bluuebunny/crossref_metadata_2025 huggingface dataset:
Genome-wide transcriptomics of the amygdala reveals similar oligodendrocyte-related responses to acute and chronic alcohol drinking in female mice
Authors: Narendra Sharvari , Klengel Claudia , Hamzeh Bilal , Patel Drasti , Otten Joy , Lardenoije Roy , Newman Emily L. , Miczek Klaus A. , Klengel Torsten , Ressler Kerry J. , Suh Junghyup
Published: November 2022

Repeated excessive alcohol consumption is a risk factor for alcohol use disorder (AUD). Although AUD has been more common in men than women, women develop more severe behavioral and physical impairments. However, relatively few new therapeutics targeting development of AUD, particularly in women, have been validated. To gain a better understanding of molecular mechanisms underlying alcohol intake, we conducted a genome-wide RNA-sequencing analysis in female mice exposed to different modes (acute vs chronic) of ethanol drinking. We focused on transcriptional profiles in the amygdala including the central and basolateral subnuclei, brain areas previously implicated in alcohol drinking and seeking. Surprisingly, we found that both drinking modes triggered similar changes in gene expression and canonical pathways, including upregulation of ribosome-related/translational pathways and myelination pathways, and downregulation of chromatin binding and histone modification. In addition, analyses of hub genes and upstream regulatory pathways revealed that voluntary ethanol consumption affects epigenetic changes via histone deacetylation pathways, oligodendrocyte and myelin function, and the oligodendrocyte-related transcription factor, Sox17. Furthermore, a viral vector-assisted knockdown of Sox17 gene expression in the amygdala prevented a gradual increase in alcohol consumption during repeated accesses. Overall, these results suggest that the expression of oligodendrocyte-related genes in the amygdala is sensitive to voluntary alcohol drinking in female mice. These findings suggest potential molecular targets for future therapeutic approaches to prevent the development of AUD, due to repeated excessive alcohol consumption, particularly in women.
Nck1 activity in lateral amygdala regulates long-term fear memory formation
Authors: Ilovich Or , Dines Monica , Paul Blesson K. , Barkai Edi , Lamprecht Raphael
Published: November 2022

Fear conditioning leads to long-term fear memory formation and is a model for studying fear-related psychopathological conditions such as phobias and post-traumatic stress disorder. Long-term fear memory formation is believed to involve alterations of synaptic efficacy mediated by changes in synaptic transmission and morphology in lateral amygdala (LA). Nck1 is a key neuronal adaptor protein involved in the regulation of the actin cytoskeleton and the neuronal processes believed to be involved in memory formation. However, the role of Nck1 in memory formation is not known. Here we explored the role of Nck1 in fear memory formation in lateral amygdala (LA). Reduction of Nck1 in excitatory neurons in LA enhanced long-term, but not short-term, auditory fear conditioning memory. Activation of Nck1, by using a photoactivatable Nck1 (PA-Nck1), during auditory fear conditioning in excitatory neurons in LA impaired long-term, but not short-term, fear memory. Activation of Nck1 immediately or a day after fear conditioning did not affect fear memory. The hippocampal-mediated contextual fear memory was not affected by the reduction or activation of Nck1 in LA. We show that Nck1 is localized to the presynapses in LA. Nck1 activation in LA excitatory neurons decreased the frequency of AMPA receptors-mediated miniature excitatory synaptic currents (mEPSCs). Nck1 activation did not affect GABA receptor-mediated inhibitory synaptic currents (mIPSCs). These results show that Nck1 activity in excitatory neurons in LA regulates glutamate release and sets the threshold for fear memory formation. Moreover, our research shows that Nck1 may serve as a target for pharmacological treatment of fear and anxiety disorders.
SETD2 transcriptional control of ATG14L/S isoforms regulates autophagosome–lysosome fusion
Authors: González-Rodríguez Patricia , Delorme-Axford Elizabeth , Bernard Amélie , Keane Lily , Stratoulias Vassilis , Grabert Kathleen , Engskog-Vlachos Pinelopi , Füllgrabe Jens , Klionsky Daniel J. , Joseph Bertrand
Published: November 2022

Macroautophagy/autophagy is an evolutionarily conserved and tightly regulated catabolic process involved in the maintenance of cellular homeostasis whose dysregulation is implicated in several pathological processes. Autophagy begins with the formation of phagophores that engulf cytoplasmic cargo and mature into double-membrane autophagosomes; the latter fuse with lysosomes/vacuoles for cargo degradation and recycling. Here, we report that yeast Set2, a histone lysine methyltransferase, and its mammalian homolog, SETD2, both act as positive transcriptional regulators of autophagy. However, whereas Set2 regulates the expression of several autophagy-related (Atg) genes upon nitrogen starvation, SETD2 effects in mammals were found to be more restricted. In fact, SETD2 appears to primarily regulate the differential expression of protein isoforms encoded by the ATG14 gene. SETD2 promotes the expression of a long ATG14 isoform, ATG14L, that contains an N-terminal cysteine repeats domain, essential for the efficient fusion of the autophagosome with the lysosome, that is absent in the short ATG14 isoform, ATG14S. Accordingly, SETD2 loss of function decreases autophagic flux, as well as the turnover of aggregation-prone proteins such as mutant HTT (huntingtin) leading to increased cellular toxicity. Hence, our findings bring evidence to the emerging concept that the production of autophagy-related protein isoforms can differentially affect core autophagy machinery bringing an additional level of complexity to the regulation of this biological process in more complex organisms.
ADCK1 is a potential therapeutic target of osteosarcoma
Authors: Zhuo Bao-biao , Zhu Lun-qing , Yao Chen , Wang Xi-hua , Li Shi-xian , Wang Rong , Li Yuan , Ling Zhuo-yan
Published: November 2022

We here showed that ADCK1 (AarF domain-containing kinase 1), a mitochondrial protein, is upregulated in human osteosarcoma (OS) tissues and OS cells. In primary and established OS cells, ADCK1 shRNA or CRISPR/Cas9-induced ADCK1 knockout (KO) remarkably inhibited cell viability, proliferation and migration, and provoked apoptosis activation. Conversely, ectopic ADCK1 overexpression exerted pro-cancerous activity by promoting OS cell proliferation and migration. ADCK1 depletion disrupted mitochondrial functions in OS cells and induced mitochondrial membrane potential reduction, ATP depletion, reactive oxygen species production. Significantly, ADCK1 silencing augmented doxorubicin-induced apoptosis in primary OS cells. mTOR activation is important for ADCK1 expression in OS cells. The mTOR inhibitors, rapamycin and AZD2014, as well as mTOR shRNA, potently decreased ADCK1 expression in primary OS cells. In nude mice, the growth of subcutaneous pOS-1 xenografts was largely inhibited when bearing ADCK1 shRNA or ADCK1 KO construct. Moreover, ADCK1 KO largely inhibited pOS-1 xenograft in situ growth in proximal tibia of nude mice. ADCK1 depletion, apoptosis activation and ATP reduction were detected in pOS-1 xenografts bearing ADCK1 shRNA or ADCK1 KO construct. Together, the mitochondrial protein ADCK1 is required for OS cell growth and is a novel therapeutic target of OS.
LINC00472 inhibits cell migration by enhancing intercellular adhesion and regulates H3K27ac level via interacting with P300 in renal clear cell carcinoma
Authors: Wang Songmao , Luo Cheng , Li Bing , Zhang Shikuan , Liao Weijie , Xin Qilei , Xu Naihan , Xie Weidong , Zhu Yuanchang , Zhang Yaou
Published: November 2022

Renal clear cell carcinoma (RCCC) is the most common type of renal cell carcinoma, which is also difficult to diagnose and easy to metastasize. Currently, there is still a lack of effective clinical diagnostic indicators and treatment targets. This study aims to find effective diagnostic markers and therapeutic targets from the perspective of noncoding RNA. In this study, we found that the expression of Long noncoding RNA LINC00472 was significantly decreased in RCCC and showed a downward trend with the progression of cancer stage. Patients with low LINC00472 expression have poor prognosis. Inhibition of LINC00472 significantly increased cell proliferation and migration, while overexpression of LINC00472 obviously inhibited cell proliferation and enhanced intercellular adhesion. Transcriptome sequencing analysis demonstrated that LINC00472 was highly correlated with extracellular matrix and cell metastasis-related pathways, and the consistent results were obtained by The Cancer Genome Atlas (TCGA) data analysis. Additionally, we discovered that the integrin family protein ITGB8 is a potential target gene of LINC00472. Mechanistically, we found that the change of LINC00472 affected the acetylation level of H3K27 site in cells, and we speculate that this effect is likely to be generated through the interaction with acetyltransferase P300. In conclusion, LINC00472 has an important impact on the proliferation and metastasis of renal clear cells, and probably participate in the regulation of histone modification, and it may be used as a potential diagnostic marker of RCCC.
CLIMB: High-dimensional association detection in large scale genomic data
Authors: Koch Hillary , Keller Cheryl A. , Xiang Guanjue , Giardine Belinda , Zhang Feipeng , Wang Yicheng , Hardison Ross C. , Li Qunhua
Published: November 2022

Joint analyses of genomic datasets obtained in multiple different conditions are essential for understanding the biological mechanism that drives tissue-specificity and cell differentiation, but they still remain computationally challenging. To address this we introduce CLIMB (Composite LIkelihood eMpirical Bayes), a statistical methodology that learns patterns of condition-specificity present in genomic data. CLIMB provides a generic framework facilitating a host of analyses, such as clustering genomic features sharing similar condition-specific patterns and identifying which of these features are involved in cell fate commitment. We apply CLIMB to three sets of hematopoietic data, which examine CTCF ChIP-seq measured in 17 different cell populations, RNA-seq measured across constituent cell populations in three committed lineages, and DNase-seq in 38 cell populations. Our results show that CLIMB improves upon existing alternatives in statistical precision, while capturing interpretable and biologically relevant clusters in the data.
Distinct immunological and molecular signatures underpinning influenza vaccine responsiveness in the elderly
Authors: Riese Peggy , Trittel Stephanie , Akmatov Manas K. , May Marcus , Prokein Jana , Illig Thomas , Schindler Christoph , Sawitzki Birgit , Elfaki Yassin , Floess Stefan , Huehn Jochen , Błażejewski Adrian J. , Strowig Till , Hernandez-Vargas Esteban A. , Geffers Robert , Zhang Bowen , Li Yang , Pessler Frank , Guzmán Carlos A.
Published: November 2022

Seasonal influenza outbreaks, especially in high-risk groups such as the elderly, represent an important public health problem. Prevailing inadequate efficacy of seasonal vaccines is a crucial bottleneck. Understanding the immunological and molecular mechanisms underpinning differential influenza vaccine responsiveness is essential to improve vaccination strategies. Here we show comprehensive characterization of the immune response of randomly selected elderly participants (≥ 65 years), immunized with the adjuvanted influenza vaccine Fluad. In-depth analyses by serology, multi-parametric flow cytometry, multiplex and transcriptome analysis, coupled to bioinformatics and mathematical modelling, reveal distinguishing immunological and molecular features between responders and non-responders defined by vaccine-induced seroconversion. Non-responders are specifically characterized by multiple suppressive immune mechanisms. The generated comprehensive high dimensional dataset enables the identification of putative mechanisms and nodes responsible for vaccine non-responsiveness independently of confounding age-related effects, with the potential to facilitate development of tailored vaccination strategies for the elderly.
Long-range GABAergic projections contribute to cortical feedback control of sensory processing
Authors: Mazo Camille , Nissant Antoine , Saha Soham , Peroni Enzo , Lledo Pierre-Marie , Lepousez Gabriel
Published: November 2022

In the olfactory system, the olfactory cortex sends glutamatergic projections back to the first stage of olfactory processing, the olfactory bulb (OB). Such corticofugal excitatory circuits — a canonical circuit motif described in all sensory systems— dynamically adjust early sensory processing. Here, we uncover a corticofugal inhibitory feedback to OB, originating from a subpopulation of GABAergic neurons in the anterior olfactory cortex and innervating both local and output OB neurons. In vivo imaging and network modeling showed that optogenetic activation of cortical GABAergic projections drives a net subtractive inhibition of both spontaneous and odor-evoked activity in local as well as output neurons. In output neurons, stimulation of cortical GABAergic feedback enhances separation of population odor responses in tufted cells, but not mitral cells. Targeted pharmacogenetic silencing of cortical GABAergic axon terminals impaired discrimination of similar odor mixtures. Thus, corticofugal GABAergic projections represent an additional circuit motif in cortical feedback control of sensory processing.
Site-selective photocatalytic functionalization of peptides and proteins at selenocysteine
Authors: Dowman Luke J. , Kulkarni Sameer S. , Alegre-Requena Juan V. , Giltrap Andrew M. , Norman Alexander R. , Sharma Ashish , Gallegos Liliana C. , Mackay Angus S. , Welegedara Adarshi P. , Watson Emma E. , van Raad Damian , Niederacher Gerhard , Huhmann Susanne , Proschogo Nicholas , Patel Karishma , Larance Mark , Becker Christian F. W. , Mackay Joel P. , Lakhwani Girish , Huber Thomas , Paton Robert S. , Payne Richard J.
Published: November 2022

The importance of modified peptides and proteins for applications in drug discovery, and for illuminating biological processes at the molecular level, is fueling a demand for efficient methods that facilitate the precise modification of these biomolecules. Herein, we describe the development of a photocatalytic method for the rapid and efficient dimerization and site-specific functionalization of peptide and protein diselenides. This methodology, dubbed the photocatalytic diselenide contraction, involves irradiation at 450 nm in the presence of an iridium photocatalyst and a phosphine and results in rapid and clean conversion of diselenides to reductively stable selenoethers. A mechanism for this photocatalytic transformation is proposed, which is supported by photoluminescence spectroscopy and density functional theory calculations. The utility of the photocatalytic diselenide contraction transformation is highlighted through the dimerization of selenopeptides, and by the generation of two families of protein conjugates via the site-selective modification of calmodulin containing the 21stamino acid selenocysteine, and the C-terminal modification of a ubiquitin diselenide.
DOPAnization of tyrosine in α-synuclein by tyrosine hydroxylase leads to the formation of oligomers
Authors: Jin Mingyue , Matsumoto Sakiko , Ayaki Takashi , Yamakado Hodaka , Taguchi Tomoyuki , Togawa Natsuko , Konno Ayumu , Hirai Hirokazu , Nakajima Hiroshi , Komai Shoji , Ishida Ryuichi , Chiba Syuhei , Takahashi Ryosuke , Takao Toshifumi , Hirotsune Shinji
Published: November 2022

Parkinson’s disease is a progressive neurodegenerative disorder characterized by the preferential loss of tyrosine hydroxylase (TH)-expressing dopaminergic neurons in the substantia nigra. Although the abnormal accumulation and aggregation of α-synuclein have been implicated in the pathogenesis of Parkinson’s disease, the underlying mechanisms remain largely elusive. Here, we found that TH converts Tyr136 in α-synuclein into dihydroxyphenylalanine (DOPA; Y136DOPA) through mass spectrometric analysis. Y136DOPA modification was clearly detected by a specific antibody in the dopaminergic neurons of α-synuclein-overexpressing mice as well as human α-synucleinopathies. Furthermore, dopanized α-synuclein tended to form oligomers rather than large fibril aggregates and significantly enhanced neurotoxicity. Our findings suggest that the dopanization of α-synuclein by TH may contribute to oligomer and/or seed formation causing neurodegeneration with the potential to shed light on the pathogenesis of Parkinson’s disease.
Ultra-fast triplet-triplet-annihilation-mediated high-lying reverse intersystem crossing triggered by participation of nπ*-featured excited states
Authors: Luo Yanju , Zhang Kai , Ding Zhenming , Chen Ping , Peng Xiaomei , Zhao Yihuan , Chen Kuan , Li Chuan , Zheng Xujun , Huang Yan , Pu Xuemei , Liu Yu , Su Shi-Jian , Hou Xiandeng , Lu Zhiyun
Published: November 2022

The harvesting of ‘hot’ triplet excitons through high-lying reverse intersystem crossing mechanism has emerged as a hot research issue in the field of organic light-emitting diodes. However, if high-lying reverse intersystem crossing materials lack the capability to convert ‘cold’ T1 excitons into singlet ones, the actual maximum exciton utilization efficiency would generally deviate from 100%. Herein, through comparative studies on two naphthalimide-based compounds CzNI and TPANI, we revealed that the ‘cold’ T1 excitons in high-lying reverse intersystem crossing materials can be utilized effectively through the triplet-triplet annihilation-mediated high-lying reverse intersystem crossing process if they possess certain triplet-triplet upconversion capability. Especially, quite effective triplet-triplet annihilation-mediated high-lying reverse intersystem crossing can be triggered by endowing the high-lying reverse intersystem crossing process with a 3ππ*→1nπ* character. By taking advantage of the permanent orthogonal orbital transition effect of 3ππ*→1nπ*, spin–orbit coupling matrix elements of ca. 10 cm−1 can be acquired, and hence ultra-fast mediated high-lying reverse intersystem crossing process with rate constant over 109 s−1 can be realized.
Identification of visual cortex cell types and species differences using single-cell RNA sequencing
Authors: Wei Jia-Ru , Hao Zhao-Zhe , Xu Chuan , Huang Mengyao , Tang Lei , Xu Nana , Liu Ruifeng , Shen Yuhui , Teichmann Sarah A. , Miao Zhichao , Liu Sheng
Published: November 2022

The primate neocortex exerts high cognitive ability and strong information processing capacity. Here, we establish a single-cell RNA sequencing dataset of 133,454 macaque visual cortical cells. It covers major cortical cell classes including 25 excitatory neuron types, 37 inhibitory neuron types and all glial cell types. We identified layer-specific markers includingHPCAL1andNXPH4, and also identified two cell types, anNPY-expressing excitatory neuron type that expresses the dopamine receptor D3 gene; and a primate specific activity-dependentOSTN + sensory neuron type. Comparisons of our dataset with humans and mice show that the gene expression profiles differ between species in relation to genes that are implicated in the synaptic plasticity and neuromodulation of excitatory neurons. The comparisons also revealed that glutamatergic neurons may be more diverse across species than GABAergic neurons and non-neuronal cells. These findings pave the way for understanding how the primary cortex fulfills the high-cognitive functions.
TLR3 forms a highly organized cluster when bound to a poly(I:C) RNA ligand
Authors: Lim Chan Seok , Jang Yoon Ha , Lee Ga Young , Han Gu Min , Jeong Hye Jin , Kim Ji Won , Lee Jie-Oh
Published: November 2022

Toll-like Receptor 3 (TLR3) initiates a potent anti-viral immune response by binding to double-stranded RNA ligands. Previous crystallographic studies showed that TLR3 forms a homodimer when bound to a 46-base pair RNA ligand. However, this short RNA fails to initiate a robust immune response. To obtain structural insights into the length dependency of TLR3 ligands, we determine the cryo-electron microscopy structure of full-length TLR3 in a complex with a synthetic RNA ligand with an average length of ~400 base pairs. In the structure, the dimeric TLR3 units are clustered along the double-stranded RNA helix in a highly organized and cooperative fashion with a uniform inter-dimer spacing of 103 angstroms. The intracellular and transmembrane domains are dispensable for the clustering because their deletion does not interfere with the cluster formation. Our structural observation suggests that ligand-induced clustering of TLR3 dimers triggers the ordered assembly of intracellular signaling adaptors and initiates a robust innate immune response.
A multivesicular body-like organelle mediates stimulus-regulated trafficking of olfactory ciliary transduction proteins
Authors: Maurya Devendra Kumar , Berghard Anna , Bohm Staffan
Published: November 2022

Stimulus transduction in cilia of olfactory sensory neurons is mediated by odorant receptors, Gαolf, adenylate cyclase-3, cyclic nucleotide-gated and chloride ion channels. Mechanisms regulating trafficking and localization of these proteins in the dendrite are unknown. By lectin/immunofluorescence staining and in vivo correlative light-electron microscopy (CLEM), we identify a retinitis pigmentosa-2 (RP2), ESCRT-0 and synaptophysin-containing multivesicular organelle that is not part of generic recycling/degradative/exosome pathways. The organelle’s intraluminal vesicles contain the olfactory transduction proteins except for Golf subunits Gγ13 and Gβ1. Instead, Gβ1 colocalizes with RP2 on the organelle’s outer membrane. The organelle accumulates in response to stimulus deprivation, while odor stimuli or adenylate cyclase activation cause outer membrane disintegration, release of intraluminal vesicles, and RP2/Gβ1 translocation to the base of olfactory cilia. Together, these findings reveal the existence of a dendritic organelle that mediates both stimulus-regulated storage of olfactory ciliary transduction proteins and membrane-delimited sorting important for G protein heterotrimerization.
Unimon qubit
Authors: Hyyppä Eric , Kundu Suman , Chan Chun Fai , Gunyhó András , Hotari Juho , Janzso David , Juliusson Kristinn , Kiuru Olavi , Kotilahti Janne , Landra Alessandro , Liu Wei , Marxer Fabian , Mäkinen Akseli , Orgiazzi Jean-Luc , Palma Mario , Savytskyi Mykhailo , Tosto Francesca , Tuorila Jani , Vadimov Vasilii , Li Tianyi , Ockeloen-Korppi Caspar , Heinsoo Johannes , Tan Kuan Yen , Hassel Juha , Möttönen Mikko
Published: November 2022

Superconducting qubits seem promising for useful quantum computers, but the currently wide-spread qubit designs and techniques do not yet provide high enough performance. Here, we introduce a superconducting-qubit type, the unimon, which combines the desired properties of increased anharmonicity, full insensitivity to dc charge noise, reduced sensitivity to flux noise, and a simple structure consisting only of a single Josephson junction in a resonator. In agreement with our quantum models, we measure the qubit frequency, ω01/(2π), and increased anharmonicity α/(2π) at the optimal operation point, yielding, for example, 99.9% and 99.8% fidelity for 13 ns single-qubit gates on two qubits with (ω01, α) = (4.49 GHz, 434 MHz) × 2π and (3.55 GHz, 744 MHz) × 2π, respectively. The energy relaxation seems to be dominated by dielectric losses. Thus, improvements of the design, materials, and gate time may promote the unimon to break the 99.99% fidelity target for efficient quantum error correction and possible useful quantum advantage with noisy systems.
Pinpointing the axial ligand effect on platinum single-atom-catalyst towards efficient alkaline hydrogen evolution reaction
Authors: Zhang Tianyu , Jin Jing , Chen Junmei , Fang Yingyan , Han Xu , Chen Jiayi , Li Yaping , Wang Yu , Liu Junfeng , Wang Lei
Published: November 2022

Developing active single-atom-catalyst (SAC) for alkaline hydrogen evolution reaction (HER) is a promising solution to lower the green hydrogen cost. However, the correlations are not clear between the chemical environments around the active-sites and their desired catalytic activity. Here we study a group of SACs prepared by anchoring platinum atoms on NiFe-layered-double-hydroxide. While maintaining the homogeneity of the Pt-SACs, various axial ligands (−F, −Cl, −Br, −I, −OH) are employedviaa facile irradiation-impregnation procedure, enabling us to discover definite chemical-environments/performance correlations. Owing to its high first-electron-affinity, chloride chelated Pt-SAC exhibits optimized bindings with hydrogen and hydroxide, which favor the sluggish water dissociation and further promote the alkaline HER. Specifically, it shows high mass-activity of 30.6 A mgPt−1and turnover frequency of 30.3  H2s−1at 100 mV overpotential, which are significantly higher than those of the state-of-the-art Pt-SACs and commercial Pt/C catalyst. Moreover, high energy efficiency of 80% is obtained for the alkaline water electrolyser assembled using the above catalyst under practical-relevant conditions.
The SOD1-mediated ALS phenotype shows a decoupling between age of symptom onset and disease duration
Authors: Opie-Martin Sarah , Iacoangeli Alfredo , Topp Simon D. , Abel Olubunmi , Mayl Keith , Mehta Puja R. , Shatunov Aleksey , Fogh Isabella , Bowles Harry , Limbachiya Naomi , Spargo Thomas P. , Al-Khleifat Ahmad , Williams Kelly L. , Jockel-Balsarotti Jennifer , Bali Taha , Self Wade , Henden Lyndal , Nicholson Garth A. , Ticozzi Nicola , McKenna-Yasek Diane , Tang Lu , Shaw Pamela J. , Chio Adriano , Ludolph Albert , Weishaupt Jochen H. , Landers John E. , Glass Jonathan D. , Mora Jesus S. , Robberecht Wim , Damme Philip Van , McLaughlin Russell , Hardiman Orla , van den Berg Leonard , Veldink Jan H. , Corcia Phillippe , Stevic Zorica , Siddique Nailah , Silani Vincenzo , Blair Ian P. , Fan Dong-sheng , Esselin Florence , de la Cruz Elisa , Camu William , Basak Nazli A. , Siddique Teepu , Miller Timothy , Brown Robert H. , Al-Chalabi Ammar , Shaw Christopher E.
Published: November 2022

Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1-ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring using Cox proportional-hazards regression. The SOD1-ALS dataset reports age of onset for 1122 and disease duration for 883 people; the comparator population includes 10,214 and 9010 people respectively. Eight variants are associated with younger age of onset and distinct survival trajectories; a further eight associated with younger onset only and one with distinct survival only. Here we show that onset and survival are decoupled in SOD1-ALS. Future research should characterise rarer variants and molecular mechanisms causing the observed variability.
Stress-driven potentiation of lateral hypothalamic synapses onto ventral tegmental area dopamine neurons causes increased consumption of palatable food
Authors: Linders Louisa E. , Patrikiou Lefkothea , Soiza-Reilly Mariano , Schut Evelien H. S. , van Schaffelaar Bram F. , Böger Leonard , Wolterink-Donselaar Inge G. , Luijendijk Mieneke C. M. , Adan Roger A. H. , Meye Frank J.
Published: November 2022

Stress can cause overconsumption of palatable high caloric food. Despite the important role of stress eating in obesity and (binge) eating disorders, its underlying neural mechanisms remain unclear. Here we demonstrate in mice that stress alters lateral hypothalamic area (LHA) control over the ventral tegmental area (VTA), thereby promoting overconsumption of palatable food. Specifically, we show that glutamatergic LHA neurons projecting to the VTA are activated by social stress, after which their synapses onto dopamine neurons are potentiated via AMPA receptor subunit alterations. We find that stress-driven strengthening of these specific synapses increases LHA control over dopamine output in key target areas like the prefrontal cortex. Finally, we demonstrate that while inducing LHA-VTA glutamatergic potentiation increases palatable fat intake, reducing stress-driven potentiation of this connection prevents such stress eating. Overall, this study provides insights in the neural circuit adaptations caused by stress that drive overconsumption of palatable food.
IL-33 induces thymic involution-associated naive T cell aging and impairs host control of severe infection
Authors: Xu Lei , Wei Chuan , Chen Ying , Wu Yue , Shou Xiaoli , Chen Wenjie , Lu Di , Sun Haoran , Li Wei , Yu Beibei , Wang Xiaowei , Zhang Xiaojun , Yu Yanxiong , Lei Zhigang , Tang Rui , Zhu Jifeng , Li Yalin , Lu Linrong , Zhou Hong , Zhou Sha , Su Chuan , Chen Xiaojun
Published: November 2022

Severe infection commonly results in immunosuppression, which leads to impaired pathogen clearance or increased secondary infection in both humans and animals. However, the exact mechanisms remain poorly understood. Here, we demonstrate that IL-33 results in immunosuppression by inducing thymic involution-associated naive T cell dysfunction with aberrant expression of aging-associated genes and impairs host control of infection in mouse disease models of schistosomiasis or sepsis. Furthermore, we illustrate that IL-33 triggers the excessive generation of medullary thymic epithelial cell (mTEC) IV (thymic tuft cells) in a Pou2f3-dependent manner, as a consequence, disturbs mTEC/cortical TEC (cTEC) compartment and causes thymic involution during severe infection. More importantly, IL-33 deficiency, the anti-IL-33 neutralizing antibody treatment, or IL-33 receptor ST2 deficient thymus transplantation rescues T cell immunity to better control infection in mice. Our findings not only uncover a link between severe infection-induced IL-33 and thymic involution-mediated naive T cell aging, but also suggest that targeting IL-33 or ST2 is a promising strategy to rejuvenate T cell immunity to better control severe infection.
Ozone impact from solar energetic particles cools the polar stratosphere
Authors: Szela̧g Monika E. , Marsh Daniel R. , Verronen Pekka T. , Seppälä Annika , Kalakoski Niilo
Published: November 2022

Understanding atmospheric impacts of solar energetic particle precipitation (EPP) remains challenging, from quantification of the response in ozone, to implications on temperature. Both are necessary to understand links between EPP and regional climate variability. Here we use a chemistry-climate model to assess the importance of EPP on late winter/spring polar stratosphere. In transient simulations, the impact on NOy, ozone, and temperature is underestimated when using EPP forcing from the current recommendation of the Coupled Model Intercomparison Project (CMIP6). The resulting temperature response is largely masked by overall dynamical variability. An idealised experiment with EPP forcing that reproduces observed levels of NOyresults in a significant reduction of ozone (up to 25%), cooling the stratosphere (up to 3 K) during late winter/spring. Our results unravel the inconsistency regarding the temperature response to EPP-driven springtime ozone decrease, and highlight the need for an improved EPP forcing in climate simulations.
Enterotoxigenic Escherichia coli heat-labile toxin drives enteropathic changes in small intestinal epithelia
Authors: Sheikh Alaullah , Tumala Brunda , Vickers Tim J. , Martin John C. , Rosa Bruce A. , Sabui Subrata , Basu Supratim , Simoes Rita D. , Mitreva Makedonka , Storer Chad , Tyksen Erik , Head Richard D. , Beatty Wandy , Said Hamid M. , Fleckenstein James M.
Published: November 2022

EnterotoxigenicE. coli(ETEC) produce heat-labile (LT) and/or heat-stable (ST) enterotoxins, and commonly cause diarrhea in resource-poor regions. ETEC have been linked repeatedly to sequelae in children including enteropathy, malnutrition, and growth impairment. Although cellular actions of ETEC enterotoxins leading to diarrhea are well-established, their contributions to sequelae remain unclear. LT increases cellular cAMP to activate protein kinase A (PKA) that phosphorylates ion channels driving intestinal export of salt and water resulting in diarrhea. As PKA also modulates transcription of many genes, we interrogated transcriptional profiles of LT-treated intestinal epithelia. Here we show that LT significantly alters intestinal epithelial gene expression directing biogenesis of the brush border, the major site for nutrient absorption, suppresses transcription factors HNF4 and SMAD4 critical to enterocyte differentiation, and profoundly disrupts microvillus architecture and essential nutrient transport. In addition, ETEC-challenged neonatal mice exhibit substantial brush border derangement that is prevented by maternal vaccination with LT. Finally, mice repeatedly challenged with toxigenic ETEC exhibit impaired growth recapitulating the multiplicative impact of recurring ETEC infections in children. These findings highlight impacts of ETEC enterotoxins beyond acute diarrheal illness and may inform approaches to prevent major sequelae of these common infections including malnutrition that impact millions of children.
Generative deep learning enables the discovery of a potent and selective RIPK1 inhibitor
Authors: Li Yueshan , Zhang Liting , Wang Yifei , Zou Jun , Yang Ruicheng , Luo Xinling , Wu Chengyong , Yang Wei , Tian Chenyu , Xu Haixing , Wang Falu , Yang Xin , Li Linli , Yang Shengyong
Published: November 2022

The retrieval of hit/lead compounds with novel scaffolds during early drug development is an important but challenging task. Various generative models have been proposed to create drug-like molecules. However, the capacity of these generative models to design wet-lab-validated and target-specific molecules with novel scaffolds has hardly been verified. We herein propose a generative deep learning (GDL) model, a distribution-learning conditional recurrent neural network (cRNN), to generate tailor-made virtual compound libraries for given biological targets. The GDL model is then applied to RIPK1. Virtual screening against the generated tailor-made compound library and subsequent bioactivity evaluation lead to the discovery of a potent and selective RIPK1 inhibitor with a previously unreported scaffold, RI-962. This compound displays potent in vitro activity in protecting cells from necroptosis, and good in vivo efficacy in two inflammatory models. Collectively, the findings prove the capacity of our GDL model in generating hit/lead compounds with unreported scaffolds, highlighting a great potential of deep learning in drug discovery.
Prognostic and predictive value of a pathomics signature in gastric cancer
Authors: Chen Dexin , Fu Meiting , Chi Liangjie , Lin Liyan , Cheng Jiaxin , Xue Weisong , Long Chenyan , Jiang Wei , Dong Xiaoyu , Sui Jian , Lin Dajia , Lu Jianping , Zhuo Shuangmu , Liu Side , Li Guoxin , Chen Gang , Yan Jun
Published: November 2022

The current tumour-node-metastasis (TNM) staging system alone cannot provide adequate information for prognosis and adjuvant chemotherapy benefits in patients with gastric cancer (GC). Pathomics, which is based on the development of digital pathology, is an emerging field that might improve clinical management. Herein, we propose a pathomics signature (PSGC) that is derived from multiple pathomics features of haematoxylin and eosin-stained slides. We find that the PSGC is an independent predictor of prognosis. A nomogram incorporating the PSGC and TNM staging system shows significantly improved accuracy in predicting the prognosis compared to the TNM staging system alone. Moreover, in stage II and III GC patients with a low PSGC (but not in those with a high PSGC), satisfactory chemotherapy benefits are observed. Therefore, the PSGC could serve as a prognostic predictor in patients with GC and might be a potential predictive indicator for decision-making regarding adjuvant chemotherapy.
REM sleep is associated with distinct global cortical dynamics and controlled by occipital cortex
Authors: Wang Ziyue , Fei Xiang , Liu Xiaotong , Wang Yanjie , Hu Yue , Peng Wanling , Wang Ying-wei , Zhang Siyu , Xu Min
Published: November 2022

The cerebral cortex is spontaneously active during sleep, yet it is unclear how this global cortical activity is spatiotemporally organized, and whether such activity not only reflects sleep states but also contributes to sleep state switching. Here we report that cortex-wide calcium imaging in mice revealed distinct sleep stage-dependent spatiotemporal patterns of global cortical activity, and modulation of such patterns could regulate sleep state switching. In particular, elevated activation in the occipital cortical regions (including the retrosplenial cortex and visual areas) became dominant during rapid-eye-movement (REM) sleep. Furthermore, such pontogeniculooccipital (PGO) wave-like activity was associated with transitions to REM sleep, and optogenetic inhibition of occipital activity strongly promoted deep sleep by suppressing the NREM-to-REM transition. Thus, whereas subcortical networks are critical for initiating and maintaining sleep and wakefulness states, distinct global cortical activity also plays an active role in controlling sleep states.
Dust emission reduction enhanced gas-to-particle conversion of ammonia in the North China Plain
Authors: Liu Yongchun , Zhan Junlei , Zheng Feixue , Song Boying , Zhang Yusheng , Ma Wei , Hua Chenjie , Xie Jiali , Bao Xiaolei , Yan Chao , Bianchi Federico , Petäjä Tuukka , Ding Aijun , Song Yu , He Hong , Kulmala Markku
Published: November 2022

Ammonium salt is an important component of particulate matter with aerodynamic diameter less than 2.5 µm (PM2.5) and has significant impacts on air quality, climate, and natural ecosystems. However, a fundamental understanding of the conversion kinetics from ammonia to ammonium in unique environments of high aerosol loading is lacking. Here, we report the uptake coefficient of ammonia (γNH3) on ambient PM2.5 varying from 2.2 × 10−4 to 6.0 × 10−4 in the North China Plain. It is significantly lower than those on the model particles under simple conditions reported in the literature. The probability-weighted γNH3 increases obviously, which is well explained by the annual decrease in aerosol pH due to the significant decline in alkali and alkali earth metal contents from the emission source of dust. Our results elaborate on the complex interactions between primary emissions and the secondary formation of aerosols and the important role of dust in atmospheric chemistry.
Hypothermia evoked by stimulation of medial preoptic nucleus protects the brain in a mouse model of ischaemia
Authors: Zhang Shuai , Zhang Xinpei , Zhong Haolin , Li Xuanyi , Wu Yujie , Ju Jun , Liu Bo , Zhang Zhenyu , Yan Hai , Wang Yizheng , Song Kun , Hou Sheng-Tao
Published: November 2022

Therapeutic hypothermia at 32-34 °C during or after cerebral ischaemia is neuroprotective. However, peripheral cold sensor-triggered hypothermia is ineffective and evokes vigorous counteractive shivering thermogenesis and complications that are difficult to tolerate in awake patients. Here, we show in mice that deep brain stimulation (DBS) of warm-sensitive neurones (WSNs) in the medial preoptic nucleus (MPN) produces tolerable hypothermia. In contrast to surface cooling-evoked hypothermia, DBS mice exhibit a torpor-like state without counteractive shivering. Like hypothermia evoked by chemogenetic activation of WSNs, DBS in free-moving mice elicits a rapid lowering of the core body temperature to 32-34 °C, which confers significant brain protection and motor function reservation. Mechanistically, activation of WSNs contributes to DBS-evoked hypothermia. Inhibition of WSNs prevents DBS-evoked hypothermia. Maintaining the core body temperature at normothermia during DBS abolishes DBS-mediated brain protection. Thus, the MPN is a DBS target to evoke tolerable therapeutic hypothermia for stroke treatment.
Structural basis for mechanotransduction in a potassium-dependent mechanosensitive ion channel
Authors: Mount Jonathan , Maksaev Grigory , Summers Brock T. , Fitzpatrick James A. J. , Yuan Peng
Published: November 2022

Mechanosensitive channels of small conductance, found in many living organisms, open under elevated membrane tension and thus play crucial roles in biological response to mechanical stress. Amongst these channels, MscK is unique in that its activation also requires external potassium ions. To better understand this dual gating mechanism by force and ligand, we elucidate distinct structures of MscK along the gating cycle using cryo-electron microscopy. The heptameric channel comprises three layers: a cytoplasmic domain, a periplasmic gating ring, and a markedly curved transmembrane domain that flattens and expands upon channel opening, which is accompanied by dilation of the periplasmic ring. Furthermore, our results support a potentially unifying mechanotransduction mechanism in ion channels depicted as flattening and expansion of the transmembrane domain.
Simultaneous enhancement in electrical conductivity and Seebeck coefficient by single- to double-valley transition in a Dirac-like band
Authors: Dai Yu , Zhou Wenjiang , Kim Hyun-Jung , Song Qichen , Qian Xin , Liu Te-Huan , Yang Ronggui
Published: November 2022

SnTe possesses a single- to double-valley transition in the conduction band minimum when a compressive strain is applied. Through a tight-binding analysis, it is shown that the variation of the band structure is attributed to the strain-induced delocalization of both the Sn-5s orbitals and Te-5p orbitals with different angular momenta. This effect can largely increase the electron density of states near the band edge and thus keep the Fermi level of the compressed SnTe closer to it, where the electrons have lower scattering rates. The strain-induced double valleys lead to simultaneous increases in the electrical conductivity and the Seebeck coefficient and thereby nearly four times the enhancement of the power factor at the doping concentration of 5×1019 cm–3. This work suggests a feasible concept that can be employed to promote the power factor of a Dirac semiconductor via manipulating the valley degeneracy in the conduction band minimum.
APOE E4 is associated with impaired self-declared cognition but not disease risk or age of onset in Nigerians with Parkinson’s disease
Authors: Okubadejo Njideka U. , Okunoye Olaitan , Ojo Oluwadamilola O. , Arabambi Babawale , Akinyemi Rufus O. , Osaigbovo Godwin O. , Abubakar Sani A. , Iwuozo Emmanuel U. , Wahab Kolawole W. , Agabi Osigwe P. , Agulanna Uchechi , Imarhiagbe Frank A. , Abiodun Oladunni V. , Achoru Charles O. , Adebowale Akintunde A. , Adeniji Olaleye , Akpekpe John E. , Ali Mohammed W. , Ani-Osheku Ifeyinwa , Arigbodi Ohwotemu , Balarabe Salisu A. , Bello Abiodun H. , Ekenze Oluchi S. , Erameh Cyril O. , Farombi Temitope H. , Fawale Michael B. , Komolafe Morenikeji A. , Nwani Paul O. , Nwazor Ernest O. , Nyandaiti Yakub , Obehighe Emmanuel E. , Obiabo Yahaya O. , Odeniyi Olanike A. , Odiase Francis E. , Ojini Francis I. , Onwuegbuzie Gerald A. , Osemwegie Nosakhare , Oshinaike Olajumoke O. , Otubogun Folajimi M. , Oyakhire Shyngle I. , Taiwo Funlola T. , Williams Uduak E. , Ozomma Simon , Zubair Yusuf , Hernandez Dena , Bandres-Ciga Sara , Blauwendraat Cornelis , Singleton Andrew , Houlden Henry , Hardy John , Rizig Mie
Published: November 2022

The relationship between APOE polymorphisms and Parkinson’s disease (PD) in black Africans has not been previously investigated. We evaluated the association between APOE polymorphic variability and self-declared cognition in 1100 Nigerians with PD and 1097 age-matched healthy controls. Cognition in PD was assessed using the single item cognition question (item 1.1) of the MDS-UPDRS. APOE genotype and allele frequencies did not differ between PD and controls (p > 0.05). No allelic or genotypic association was observed between APOE and age at onset of PD. In PD, APOE ε4/ε4 conferred a two-fold risk of cognitive impairment compared to one or no ε4 (HR: 2.09 (95% CI: 1.13–3.89; p = 0.02)), while APOE ε2 was associated with modest protection against cognitive impairment (HR: 0.41 (95% CI 0.19–0.99, p = 0.02)). Of 773 PD with motor phenotype and APOE characterized, tremor-dominant (TD) phenotype predominated significantly in ε2 carriers (87/135, 64.4%) compared to 22.2% in persons with postural instability/gait difficulty (PIGD) (30/135) and 13.3% in indeterminate (ID) (18/135, 13.3%) (p = 0.037). Although the frequency of the TD phenotype was highest in homozygous ε2 carriers (85.7%), the distribution of motor phenotypes across the six genotypes did not differ significantly (p = 0.18). Altogether, our findings support previous studies in other ethnicities, implying a role for APOE ε4 and ε2 as risk and protective factors, respectively, for cognitive impairment in PD.
Transcriptomic analysis reveals an association of FCGBP with Parkinson’s disease
Authors: Gómez-Garre Pilar , Periñán María Teresa , Jesús Silvia , Bacalini Maria Giulia , Garagnani Paolo , Mollenhauer Brit , Pirazzini Chiara , Provini Federica , Trenkwalder Claudia , Franceschi Claudio , Mir Pablo ,   on behalf of the PROPAG-AGEING consortium
Published: November 2022

Transcriptomics in Parkinson’s disease (PD) offers new insights into the molecular mechanism of PD pathogenesis. Several pathways, such as inflammation and protein degradation, have been identified by differential gene expression analysis. Our aim was to identify gene expression differences underlying the disease etiology and the discovery of pre-symptomatic risk biomarkers for PD from a multicenter study in the context of the PROPAG-AGEING project. We performed RNA sequencing from 47 patients with de novo PD, 10 centenarians, and 65 healthy controls. Using identified differentially expressed genes, functional annotations were assigned using gene ontology to unveil significant enriched biological processes. The expression of 16 selected genes was validated using OpenArray® assays and samples from independent cohorts of 201 patients with advanced PD, 340 healthy siblings of PD patients, and 177 healthy controls. Differential gene expression analysis identified higher FCGBP expression in patients with de novo PD compared with healthy controls and compared with centenarians. Furthermore, FCGBP showed no differences in terms of population origin or aging process. The increased FCGBP expression was validated in patients with advanced PD and their siblings. Thus, we provided evidence for an upregulation of FCGBP mRNA levels not only in patients with PD but also in individuals at putative higher risk of PD, suggesting that it could be important in gut–brain PD interaction, mediating the connection between microbiota and intestinal inflammatory processes, as well as neuroinflammation and neurodegeneration.