bluuebunny/crossref_metadata_2025 huggingface dataset:
Quantifying the Impact of Land Use and Land Cover Change on Moisture Recycling With Convection‐Permitting WRF‐Tagging Modeling in the Agro‐Pastoral Ecotone of Northern China
Authors: Wang Xuejin , Zhang Zhenyu , Zhang Baoqing , Tian Lei , Tian Jie , Arnault Joël , Kunstmann Harald , He Chansheng
Published: April 2023

Land use and land cover change (LUCC) can influence the regional atmospheric water budget. In this study, the Weather Research and Forecasting model embedded with evapotranspiration (ET)‐tagging (WRF‐tagging) is used to investigate the atmospheric pathways of ET as well as where and to what extent ET returns as precipitation (P) in the agro‐pastoral ecotone of northern China (APENC). First, we updated the default land use and vegetation indices in the WRF‐tagging with high‐resolution and real‐time datasets. WRF‐tagging modeling reproduces the spatial distribution of P and ET reasonably after updating surface characteristics. Second, we analyzed and quantified the contribution of ET to atmospheric moisture and regional P in the APENC. The water vapor originating as ET is advected in the atmosphere below 600 hPa to hundreds of kilometers by the prevailing winds. Moisture recycling shows that 5.83% of P comes from local ET during the growing season in the core region of the APENC. Furthermore, to quantify the impact of LUCC on moisture recycling, we designed two different vegetation scenarios (Afforestation and Degradation) by changing land use and vegetation indices in the model. Results show that the precipitation recycling ratio increased to 6.31% in the Afforestation scenario, and decreased to 5.19% in the Degradation scenario, demonstrating the non‐neglectable positive feedback of vegetation on P. An analysis of land surface‐precipitation feedback processes indicates that the LUCC‐induced change in precipitation efficiency dominates P changes. Our findings highlight the importance of LUCC on local and regional moisture recycling in the APENC.
The Impact of a Land‐Sea Contrast on Convective Aggregation in Radiative‐Convective Equilibrium
Authors: Dingley Beth , Dagan Guy , Stier Philip , Herbert Ross
Published: April 2023

Convective aggregation is an important atmospheric phenomenon which frequently occurs in idealized models in radiative‐convective equilibrium (RCE), where the effects of land, rotation, sea surface temperature gradients, and the diurnal cycle are often removed. This aggregation is often triggered and maintained by self‐generated radiatively driven circulations, for which longwave feedbacks are essential. Many questions remain over how important the driving processes of aggregation in idealized models are in the real atmosphere. We approach this question by adding a continentally sized, idealized tropical rainforest island into an RCE model to investigate how land‐sea contrasts impact convective aggregation and its mechanisms. We show that convection preferentially forms over the island persistently in our simulation. This is forced by a large‐scale, thermally driven circulation. First, a sea‐breeze circulation is triggered by the land‐sea thermal contrast, driven by surface sensible heating. This sea‐breeze circulation triggers convection which then generates longwave heating anomalies. Through mechanism denial tests we find that removing the longwave feedbacks reduces the large‐scale effects of aggregation but does not prevent aggregation from occurring, and thus we highlight there must be another process aiding the aggregation of convection. We also show, by varying the island size, that the aggregated convective cluster appears to have a maximum spatial extent of (10,000 km). These results highlight that the mechanisms of idealized aggregation remain relevant when land is included in the model, and therefore these mechanisms could help us understand convective organization in the real world.
Enhanced Monsoon‐Driven Upwelling in Southeast Asia During the Little Ice Age
Authors: Chen Mengli , Martin Patrick , Ren Haojia , Zhang Run , Samanta Dhrubajyoti , Chen Yi‐Chi , Hughen Konrad A. , Phan Kim Hoang , Vo Si Tuan , Goodkin Nathalie F.
Published: April 2023

Climate change impacts ocean nutrient availability and will likely alter the marine food web. While climate models predict decreased average ocean productivity, the extent of these changes, especially in the marginal seas upon which large human populations depend, is not well understood. Here, we reconstructed changes in seawater phosphate concentration and nitrate source over the past 400 years, which reveals a more than 50% decline in residence time of seawater phosphate, and 8%–48% decline in subsurface nitrogen supply following the coldest period of Little Ice Age. Our data indicates a link between surface ocean nutrient supply and the East Asian Summer Monsoon strength in an economically important marginal sea. As climate models predict that the East Asian Summer monsoon will strengthen in the future, our study implies that surface ocean primary productivity may increase in the South China Sea, contrary to the predicted decrease in global average ocean productivity.
Science Communication That Goes Beyond Words
Authors: Reber Jacqueline , Moss Kimberly
Published: April 2023

Earth science graduate students and scientific illustration undergraduates teamed up to create accessible, engaging visualizations of research that transcend limitations of using language alone.
Structure of Post‐Midnight Enhancements in Electron Density at the Low Latitude F‐Layer Ionosphere
Authors: Liu Libo , Yang Yuyan , Zhang Ruilong , Tariq M. Arslan , Le Huijun , Chen Yiding , Zhang Hui , Li Guozhu , Yue Xinan
Published: April 2023

It has previously found that at Sanya (109.6°E, 18.3°N) a post‐midnight enhancement in the F2‐layer peak electron density (NmF2) is often accompanied by the increase in the bottom side F layer electron density (Ne) and a reduction in the top side F layer Ne. We conduct a case study to explore the complete spatial coverage of the post‐midnight enhancements of electron density in the low latitude ionosphere. The total electron content (TEC) data are retrieved from the Beidou Geostationary Earth Orbit (GEO) satellite signals recorded by a network of Global Navigation Satellite System (GNSS) receivers in Asia‐Australia. The F2‐layer peak parameters and the altitudinal profiles of Ne are measured by the ionosonde, and incoherent scatter radar at Sanya (109.6°E, 18.3°N). The GEO‐TEC does not always completely follow the enhancement of NmF2. The enhancements may peak roughly simultaneously or with significant time shifts in the west‐east direction, even in the GEO‐TEC series recorded by a GNSS receiver in an event, which indicates possibly the enhancement of different longitudinal scales. Further, in the cases the enhancement is clustered in a limited area. The low latitude enhancements show a hemispheric asymmetry; they occur mainly in the northern hemisphere and usually have no correspondingly magnetic conjugate symmetrical features in the southern hemisphere. The hemispheric asymmetry of the enhancements highlights that both the field‐aligned plasma transport and electric fields are possibly responsible for regulating the limited spatial presence of post‐midnight enhancements in the low latitude ionosphere.
Genomic insights into the coupling of aChlorella-like microeukaryote and sulfur bacteria in the chemocline of permanently stratified Lake Cadagno
Authors: Saini Jaspreet S , Manni Mosè , Hassler Christel , Cable Rachel N , Duhaime Melissa B , Zdobnov Evgeny M
Published: April 2023

Meromictic Lake Cadagno is a permanently stratified system with a persistent microbial bloom within the oxic-anoxic boundary called the chemocline. The association between oxygenic and anoxygenic photosynthesis within the chemocline has been known for at least two decades. Although anoxygenic purple and green sulfur bacteria have been well studied, reports on oxygenic phytoplankton have remained sparse since their discovery in the 1920s. Nearly a century later, this study presents the first near-complete genome of a photosynthetic microbial eukaryote from the chemocline of Lake Cadagno, provisionally named Chlorella-like MAG. The 18.9 Mbp nuclear genome displays a high GC content (71.5%), and the phylogenetic placement suggests that it is a novel species of the genus Chlorella of Chlorophytes. Functional annotation of the Chlorella-like metagenome-assembled genome predicted 10,732 protein-coding genes, with an approximate 0.6% proportion potentially involved in carbon, sulfur, and nitrogen (C, N, and S) metabolism. In addition to C4 photosynthesis, this study detected genes for heat shock proteins (HSPs) in the Chlorella-like algae, consistent with the other Chlorella species. Altogether, the genomic insights in this study suggest the cooperation of photosynthetic algae with phototrophic sulfur bacteria via C, N, and S metabolism, which may aid their collective persistence in the Lake Cadagno chemocline. Furthermore, this work additionally presents the chloroplast genome of Cryptomonas-like species, which was likely to be presumed as cyanobacteria in previous studies because of the presence of phycobilisomes.
Mesophilic and thermophilic viruses are associated with nutrient cycling during hyperthermophilic composting
Authors: Liao Hanpeng , Liu Chen , Ai Chaofan , Gao Tian , Yang Qiu-E , Yu Zhen , Gao Shaoming , Zhou Shungui , Friman Ville-Petri
Published: April 2023

While decomposition of organic matter by bacteria plays a major role in nutrient cycling in terrestrial ecosystems, the significance of viruses remains poorly understood. Here we combined metagenomics and metatranscriptomics with temporal sampling to study the significance of mesophilic and thermophilic bacteria and their viruses on nutrient cycling during industrial-scale hyperthermophilic composting (HTC). Our results show that virus-bacteria density dynamics and activity are tightly coupled, where viruses specific to mesophilic and thermophilic bacteria track their host densities, triggering microbial community succession via top-down control during HTC. Moreover, viruses specific to mesophilic bacteria encoded and expressed several auxiliary metabolic genes (AMGs) linked to carbon cycling, impacting nutrient turnover alongside bacteria. Nutrient turnover correlated positively with virus–host ratio, indicative of a positive relationship between ecosystem functioning, viral abundances, and viral activity. These effects were predominantly driven by DNA viruses as most detected RNA viruses were associated with eukaryotes and not associated with nutrient cycling during the thermophilic phase of composting. Our findings suggest that DNA viruses could drive nutrient cycling during HTC by recycling bacterial biomass through cell lysis and by expressing key AMGs. Viruses could hence potentially be used as indicators of microbial ecosystem functioning to optimize productivity of biotechnological and agricultural systems.
Heroin and its metabolites: relevance to heroin use disorder
Authors: Milella Michele Stanislaw , D’Ottavio Ginevra , De Pirro Silvana , Barra Massimo , Caprioli Daniele , Badiani Aldo
Published: April 2023

Heroin is an opioid agonist commonly abused for its rewarding effects. Since its synthesis at the end of the nineteenth century, its popularity as a recreational drug has ebbed and flowed. In the last three decades, heroin use has increased again, and yet the pharmacology of heroin is still poorly understood. After entering the body, heroin is rapidly deacetylated to 6-monoacetylmorphine (6-MAM), which is then deacetylated to morphine. Thus, drug addiction literature has long settled on the notion that heroin is little more than a pro-drug. In contrast to these former views, we will argue for a more complex interplay among heroin and its active metabolites: 6-MAM, morphine, and morphine-6-glucuronide (M6G). In particular, we propose that the complex temporal pattern of heroin effects results from the sequential, only partially overlapping, actions not only of 6-MAM, morphine, and M6G, but also of heroin per se, which, therefore, should not be seen as a mere brain-delivery system for its active metabolites. We will first review the literature concerning the pharmacokinetics and pharmacodynamics of heroin and its metabolites, then examine their neural and behavioral effects, and finally discuss the possible implications of these data for a better understanding of opioid reward and heroin addiction. By so doing we hope to highlight research topics to be investigated by future clinical and pre-clinical studies.
Orbitofrontal cortex microRNAs support long-lasting heroin seeking behavior in male rats
Authors: Zanda Mary Tresa , Floris Gabriele , Daws Stephanie E.
Published: April 2023

Recovery from opioid use disorder (OUD) and maintenance of abstinence from opioid use is hampered by perseverant drug cravings that may persist for months after cessation of drug use. Drug cravings can intensify during the abstinence period, a phenomenon referred to as the ‘incubation of craving’ that has been well-described in preclinical studies. We previously reported that animals that self-administered heroin at a dosage of 0.075 mg/kg/infusion (HH) paired with discrete drug cues displayed robust incubation of heroin craving behavior after 21 days (D) of forced abstinence, an effect that was not observed with a lower dosage (0.03 mg/kg/infusion; HL). Here, we sought to elucidate molecular mechanisms underlying long-term heroin seeking behavior by profiling microRNA (miRNA) pathways in the orbitofrontal cortex (OFC), a brain region that modulates incubation of heroin seeking. miRNAs are small noncoding RNAs with long half-lives that have emerged as critical regulators of drug seeking behavior but their expression in the OFC has not been examined in any drug exposure paradigm. We employed next generation sequencing to detect OFC miRNAs differentially expressed after 21D of forced abstinence between HH and HL animals, and proteomics analysis to elucidate miRNA-dependent translational neuroadaptations. We identified 55 OFC miRNAs associated with incubation of heroin craving, including miR-485-5p, which was significantly downregulated following 21D forced abstinence in HH but not HL animals. We bidirectionally manipulated miR-485-5p in the OFC to demonstrate that miR-485-5p can regulate long-lasting heroin seeking behavior after extended forced abstinence. Proteomics analysis identified 45 proteins selectively regulated in the OFC of HH but not HL animals that underwent 21D forced abstinence, of which 7 were putative miR-485-5p target genes. Thus, the miR-485-5p pathway is dysregulated in animals with a phenotype of persistent heroin craving behavior and OFC miR-485-5p pathways may function to support long-lasting heroin seeking.
Immunological and prognostic significance of tumour necrosis in colorectal cancer
Authors: Kastinen Meeri , Sirniö Päivi , Elomaa Hanna , Ahtiainen Maarit , Väyrynen Sara A. , Herzig Karl-Heinz , Meriläinen Sanna , Aro Raila , Häivälä Reetta , Rautio Tero , Saarnio Juha , Wirta Erkki-Ville , Helminen Olli , Seppälä Toni T. , Kuopio Teijo , Böhm Jan , Tuomisto Anne , Mecklin Jukka-Pekka , Mäkinen Markus J. , Väyrynen Juha P.
Published: April 2023

Background

Colorectal cancer (CRC) causes the second most cancer deaths worldwide, but the disease course varies according to tumour characteristics and immunological factors. Our objective was to examine the associations of tumour necrosis with tumour characteristics, immune cell infiltrates, serum cytokine concentrations, as well as prognosis in CRC.

Methods

Three independent CRC cohorts, including 1413 patients, were analysed. Associations of the areal percentage of tumour necrosis with clinicopathologic parameters, tumour infiltrating immune cells, cytokine concentrations in systemic and mesenteric vein blood, and survival were examined.

Results

Higher tumour necrosis percentage associated with shorter colorectal cancer-specific survival independent of tumour grade, T, N or M-class, mismatch repair status, BRAF status, and other possible confounding factors. In the largest cohort (N = 1100), the HR for high tumour necrosis percentage (≥40% vs. <3%) was 3.22 (95% CI 1.68–6.17, Ptrend < 0.0001). Tumour necrosis percentage positively correlated with peripheral serum levels of CXCL8, a proinflammatory chemokine, and negatively correlated with mesenteric serum levels of CXCL10 and mast cell densities in the invasive margin of the tumour.

Conclusions

Our results support the value of tumour necrosis as a prognostic factor in colorectal cancer. CXCL8 may have a role in the systemic effects of tumour necrosis.
BCL-G: 20 years of research on a non-typical protein from the BCL-2 family
Authors: Hartman Mariusz L. , Czyz Malgorzata
Published: April 2023

Proteins from the BCL-2 family control cell survival and apoptosis in health and disease, and regulate apoptosis-unrelated cellular processes. BCL-Gonad (BCL-G, also known as BCL2-like 14) is a non-typical protein of the family as its long isoform (BCL-GL) consists of BH2 and BH3 domains without the BH1 motif. BCL-G is predominantly expressed in normal testes and different organs of the gastrointestinal tract. The complexity of regulatory mechanisms of BCL-G expression and post-translational modifications suggests that BCL-G may play distinct roles in different types of cells and disorders. While several genetic alterations of BCL2L14 have been reported, gene deletions and amplifications prevail, which is also confirmed by the analysis of sequencing data for different types of cancer. Although the studies validating the phenotypic consequences of genetic manipulations of BCL-G are limited, the role of BCL-G in apoptosis has been undermined. Recent studies using gene-perturbation approaches have revealed apoptosis-unrelated functions of BCL-G in intracellular trafficking, immunomodulation, and regulation of the mucin scaffolding network. These studies were, however, limited mainly to the role of BCL-G in the gastrointestinal tract. Therefore, further efforts using state-of-the-art methods and various types of cells are required to find out more about BCL-G activities. Deciphering the isoform-specific functions of BCL-G and the BCL-G interactome may result in the designing of novel therapeutic approaches, in which BCL-G activity will be either imitated using small-molecule BH3 mimetics or inhibited to counteract BCL-G upregulation. This review summarizes two decades of research on BCL-G.
The hunger strikes back: an epigenetic memory for autophagy
Authors: González-Rodríguez Patricia , Füllgrabe Jens , Joseph Bertrand
Published: April 2023

Historical and demographical human cohorts of populations exposed to famine, as well as animal studies, revealed that exposure to food deprivation is associated to lasting health-related effects for the exposed individuals, as well as transgenerational effects in their offspring that affect their diseases’ risk and overall longevity. Autophagy, an evolutionary conserved catabolic process, serves as cellular response to cope with nutrient starvation, allowing the mobilization of an internal source of stored nutrients and the production of energy. We review the evidence obtained in multiple model organisms that support the idea that autophagy induction, including through dietary regimes based on reduced food intake, is in fact associated to improved health span and extended lifespan. Thereafter, we expose autophagy-induced chromatin remodeling, such as DNA methylation and histone posttranslational modifications that are known heritable epigenetic marks, as a plausible mechanism for transgenerational epigenetic inheritance of hunger.
Radiation induces IRAK1 expression to promote radioresistance by suppressing autophagic cell death via decreasing the ubiquitination of PRDX1 in glioma cells
Authors: Li Jing , Sun Yuchen , Zhao Xu , Ma Yuan , Xie Yuchen , Liu Siqi , Hui Beina , Shi Xiaobo , Sun Xuanzi , Zhang Xiaozhi
Published: April 2023

Radiotherapy is the standard adjuvant treatment for glioma patients; however, the efficacy is limited by radioresistance. The function of Interleukin-1 receptor associated kinase 1 (IRAK1) in tumorigenesis and radioresistance remains to be elucidated. IRAK1 expression and its correlation with prognosis were analyzed in glioma tissues. We found that glioma patients with overexpressed IRAK1 show a poor prognosis. Notably, ionizing radiation (IR) remarkably induces IRAK1 expression, which was decreased by STING antagonist H-151 treatment. JASPAR prediction, ChIP assays, and dual luciferase reporter assays indicated that transcription factor FOXA2, suppressed by STING inhibition, directly binds to the IRAK1 promoter region and activates its transcription. IRAK1 knockdown inhibits malignancy and enhances the radiosensitivity of glioma in vitro and in vivo. To explore the potential IRAK1 interacting targets mediating the radioresistance of glioma cells, IP/Co-IP, LC-MS/MS, GST pull-down, and ubiquitination analyses were conducted. Mechanistically, IRAK1 bound to PRDX1, a major member of antioxidant enzymes, and further prevents ubiquitination and degradation of PRDX1 mediated by E3 ubiquitin ligase HECTD3; Both the DOC and HECT domains of HECTD3 directly interacted with PRDX1 protein. Overexpression of PRDX1 reverses the radiotherapy sensitization effect of IRAK1 depletion by diminishing autophagic cell death. These results suggest the IRAK1-PRDX1 axis provides a potential therapeutic target for glioma patients.
PLCG2 can exist in eccDNA and contribute to the metastasis of non-small cell lung cancer by regulating mitochondrial respiration
Authors: Yang Yongfeng , Yang Ying , Huang Hong , Song Tingting , Mao Shengqiang , Liu Dan , Zhang Li , Li Weimin
Published: April 2023

Extrachromosomal circular DNAs (eccDNAs) participate in tumorigenesis and tumor progression. However, the role and mechanism of eccDNAs have yet to be elucidated in non-small cell lung cancer (NSCLC). In our research, three surgically matched NSCLC tissue samples, NSCLC cell lines (H1299, A549, and H460), and a normal lung cell line (MRC-5) were used as study objects. High-throughput eccDNA sequencing and bioinformatics analysis were performed to study the distribution pattern and level of eccDNA expression. The upregulated candidate eccDNA-encoding PLCG2 was validated by routine PCR. Plasmid transfection, RNA interference, qRT‒PCR and western blotting experiments were used to verify the expression level of PLCG2. Our results showed that the chromosome distribution, length distribution, and genomic annotation of the eccDNAs were comparable between the NSCLC and normal groups. Nevertheless, there were no significant differences in eccDNAs between NSCLC tissues and matched normal lung tissues. The eccDNA derived from PLCG2 was upregulated in NSCLC cells. TCGA analysis and immunohistochemistry showed that PLCG2 was highly expressed in lung cancer tissues and tended to be associated with poor outcome. We also demonstrated that PLCG2 can promote metastasis through the regulation of mitochondrial respiration. These results suggested that PLCG2 identified by eccDNA sequencing acts as an oncogene and might be a new biomarker for NSCLC diagnosis and prognosis evaluation.
Identification of a novel type of focal adhesion remodelling via FAK/FRNK replacement, and its contribution to cancer progression
Authors: Tsujioka Masatsune , Miyazawa Keisuke , Ohmuraya Masaki , Nibe Yoichi , Shirokawa Tetsuya , Hayasaka Haruko , Mizushima Tsunekazu , Fukuma Takeshi , Shimizu Shigeomi
Published: April 2023

Numerous studies have investigated the various cellular responses against genotoxic stress, including those mediated by focal adhesions. We here identified a novel type of focal adhesion remodelling that occurs under genotoxic stress conditions, which involves the replacement of active focal adhesion kinase (FAK) with FAK-related non-kinase (FRNK). FRNK stabilized focal adhesions, leading to strong cell-matrix adhesion, and FRNK-depleted cells were easily detached from extracellular matrix upon genotoxic stress. This remodelling occurred in a wide variety of cells. In vivo, the stomachs of Frnk-knockout mice were severely damaged by genotoxic stress, highlighting the protective role of FRNK against genotoxic stress. FRNK was also found to play a vital role in cancer progression, because FRNK depletion significantly inhibited cancer dissemination and progression in a mouse cancer model. Furthermore, in human cancers, FRNK was predominantly expressed in metastatic tissues and not in primary tissues. We hence conclude that this novel type of focal adhesion remodelling reinforces cell adhesion and acts against genotoxic stress, which results in the protection of normal tissues, but in turn facilitates cancer progression.
PRPF19 facilitates colorectal cancer liver metastasis through activation of the Src-YAP1 pathway via K63-linked ubiquitination of MYL9
Authors: Zhou Rui , Chen Jie , Xu Yunxiuxiu , Ye Yibiao , Zhong Guoping , Chen Tao , Qiu Lin
Published: April 2023

Distant metastasis is one of the leading causes of cancer-related mortality of colorectal cancer (CRC). Dysregulation of E3 ubiquitin ligases has been implicated in acting vital roles in multiple cancers. In this study, we found that the E3 ubiquitin ligase, PRPF19 was positively correlated with liver metastasis, and predicted a worse clinical outcome in CRC. However, the biological effects and the underlying molecular mechanisms of PRPF19 in CRC remain elusive thus far. We illustrated that PRPF19 promoted the migration and invasion capability of CRC cells in both gain- and loss- of function assays. Mechanistically, we uncovered that myosin light chain 9 (MYL9) was the downstream substrate of PRPF19. PRPF19 enhanced the stability of MYL9 via K63-linked ubiquitination, and promoted the migration and invasion capability of CRC cells in an MYL9-mediated manner. Furthermore, the Src–YAP1 cascade was identified as the downstream effector mechanism by which the PRPF19/MYL9 axis promoted metastasis in CRC. Taken together, our findings highlighted that the PRPF19/MYL9 axis served as a novel mechanism in CRC metastasis, which provided an attractive therapeutic strategy for CRC treatment.
Multiple sclerosis plasma IgG aggregates induce complement-dependent neuronal apoptosis
Authors: Zhou Wenbo , Graner Michael , Paucek Petr , Beseler Cheryl , Boisen Matthew , Bubak Andrew , Asturias Francisco , George Woro , Graner Arin , Ormond David , Vollmer Timothy , Alvarez Enrique , Yu Xiaoli
Published: April 2023

Grey matter pathology is central to the progression of multiple sclerosis (MS). We discovered that MS plasma immunoglobulin G (IgG) antibodies, mainly IgG1, form large aggregates (>100 nm) which are retained in the flow-through after binding to Protein A. Utilizing an annexin V live-cell apoptosis detection assay, we demonstrated six times higher levels of neuronal apoptosis induced by MS plasma IgG aggregates (n = 190, from two cohorts) compared to other neurological disorders (n = 116) and healthy donors (n = 44). MS IgG aggregate-mediated, complement-dependent neuronal apoptosis was evaluated in multiple model systems including primary human neurons, primary human astrocytes, neuroblastoma SH-SY5Y cells, and newborn mouse brain slices. Immunocytochemistry revealed the co-deposition of IgG, early and late complement activation products (C1q, C3b, and membrane attack complex C5b9), as well as active caspase 3 in treated neuronal cells. Furthermore, we found that MS plasma cytotoxic antibodies are not present in Protein G flow-through, nor in the paired plasma. The neuronal apoptosis can be inhibited by IgG depletion, disruption of IgG aggregates, pan-caspase inhibitor, and is completely abolished by digestion with IgG-cleaving enzyme IdeS. Transmission electron microscopy and nanoparticle tracking analysis revealed the sizes of MS IgG aggregates are greater than 100 nm. Our data support the pathological role of MS IgG antibodies and corroborate their connection to complement activation and axonal damage, suggesting that apoptosis may be a mechanism of neurodegeneration in MS.
Cathepsin B in programmed cell death machinery: mechanisms of execution and regulatory pathways
Authors: Xie Zhen , Zhao Mengyuan , Yan Chengxiang , Kong Wei , Lan Fei , Narengaowa  , Zhao Shuxuan , Yang Qinghu , Bai Zhantao , Qing Hong , Ni Junjun
Published: April 2023

Cathepsin B (CatB), a cysteine protease, is primarily localized within subcellular endosomal and lysosomal compartments. It is involved in the turnover of intracellular and extracellular proteins. Interest is growing in CatB due to its diverse roles in physiological and pathological processes. In functional defective tissues, programmed cell death (PCD) is one of the regulable fundamental mechanisms mediated by CatB, including apoptosis, pyroptosis, ferroptosis, necroptosis, and autophagic cell death. However, CatB-mediated PCD is responsible for disease progression under pathological conditions. In this review, we provide an overview of the critical roles and regulatory pathways of CatB in different types of PCD, and discuss the possibility of CatB as an attractive target in multiple diseases. We also summarize current gaps in the understanding of the involvement of CatB in PCD to highlight future avenues for research.
Single cell transcriptomic analysis of HPV16-infected epithelium identifies a keratinocyte subpopulation implicated in cancer
Authors: Bedard Mary C. , Chihanga Tafadzwa , Carlile Adrean , Jackson Robert , Brusadelli Marion G. , Lee Denis , VonHandorf Andrew , Rochman Mark , Dexheimer Phillip J. , Chalmers Jeffrey , Nuovo Gerard , Lehn Maria , Williams David E. J. , Kulkarni Aditi , Carey Molly , Jackson Amanda , Billingsley Caroline , Tang Alice , Zender Chad , Patil Yash , Wise-Draper Trisha M. , Herzog Thomas J. , Ferris Robert L. , Kendler Ady , Aronow Bruce J. , Kofron Matthew , Rothenberg Marc E. , Weirauch Matthew T. , Van Doorslaer Koenraad , Wikenheiser-Brokamp Kathryn A. , Lambert Paul F. , Adam Mike , Steven Potter S. , Wells Susanne I.
Published: April 2023

Persistent HPV16 infection is a major cause of the global cancer burden. The viral life cycle is dependent on the differentiation program of stratified squamous epithelium, but the landscape of keratinocyte subpopulations which support distinct phases of the viral life cycle has yet to be elucidated. Here, single cell RNA sequencing of HPV16 infected compared to uninfected organoids identifies twelve distinct keratinocyte populations, with a subset mapped to reconstruct their respective 3D geography in stratified squamous epithelium. Instead of conventional terminally differentiated cells, an HPV-reprogrammed keratinocyte subpopulation (HIDDEN cells) forms the surface compartment and requires overexpression of the ELF3/ESE-1 transcription factor. HIDDEN cells are detected throughout stages of human carcinogenesis including primary human cervical intraepithelial neoplasias and HPV positive head and neck cancers, and a possible role in promoting viral carcinogenesis is supported by TCGA analyses. Single cell transcriptome information on HPV-infected versus uninfected epithelium will enable broader studies of the role of individual keratinocyte subpopulations in tumor virus infection and cancer evolution.
Observation of entanglement transition of pseudo-random mixed states
Authors: Liu Tong , Liu Shang , Li Hekang , Li Hao , Huang Kaixuan , Xiang Zhongcheng , Song Xiaohui , Xu Kai , Zheng Dongning , Fan Heng
Published: April 2023

Random quantum states serve as a powerful tool in various scientific fields, including quantum supremacy and black hole physics. It has been theoretically predicted that entanglement transitions may happen for different partitions of multipartite random quantum states; however, the experimental observation of these transitions is still absent. Here, we experimentally demonstrate the entanglement transitions witnessed by negativity on a fully connected superconducting processor. We apply parallel entangling operations, that significantly decrease the depth of the pseudo-random circuits, to generate pseudo-random pure states of up to 15 qubits. By quantum state tomography of the reduced density matrix of six qubits, we measure the negativity spectra. Then, by changing the sizes of the environment and subsystems, we observe the entanglement transitions that are directly identified by logarithmic entanglement negativities based on the negativity spectra. In addition, we characterize the randomness of our circuits by measuring the distance between the distribution of output bit-string probabilities and the Porter-Thomas distribution. Our results show that superconducting processors with all-to-all connectivity constitute a promising platform for generating random states and understanding the entanglement structure of multipartite quantum systems.
Circulating blood eNAMPT drives the circadian rhythms in locomotor activity and energy expenditure
Authors: Park Jae Woo , Roh Eun , Kang Gil Myoung , Gil So Young , Kim Hyun Kyong , Lee Chan Hee , Jang Won Hee , Park Se Eun , Moon Sang Yun , Kim Seong Jun , Jeong So Yeon , Park Chae Beom , Lim Hyo Sun , Oh Yu Rim , Jung Han Na , Kwon Obin , Youn Byung Soo , Son Gi Hoon , Min Se Hee , Kim Min-Seon
Published: April 2023

Nicotinamide adenine dinucleotide (NAD+) is an essential cofactor of critical enzymes including protein deacetylase sirtuins/SIRTs and its levels in mammalian cells rely on the nicotinamide phosphoribosyltransferase (NAMPT)-mediated salvage pathway. Intracellular NAMPT (iNAMPT) is secreted and found in the blood as extracellular NAMPT (eNAMPT). In the liver, the iNAMPT−NAD+ axis oscillates in a circadian manner and regulates the cellular clockwork. Here we show that the hypothalamic NAD+ levels show a distinct circadian fluctuation with a nocturnal rise in lean mice. This rhythm is in phase with that of plasma eNAMPT levels but not with that of hypothalamic iNAMPT levels. Chemical and genetic blockade of eNAMPT profoundly inhibit the nighttime elevations in hypothalamic NAD+ levels as well as those in locomotor activity (LMA) and energy expenditure (EE). Conversely, elevation of plasma eNAMPT by NAMPT administration increases hypothalamic NAD+ levels and stimulates LMA and EE via the hypothalamic NAD+−SIRT−FOXO1−melanocortin pathway. Notably, obese animals display a markedly blunted circadian oscillation in blood eNAMPT−hypothalamic NAD+−FOXO1 axis as well as LMA and EE. Our findings indicate that the eNAMPT regulation of hypothalamic NAD+ biosynthesis underlies circadian physiology and that this system can be significantly disrupted by obesity.
A supramolecular gel-elastomer system for soft iontronic adhesives
Authors: Gao Dace , Thangavel Gurunathan , Lee Junwoo , Lv Jian , Li Yi , Ciou Jing-Hao , Xiong Jiaqing , Park Taiho , Lee Pooi See
Published: April 2023

Electroadhesion provides a promising route to augment robotic functionalities with continuous, astrictive, and reversible adhesion force. However, the lack of suitable conductive/dielectric materials and processing capabilities have impeded the integration of electroadhesive modules into soft robots requiring both mechanical compliance and robustness. We present herein an iontronic adhesive based on a dynamically crosslinked gel-elastomer system, including an ionic organohydrogel as adhesive electrodes and a resilient polyurethane with high electrostatic energy density as dielectric layers. Through supramolecular design and synthesis, the dual-material system exhibits cohesive heterolayer bonding and autonomous self-healing from damages. Iontronic soft grippers that seamlessly integrate actuation, adhesive prehension, and exteroceptive sensation are devised via additive manufacturing. The grippers can capture soft and deformable items, bear high payload under reduced voltage input, and rapidly release foreign objects in contrast to electroadhesives. Our materials and iontronic mechanisms pave the way for future advancement in adhesive-enhanced multifunctional soft devices.
Predicting compound activity from phenotypic profiles and chemical structures
Authors: Moshkov Nikita , Becker Tim , Yang Kevin , Horvath Peter , Dancik Vlado , Wagner Bridget K. , Clemons Paul A. , Singh Shantanu , Carpenter Anne E. , Caicedo Juan C.
Published: April 2023

Predicting assay results for compounds virtually using chemical structures and phenotypic profiles has the potential to reduce the time and resources of screens for drug discovery. Here, we evaluate the relative strength of three high-throughput data sources—chemical structures, imaging (Cell Painting), and gene-expression profiles (L1000)—to predict compound bioactivity using a historical collection of 16,170 compounds tested in 270 assays for a total of 585,439 readouts. All three data modalities can predict compound activity for 6–10% of assays, and in combination they predict 21% of assays with high accuracy, which is a 2 to 3 times higher success rate than using a single modality alone. In practice, the accuracy of predictors could be lower and still be useful, increasing the assays that can be predicted from 37% with chemical structures alone up to 64% when combined with phenotypic data. Our study shows that unbiased phenotypic profiling can be leveraged to enhance compound bioactivity prediction to accelerate the early stages of the drug-discovery process.
Improving the generalizability of protein-ligand binding predictions with AI-Bind
Authors: Chatterjee Ayan , Walters Robin , Shafi Zohair , Ahmed Omair Shafi , Sebek Michael , Gysi Deisy , Yu Rose , Eliassi-Rad Tina , Barabási Albert-László , Menichetti Giulia
Published: April 2023

Identifying novel drug-target interactions is a critical and rate-limiting step in drug discovery. While deep learning models have been proposed to accelerate the identification process, here we show that state-of-the-art models fail to generalize to novel (i.e., never-before-seen) structures. We unveil the mechanisms responsible for this shortcoming, demonstrating how models rely on shortcuts that leverage the topology of the protein-ligand bipartite network, rather than learning the node features. Here we introduce AI-Bind, a pipeline that combines network-based sampling strategies with unsupervised pre-training to improve binding predictions for novel proteins and ligands. We validate AI-Bind predictions via docking simulations and comparison with recent experimental evidence, and step up the process of interpreting machine learning prediction of protein-ligand binding by identifying potential active binding sites on the amino acid sequence. AI-Bind is a high-throughput approach to identify drug-target combinations with the potential of becoming a powerful tool in drug discovery.
A neutrophil mimicking metal-porphyrin-based nanodevice loaded with porcine pancreatic elastase for cancer therapy
Authors: Cui Tingting , Zhang Yu , Qin Geng , Wei Yue , Yang Jie , Huang Ying , Ren Jinsong , Qu Xiaogang
Published: April 2023

Precise discrimination and eradication of cancer cells by immune cells independent of antigen recognition is promising for solid tumor therapeutics, yet remains a tremendous challenge. Inspired by neutrophils, here we design and construct a tumor discrimination nanodevice based on the differential histone H1 isoform expression. In this nanodevice, neutrophil membrane camouflage and glutathione (GSH)-unlocking effect on Fe-porphyrin metal−organic framework structure ensures selectivity to cancer cells. The released porcine pancreatic elastase (PPE) simulates neutrophils’ action to induce histone H1 release-dependent selective cancer cell killing. Meanwhile, nuclear localization signal (NLS) peptide-tagged porphyrin (porphyrin-NLS) acts as in-situ singlet oxygen (1O2) generator to amplify histone H1 nucleo-cytoplasmic translocation by inducing DNA double-strand breaks (DSBs) under laser irradiation, further promoting elimination of cancer cells. The overexpressed histone H1 isoform in cancer cells improves selectivity of our nanodevice to cancer cells. In vivo studies demonstrate that our design can not only inhibit primary tumor growth, but also induce adaptive T-cell response-mediated abscopal effect to against distal tumors.
A neuromorphic bionic eye with filter-free color vision using hemispherical perovskite nanowire array retina
Authors: Long Zhenghao , Qiu Xiao , Chan Chak Lam Jonathan , Sun Zhibo , Yuan Zhengnan , Poddar Swapnadeep , Zhang Yuting , Ding Yucheng , Gu Leilei , Zhou Yu , Tang Wenying , Srivastava Abhishek Kumar , Yu Cunjiang , Zou Xuming , Shen Guozhen , Fan Zhiyong
Published: April 2023

Spherical geometry, adaptive optics, and highly dense network of neurons bridging the eye with the visual cortex, are the primary features of human eyes which enable wide field-of-view (FoV), low aberration, excellent adaptivity, and preprocessing of perceived visual information. Therefore, fabricating spherical artificial eyes has garnered enormous scientific interest. However, fusing color vision, in-device preprocessing and optical adaptivity into spherical artificial eyes has always been a tremendous challenge. Herein, we demonstrate a bionic eye comprising tunable liquid crystal optics, and a hemispherical neuromorphic retina with filter-free color vision, enabled by wavelength dependent bidirectional synaptic photo-response in a metal-oxide nanotube/perovskite nanowire hybrid structure. Moreover, by tuning the color selectivity with bias, the device can reconstruct full color images. This work demonstrates a unique approach to address the color vision and optical adaptivity issues associated with artificial eyes that can bring them to a new level approaching their biological counterparts.
The IgG4 hinge with CD28 transmembrane domain improves VHH-based CAR T cells targeting a membrane-distal epitope of GPC1 in pancreatic cancer
Authors: Li Nan , Quan Alex , Li Dan , Pan Jiajia , Ren Hua , Hoeltzel Gerard , de Val Natalia , Ashworth Dana , Ni Weiming , Zhou Jing , Mackay Sean , Hewitt Stephen M. , Cachau Raul , Ho Mitchell
Published: April 2023

Heterogeneous antigen expression is a key barrier influencing the activity of chimeric antigen receptor (CAR) T cells in solid tumors. Here, we develop CAR T cells targeting glypican-1 (GPC1), an oncofetal antigen expressed in pancreatic cancer. We report the generation of dromedary camel VHH nanobody (D4)-based CAR T cells targeting GPC1 and the optimization of the hinge (H) and transmembrane domain (TM) to improve activity. We find that a structurally rigid IgG4H and CD28TM domain brings the two D4 fragments in proximity, driving CAR dimerization and leading to enhanced T-cell signaling and tumor regression in pancreatic cancer models with low antigen density in female mice. Furthermore, single-cell-based proteomic and transcriptomic analysis of D4-IgG4H-CD28TM CAR T cells reveals specific genes (e.g., HMGB1) associated with high T-cell polyfunctionality. This study demonstrates the potential of VHH-based CAR T for pancreatic cancer therapy and provides an engineering strategy for developing potent CAR T cells targeting membrane-distal epitopes.
Collateral sensitivity profiling in drug-resistant Escherichia coli identifies natural products suppressing cephalosporin resistance
Authors: Liu Dennis Y. , Phillips Laura , Wilson Darryl M. , Fulton Kelly M. , Twine Susan M. , Wong Alex , Linington Roger G.
Published: April 2023

The rapid emergence of antimicrobial resistance presents serious health challenges to the management of infectious diseases, a problem that is further exacerbated by slowing rates of antimicrobial drug discovery in recent years. The phenomenon of collateral sensitivity (CS), whereby resistance to one drug is accompanied by increased sensitivity to another, provides new opportunities to address both these challenges. Here, we present a high-throughput screening platform termed Collateral Sensitivity Profiling (CSP) to map the difference in bioactivity of large chemical libraries across 29 drug-resistant strains of E. coli. CSP screening of 80 commercial antimicrobials demonstrated multiple CS interactions. Further screening of a 6195-member natural product library revealed extensive CS relationships in nature. In particular, we report the isolation of known and new analogues of borrelidin A with potent CS activities against cephalosporin-resistant strains. Co-dosing ceftazidime with borrelidin A slows broader cephalosporin resistance with no recognizable resistance to borrelidin A itself.
Engineering tumor-specific gene nanomedicine to recruit and activate T cells for enhanced immunotherapy
Authors: Wang Yue , Zhou Shi-Kun , Wang Yan , Lu Zi-Dong , Zhang Yue , Xu Cong-Fei , Wang Jun
Published: April 2023

PD-1/PD-L1 blockade therapy that eliminates T-cell inhibition signals is successful, but poor benefits are often observed. Increasing T-cell infiltration and quantity of PD-1/PD-L1 inhibitors in tumor can improve efficacy but remains challenging. Here, we devise tumor-specific gene nanomedicines to mobilize tumor cells to secrete CXCL9 (T-cell chemokine) and anti-PD-L1 scFv (αPD-L1, PD-L1 blocking agent) for enhanced immunotherapy. The tyrosinase promoter-driven NPTyr-C9AP can specifically co-express CXCL9 and αPD-L1 in melanoma cells, thereby forming a CXCL9 gradient for T-cell recruitment and high intratumoral αPD-L1 concentration for enhancing T-cell activation. As a result, NPTyr-C9AP shows strong antimelanoma effects. Moreover, specific co-expression of CXCL9 and αPD-L1 in various tumor cells is achieved by replacing the tyrosinase promoter of NPTyr-C9AP with a survivin promoter, which increases T-cell infiltration and activation and therapeutic efficacy in multiple tumors in female mice. This study provides a strategy to maximize the immunotherapeutic outcome regardless of the heterogeneous tumor microenvironment.
A direct observation of up-converted room-temperature phosphorescence in an anti-Kasha dopant-matrix system
Authors: Li Jiuyang , Li Xun , Wang Guangming , Wang Xuepu , Wu Minjian , Liu Jiahui , Zhang Kaka
Published: April 2023

It is common sense that emission maxima of phosphorescence spectra (λP) are longer than those of fluorescence spectra (λF). Here we report a serendipitous finding of up-converted room-temperature phosphorescence (RTP) withλP < λFand phosphorescence lifetime > 0.1 s upon doping benzophenone-containing difluoroboron β-diketonate (BPBF2) into phenyl benzoate matrices. The up-converted RTP is originated from BPBF2’s Tn(n ≥ 2) states which show typical3n-π* characters from benzophenone moieties. Detailed studies reveal that, upon intersystem crossing from BPBF2’s S1states of charge transfer characters, the resultant T1and Tnstates build T1-to-Tnequilibrium. Because of their3n-π* characters, the Tnstates possess large phosphorescence rates that can strongly compete RTP(T1) to directly emit RTP(Tn) which violates Kasha’s rule. The direct observation of up-converted RTP provides deep understanding of triplet excited state dynamics and opens an intriguing pathway to devise visible-light-excitable deep-blue afterglow emitters, as well as stimuli-responsive afterglow materials.
The intestinal MUC2 mucin C-terminus is stabilized by an extra disulfide bond in comparison to von Willebrand factor and other gel-forming mucins
Authors: Gallego Pablo , Garcia-Bonete Maria-Jose , Trillo-Muyo Sergio , Recktenwald Christian V. , Johansson Malin E. V. , Hansson Gunnar C.
Published: April 2023

The MUC2 mucin polymer is the main building unit of the intestinal mucus layers separating intestinal microbiota from the host epithelium. The MUC2 mucin is a large glycoprotein with a C-terminal domain similar to the MUC5AC and MUC5B mucins and the von Willebrand factor (VWF). A structural model of the C-terminal part of MUC2, MUC2-C, was generated by combining Cryo-electron microscopy, AlphaFold prediction, information of its glycosylation, and small angle X-ray scattering information. The globular VWD4 assembly in the N-terminal of MUC2-C is followed by 3.5 linear VWC domains that form an extended flexible structure before the C-terminal cystine-knot. All gel-forming mucins and VWF form tail-tail disulfide-bonded dimers in their C-terminal cystine-knot domain, but interestingly the MUC2 mucin has an extra stabilizing disulfide bond on the N-terminal side of the VWD4 domain, likely essential for a stable intestinal mucus barrier.