected intratumorally that can predict tumor exposure and effectiveness. We find empirically and computationally that extending the tumor exposure of locally-injected interleukin-2 by increasing molecular size and/or improving matrix-targeting affinity improves therapeutic efficacy in mice. By tracking the distribution of intratumorally-injected proteins using positron emission tomography, we observe size-dependent enhancement in tumor exposure occurs by slowing the rate of diffusive escape from the tumor and by increasing partitioning to an apparent viscous region of the tumor. In elucidating how molecular weight and matrix binding interplay to determine tumor exposure, our model can aid in the design of intratumoral therapies to exert maximal therapeutic effect.
Neuronal Yin Yang1 in the prefrontal cortex regulates transcriptional and behavioral responses to chronic stress in mice
Authors: Kwon Deborah Y. , Xu Bing , Hu Peng , Zhao Ying-Tao , Beagan Jonathan A. , Nofziger Jonathan H. , Cui Yue , Phillips-Cremins Jennifer E. , Blendy Julie A. , Wu Hao , Zhou Zhaolan
Published: January 2022

Although the synaptic alterations associated with the stress-related mood disorder major depression has been well-documented, the underlying transcriptional mechanisms remain poorly understood. Here, we perform complementary bulk nuclei- and single-nucleus transcriptome profiling and map locus-specific chromatin interactions in mouse neocortex to identify the cell type-specific transcriptional changes associated with stress-induced behavioral maladaptation. We find that cortical excitatory neurons, layer 2/3 neurons in particular, are vulnerable to chronic stress and acquire signatures of gene transcription and chromatin structure associated with reduced neuronal activity and expression of Yin Yang 1 (YY1). Selective ablation of YY1 in cortical excitatory neurons enhances stress sensitivity in both male and female mice and alters the expression of stress-associated genes following an abbreviated stress exposure. These findings demonstrate how chronic stress impacts transcription in cortical excitatory neurons and identify YY1 as a regulator of stress-induced maladaptive behavior in mice.
Lifelong single-cell profiling of cranial neural crest diversification in zebrafish
Authors: Fabian Peter , Tseng Kuo-Chang , Thiruppathy Mathi , Arata Claire , Chen Hung-Jhen , Smeeton Joanna , Nelson Nellie , Crump J. Gage
Published: January 2022

The cranial neural crest generates a huge diversity of derivatives, including the bulk of connective and skeletal tissues of the vertebrate head. How neural crest cells acquire such extraordinary lineage potential remains unresolved. By integrating single-cell transcriptome and chromatin accessibility profiles of cranial neural crest-derived cells across the zebrafish lifetime, we observe progressive and region-specific establishment of enhancer accessibility for distinct fates. Neural crest-derived cells rapidly diversify into specialized progenitors, including multipotent skeletal progenitors, stromal cells with a regenerative signature, fibroblasts with a unique metabolic signature linked to skeletal integrity, and gill-specific progenitors generating cell types for respiration. By retrogradely mapping the emergence of lineage-specific chromatin accessibility, we identify a wealth of candidate lineage-priming factors, including a Gata3 regulatory circuit for respiratory cell fates. Rather than multilineage potential being established during cranial neural crest specification, our findings support progressive and region-specific chromatin remodeling underlying acquisition of diverse potential.
A bispecific monomeric nanobody induces spike trimer dimers and neutralizes SARS-CoV-2 in vivo
Authors: Hanke Leo , Das Hrishikesh , Sheward Daniel J. , Perez Vidakovics Laura , Urgard Egon , Moliner-Morro Ainhoa , Kim Changil , Karl Vivien , Pankow Alec , Smith Natalie L. , Porebski Bartlomiej , Fernandez-Capetillo Oscar , Sezgin Erdinc , Pedersen Gabriel K. , Coquet Jonathan M. , Hällberg B. Martin , Murrell Ben , McInerney Gerald M.
Published: January 2022

Antibodies binding to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike have therapeutic promise, but emerging variants show the potential for virus escape. This emphasizes the need for therapeutic molecules with distinct and novel neutralization mechanisms. Here we describe the isolation of a nanobody that interacts simultaneously with two RBDs from different spike trimers of SARS-CoV-2, rapidly inducing the formation of spike trimer–dimers leading to the loss of their ability to attach to the host cell receptor, ACE2. We show that this nanobody potently neutralizes SARS-CoV-2, including the beta and delta variants, and cross-neutralizes SARS-CoV. Furthermore, we demonstrate the therapeutic potential of the nanobody against SARS-CoV-2 and the beta variant in a human ACE2 transgenic mouse model. This naturally elicited bispecific monomeric nanobody establishes an uncommon strategy for potent inactivation of viral antigens and represents a promising antiviral against emerging SARS-CoV-2 variants.
The transcription factor ZIP-1 promotes resistance to intracellular infection in Caenorhabditis elegans
Authors: Lažetić Vladimir , Wu Fengting , Cohen Lianne B. , Reddy Kirthi C. , Chang Ya-Ting , Gang Spencer S. , Bhabha Gira , Troemel Emily R.
Published: January 2022

Defense against intracellular infection has been extensively studied in vertebrate hosts, but less is known about invertebrate hosts; specifically, the transcription factors that induce defense against intracellular intestinal infection in the model nematode Caenorhabditis elegans remain understudied. Two different types of intracellular pathogens that naturally infect the C. elegans intestine are the Orsay virus, which is an RNA virus, and microsporidia, which comprise a phylum of fungal pathogens. Despite their molecular differences, these pathogens induce a common host transcriptional response called the intracellular pathogen response (IPR). Here we show that zip-1 is an IPR regulator that functions downstream of all known IPR-activating and regulatory pathways. zip-1 encodes a putative bZIP transcription factor, and we show that zip-1 controls induction of a subset of genes upon IPR activation. ZIP-1 protein is expressed in the nuclei of intestinal cells, and is at least partially required in the intestine to upregulate IPR gene expression. Importantly, zip-1 promotes resistance to infection by the Orsay virus and by microsporidia in intestinal cells. Altogether, our results indicate that zip-1 represents a central hub for triggers of the IPR, and that this transcription factor has a protective function against intracellular pathogen infection in C. elegans.
Bone morphogenetic protein 1.3 inhibition decreases scar formation and supports cardiomyocyte survival after myocardial infarction
Authors: Vukicevic Slobodan , Colliva Andrea , Kufner Vera , Martinelli Valentina , Moimas Silvia , Vodret Simone , Rumenovic Viktorija , Milosevic Milan , Brkljacic Boris , Delic-Brkljacic Diana , Correa Ricardo , Giacca Mauro , Maglione Manuel , Bordukalo-Niksic Tatjana , Dumic-Cule Ivo , Zacchigna Serena
Published: January 2022

Despite the high prevalence of ischemic heart diseases worldwide, no antibody-based treatment currently exists. Starting from the evidence that a specific isoform of the Bone Morphogenetic Protein 1 (BMP1.3) is particularly elevated in both patients and animal models of myocardial infarction, here we assess whether its inhibition by a specific monoclonal antibody reduces cardiac fibrosis. We find that this treatment reduces collagen deposition and cross-linking, paralleled by enhanced cardiomyocyte survival, both in vivo and in primary cultures of cardiac cells. Mechanistically, we show that the anti-BMP1.3 monoclonal antibody inhibits Transforming Growth Factor β pathway, thus reducing myofibroblast activation and inducing cardioprotection through BMP5. Collectively, these data support the therapeutic use of anti-BMP1.3 antibodies to prevent cardiomyocyte apoptosis, reduce collagen deposition and preserve cardiac function after ischemia.
Polyply; a python suite for facilitating simulations of macromolecules and nanomaterials
Authors: Grünewald Fabian , Alessandri Riccardo , Kroon Peter C. , Monticelli Luca , Souza Paulo C. T. , Marrink Siewert J.
Published: January 2022

Molecular dynamics simulations play an increasingly important role in the rational design of (nano)-materials and in the study of biomacromolecules. However, generating input files and realistic starting coordinates for these simulations is a major bottleneck, especially for high throughput protocols and for complex multi-component systems. To eliminate this bottleneck, we present the polyply software suite that provides 1) a multi-scale graph matching algorithm designed to generate parameters quickly and for arbitrarily complex polymeric topologies, and 2) a generic multi-scale random walk protocol capable of setting up complex systems efficiently and independent of the target force-field or model resolution. We benchmark quality and performance of the approach by creating realistic coordinates for polymer melt simulations, single-stranded as well as circular single-stranded DNA. We further demonstrate the power of our approach by setting up a microphase-separated block copolymer system, and by generating a liquid-liquid phase separated system inside a lipid vesicle.
Mechanical force promotes dimethylarginine dimethylaminohydrolase 1-mediated hydrolysis of the metabolite asymmetric dimethylarginine to enhance bone formation
Authors: Xie Ziang , Hou Lei , Shen Shuying , Wu Yizheng , Wang Jian , Jie Zhiwei , Zhao Xiangde , Li Xiang , Zhang Xuyang , Chen Junxin , Xu Wenbin , Ning Lei , Ma Qingliang , Wang Shiyu , Wang Haoming , Yuan Putao , Fang Xiangqian , Qin An , Fan Shunwu
Published: January 2022

Mechanical force is critical for the development and remodeling of bone. Here we report that mechanical force regulates the production of the metabolite asymmetric dimethylarginine (ADMA) via regulating the hydrolytic enzyme dimethylarginine dimethylaminohydrolase 1 (Ddah1) expression in osteoblasts. The presence of -394 4 N del/ins polymorphism of Ddah1 and higher serum ADMA concentration are negatively associated with bone mineral density. Global or osteoblast-specific deletion of Ddah1 leads to increased ADMA level but reduced bone formation. Further molecular study unveils that mechanical stimulation enhances TAZ/SMAD4-induced Ddah1 transcription. Deletion of Ddah1 in osteoblast-lineage cells fails to respond to mechanical stimulus-associated bone formation. Taken together, the study reveals mechanical force is capable of down-regulating ADMA to enhance bone formation.
Interfacial-confined coordination to single-atom nanotherapeutics
Authors: Qin Limei , Gan Jie , Niu Dechao , Cao Yueqiang , Duan Xuezhi , Qin Xing , Zhang Hao , Jiang Zheng , Jiang Yongjun , Dai Sheng , Li Yongsheng , Shi Jianlin
Published: January 2022

Pursuing and developing effective methodologies to construct highly active catalytic sites to maximize the atomic and energy efficiency by material engineering are attractive. Relative to the tremendous researches of carbon-based single atom systems, the construction of bio-applicable single atom materials is still in its infancy. Herein, we propose a facile and general interfacial-confined coordination strategy to construct high-quality single-atom nanotherapeutic agent with Fe single atoms being anchored on defective carbon dots confined in a biocompatible mesoporous silica nanoreactor. Furthermore, the efficient energy conversion capability of silica-based Fe single atoms system has been demonstrated on the basis of the exogenous physical photo irradiation and endogenous biochemical reactive oxygen species stimulus in the confined mesoporous network. More importantly, the highest photothermal conversion efficiency with the mechanism of increased electron density and narrow bandgap of this single atom structure in defective carbon was proposed by the theoretical DFT calculations. The present methodology provides a scientific paradigm to design and develop versatile single atom nanotherapeutics with adjustable metal components and tune the corresponding reactions for safe and efficient tumor therapeutic strategy.
Climate changes modulated the history of Arctic iodine during the Last Glacial Cycle
Authors: Corella Juan Pablo , Maffezzoli Niccolo , Spolaor Andrea , Vallelonga Paul , Cuevas Carlos A. , Scoto Federico , Müller Juliane , Vinther Bo , Kjær Helle A. , Cozzi Giulio , Edwards Ross , Barbante Carlo , Saiz-Lopez Alfonso
Published: January 2022

Iodine has a significant impact on promoting the formation of new ultrafine aerosol particles and accelerating tropospheric ozone loss, thereby affecting radiative forcing and climate. Therefore, understanding the long-term natural evolution of iodine, and its coupling with climate variability, is key to adequately assess its effect on climate on centennial to millennial timescales. Here, using two Greenland ice cores (NEEM and RECAP), we report the Arctic iodine variability during the last 127,000 years. We find the highest and lowest iodine levels recorded during interglacial and glacial periods, respectively, modulated by ocean bioproductivity and sea ice dynamics. Our sub-decadal resolution measurements reveal that high frequency iodine emission variability occurred in pace with Dansgaard/Oeschger events, highlighting the rapid Arctic ocean-ice-atmosphere iodine exchange response to abrupt climate changes. Finally, we discuss if iodine levels during past warmer-than-present climate phases can serve as analogues of future scenarios under an expected ice-free Arctic Ocean. We argue that the combination of natural biogenic ocean iodine release (boosted by ongoing Arctic warming and sea ice retreat) and anthropogenic ozone-induced iodine emissions may lead to a near future scenario with the highest iodine levels of the last 127,000 years.
Latency reversal plus natural killer cells diminish HIV reservoir in vivo
Authors: Kim Jocelyn T. , Zhang Tian-Hao , Carmona Camille , Lee Bryanna , Seet Christopher S. , Kostelny Matthew , Shah Nisarg , Chen Hongying , Farrell Kylie , Soliman Mohamed S. A. , Dimapasoc Melanie , Sinani Michelle , Blanco Kenia Yazmin Reyna , Bojorquez David , Jiang Hong , Shi Yuan , Du Yushen , Komarova Natalia L. , Wodarz Dominik , Wender Paul A. , Marsden Matthew D. , Sun Ren , Zack Jerome A.
Published: January 2022

HIV is difficult to eradicate due to the persistence of a long-lived reservoir of latently infected cells. Previous studies have shown that natural killer cells are important to inhibiting HIV infection, but it is unclear whether the administration of natural killer cells can reduce rebound viremia when anti-retroviral therapy is discontinued. Here we show the administration of allogeneic human peripheral blood natural killer cells delays viral rebound following interruption of anti-retroviral therapy in humanized mice infected with HIV-1. Utilizing genetically barcoded virus technology, we show these natural killer cells efficiently reduced viral clones rebounding from latency. Moreover, a kick and kill strategy comprised of the protein kinase C modulator and latency reversing agent SUW133 and allogeneic human peripheral blood natural killer cells during anti-retroviral therapy eliminated the viral reservoir in a subset of mice. Therefore, combinations utilizing latency reversal agents with targeted cellular killing agents may be an effective approach to eradicating the viral reservoir.
Brain-inspired global-local learning incorporated with neuromorphic computing
Authors: Wu Yujie , Zhao Rong , Zhu Jun , Chen Feng , Xu Mingkun , Li Guoqi , Song Sen , Deng Lei , Wang Guanrui , Zheng Hao , Ma Songchen , Pei Jing , Zhang Youhui , Zhao Mingguo , Shi Luping
Published: January 2022

There are two principle approaches for learning in artificial intelligence: error-driven global learning and neuroscience-oriented local learning. Integrating them into one network may provide complementary learning capabilities for versatile learning scenarios. At the same time, neuromorphic computing holds great promise, but still needs plenty of useful algorithms and algorithm-hardware co-designs to fully exploit its advantages. Here, we present a neuromorphic global-local synergic learning model by introducing a brain-inspired meta-learning paradigm and a differentiable spiking model incorporating neuronal dynamics and synaptic plasticity. It can meta-learn local plasticity and receive top-down supervision information for multiscale learning. We demonstrate the advantages of this model in multiple different tasks, including few-shot learning, continual learning, and fault-tolerance learning in neuromorphic vision sensors. It achieves significantly higher performance than single-learning methods. We further implement the model in the Tianjic neuromorphic platform by exploiting algorithm-hardware co-designs and prove that the model can fully utilize neuromorphic many-core architecture to develop hybrid computation paradigm.
Structural mechanism for tyrosine hydroxylase inhibition by dopamine and reactivation by Ser40 phosphorylation
Authors: Bueno-Carrasco María Teresa , Cuéllar Jorge , Flydal Marte I. , Santiago César , Kråkenes Trond-André , Kleppe Rune , López-Blanco José R. , Marcilla Miguel , Teigen Knut , Alvira Sara , Chacón Pablo , Martinez Aurora , Valpuesta José M.
Published: January 2022

Tyrosine hydroxylase (TH) catalyzes the rate-limiting step in the biosynthesis of dopamine (DA) and other catecholamines, and its dysfunction leads to DA deficiency and parkinsonisms. Inhibition by catecholamines and reactivation by S40 phosphorylation are key regulatory mechanisms of TH activity and conformational stability. We used Cryo-EM to determine the structures of full-length human TH without and with DA, and the structure of S40 phosphorylated TH, complemented with biophysical and biochemical characterizations and molecular dynamics simulations. TH presents a tetrameric structure with dimerized regulatory domains that are separated 15 Å from the catalytic domains. Upon DA binding, a 20-residue α-helix in the flexible N-terminal tail of the regulatory domain is fixed in the active site, blocking it, while S40-phosphorylation forces its egress. The structures reveal the molecular basis of the inhibitory and stabilizing effects of DA and its counteraction by S40-phosphorylation, key regulatory mechanisms for homeostasis of DA and TH.
Size compatibility and concentration dependent supramolecular host–guest interactions at interfaces
Authors: Park Jintae , Park Jinwoo , Lee Jinhoon , Lim Chanoong , Lee Dong Woog
Published: January 2022

The quantification of supramolecular host–guest interactions is important for finely modulating supramolecular systems. Previously, most host–guest interactions quantified using force spectroscopic techniques have been reported in force units. However, accurately evaluating the adhesion energies of host–guest pairs remains challenging. Herein, using a surface forces apparatus, we directly quantify the interaction energies between cyclodextrin (CD)-modified surfaces and ditopic adamantane (DAd) molecules in water as a function of the DAd concentration and the CD cavity size. The adhesion energy of the β-CD–DAd complex drastically increased with increasing DAd concentration and reached saturation. Moreover, the molecular adhesion energy of a single host–guest inclusion complex was evaluated to be ~9.51 kBT. This approach has potential for quantifying fundamental information toward furthering the understanding of supramolecular chemistry and its applications, such as molecular actuators, underwater adhesives, and biosensors, which require precise tuning of specific host–guest interactions.
Structure-dynamics relationships in cryogenically deformed bulk metallic glass
Authors: Spieckermann Florian , Şopu Daniel , Soprunyuk Viktor , Kerber Michael B. , Bednarčík Jozef , Schökel Alexander , Rezvan Amir , Ketov Sergey , Sarac Baran , Schafler Erhard , Eckert Jürgen
Published: January 2022

The atomistic mechanisms occurring during the processes of aging and rejuvenation in glassy materials involve very small structural rearrangements that are extremely difficult to capture experimentally. Here we use in-situ X-ray diffraction to investigate the structural rearrangements during annealing from 77 K up to the crystallization temperature in Cu44Zr44Al8Hf2Co2 bulk metallic glass rejuvenated by high pressure torsion performed at cryogenic temperatures and at room temperature. Using a measure of the configurational entropy calculated from the X-ray pair correlation function, the structural footprint of the deformation-induced rejuvenation in bulk metallic glass is revealed. With synchrotron radiation, temperature and time resolutions comparable to calorimetric experiments are possible. This opens hitherto unavailable experimental possibilities allowing to unambiguously correlate changes in atomic configuration and structure to calorimetrically observed signals and can attribute those to changes of the dynamic and vibrational relaxations (α-, β- and γ-transition) in glassy materials. The results suggest that the structural footprint of the β-transition is related to entropic relaxation with characteristics of a first-order transition. Dynamic mechanical analysis data shows that in the range of the β-transition, non-reversible structural rearrangements are preferentially activated. The low-temperature γ-transition is mostly triggering reversible deformations and shows a change of slope in the entropic footprint suggesting second-order characteristics.
Coordination modulation of iridium single-atom catalyst maximizing water oxidation activity
Authors: Lei Zhanwu , Cai Wenbin , Rao Yifei , Wang Kuan , Jiang Yuyuan , Liu Yang , Jin Xu , Li Jianming , Lv Zhengxing , Jiao Shuhong , Zhang Wenhua , Yan Pengfei , Zhang Shuo , Cao Ruiguo
Published: January 2022

Single-atom catalysts (SACs) have attracted tremendous research interests in various energy-related fields because of their high activity, selectivity and 100% atom utilization. However, it is still a challenge to enhance the intrinsic and specific activity of SACs. Herein, we present an approach to fabricate a high surface distribution density of iridium (Ir) SAC on nickel-iron sulfide nanosheet arrays substrate (Ir1/NFS), which delivers a high water oxidation activity. The Ir1/NFS catalyst offers a low overpotential of ~170 mV at a current density of 10 mA cm−2 and a high turnover frequency of 9.85 s−1 at an overpotential of 300 mV in 1.0 M KOH solution. At the same time, the Ir1/NFS catalyst exhibits a high stability performance, reaching a lifespan up to 350 hours at a current density of 100 mA cm−2. First-principles calculations reveal that the electronic structures of Ir atoms are significantly regulated by the sulfide substrate, endowing an energetically favorable reaction pathway. This work represents a promising strategy to fabricate high surface distribution density single-atom catalysts with high activity and durability for electrochemical water splitting.
Cross-reactive memory T cells associate with protection against SARS-CoV-2 infection in COVID-19 contacts
Authors: Kundu Rhia , Narean Janakan Sam , Wang Lulu , Fenn Joseph , Pillay Timesh , Fernandez Nieves Derqui , Conibear Emily , Koycheva Aleksandra , Davies Megan , Tolosa-Wright Mica , Hakki Seran , Varro Robert , McDermott Eimear , Hammett Sarah , Cutajar Jessica , Thwaites Ryan S. , Parker Eleanor , Rosadas Carolina , McClure Myra , Tedder Richard , Taylor Graham P. , Dunning Jake , Lalvani Ajit
Published: January 2022

Cross-reactive immune responses to SARS-CoV-2 have been observed in pre-pandemic cohorts and proposed to contribute to host protection. Here we assess 52 COVID-19 household contacts to capture immune responses at the earliest timepoints after SARS-CoV-2 exposure. Using a dual cytokine FLISpot assay on peripheral blood mononuclear cells, we enumerate the frequency of T cells specific for spike, nucleocapsid, membrane, envelope and ORF1 SARS-CoV-2 epitopes that cross-react with human endemic coronaviruses. We observe higher frequencies of cross-reactive (p = 0.0139), and nucleocapsid-specific (p = 0.0355) IL-2-secreting memory T cells in contacts who remained PCR-negative despite exposure (n = 26), when compared with those who convert to PCR-positive (n = 26); no significant difference in the frequency of responses to spike is observed, hinting at a limited protective function of spike-cross-reactive T cells. Our results are thus consistent with pre-existing non-spike cross-reactive memory T cells protecting SARS-CoV-2-naïve contacts from infection, thereby supporting the inclusion of non-spike antigens in second-generation vaccines.
Tartrate-resistant acid phosphatase 5 promotes pulmonary fibrosis by modulating β-catenin signaling
Authors: Hu Yinan , Wang Qi , Yu Jun , Zhou Qing , Deng Yanhan , Liu Juan , Zhang Lei , Xu Yongjian , Xiong Weining , Wang Yi
Published: January 2022

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Tartrate-resistant acid phosphatase 5 (ACP5) performs a variety of functions. However, its role in IPF remains unclear. Here, we demonstrate that the levels of ACP5 are increased in IPF patient samples and mice with bleomycin (BLM)-induced pulmonary fibrosis. In particular, higher levels of ACP5 are present in the sera of IPF patients with a diffusing capacity of the lungs for carbonmonoxide (DLCO) less than 40% of the predicted value. Additionally, Acp5 deficiency protects mice from BLM-induced lung injury and fibrosis coupled with a significant reduction of fibroblast differentiation and proliferation. Mechanistic studies reveal that Acp5 is upregulated by transforming growth factor-β1 (TGF-β1) in a TGF-β receptor 1 (TGFβR1)/Smad family member 3 (Smad3)-dependent manner, after which Acp5 dephosphorylates p-β-catenin at serine 33 and threonine 41, inhibiting the degradation of β-catenin and subsequently enhancing β-catenin signaling in the nucleus, which promotes the differentiation, proliferation and migration of fibroblast. More importantly, the treatment of mice with Acp5 siRNA-loaded liposomes or Acp5 inhibitor reverses established lung fibrosis. In conclusions, Acp5 is involved in the initiation and progression of pulmonary fibrosis and strategies aimed at silencing or suppressing Acp5 could be considered as potential therapeutic approaches against pulmonary fibrosis.
Prefrontal cortical plasticity during learning of cognitive tasks
Authors: Tang Hua , Riley Mitchell R. , Singh Balbir , Qi Xue-Lian , Blake David T. , Constantinidis Christos
Published: January 2022

Training in working memory tasks is associated with lasting changes in prefrontal cortical activity. To assess the neural activity changes induced by training, we recorded single units, multi-unit activity (MUA) and local field potentials (LFP) with chronic electrode arrays implanted in the prefrontal cortex of two monkeys, throughout the period they were trained to perform cognitive tasks. Mastering different task phases was associated with distinct changes in neural activity, which included recruitment of larger numbers of neurons, increases or decreases of their firing rate, changes in the correlation structure between neurons, and redistribution of power across LFP frequency bands. In every training phase, changes induced by the actively learned task were also observed in a control task, which remained the same across the training period. Our results reveal how learning to perform cognitive tasks induces plasticity of prefrontal cortical activity, and how activity changes may generalize between tasks.
Transient neuronal suppression for exploitation of new sensory evidence
Authors: Shinn Maxwell , Lee Daeyeol , Murray John D. , Seo Hyojung
Published: January 2022

In noisy but stationary environments, decisions should be based on the temporal integration of sequentially sampled evidence. This strategy has been supported by many behavioral studies and is qualitatively consistent with neural activity in multiple brain areas. By contrast, decision-making in the face of non-stationary sensory evidence remains poorly understood. Here, we trained monkeys to identify and respond via saccade to the dominant color of a dynamically refreshed bicolor patch that becomes informative after a variable delay. Animals’ behavioral responses were briefly suppressed after evidence changes, and many neurons in the frontal eye field displayed a corresponding dip in activity at this time, similar to that frequently observed after stimulus onset but sensitive to stimulus strength. Generalized drift-diffusion models revealed consistency of behavior and neural activity with brief suppression of motor output, but not with pausing or resetting of evidence accumulation. These results suggest that momentary arrest of motor preparation is important for dynamic perceptual decision making.