bluuebunny/crossref_metadata_2025 huggingface dataset:
Detecting Extreme Temperature Events Using Gaussian Mixture Models
Authors: Paçal Aytaç , Hassler Birgit , Weigel Katja , Kurnaz M. Levent , Wehner Michael F. , Eyring Veronika
Published: September 2023

Extreme temperature events have traditionally been detected assuming a unimodal distribution of temperature data. We found that surface temperature data can be described more accurately with a multimodal rather than a unimodal distribution. Here, we applied Gaussian Mixture Models (GMM) to daily near‐surface maximum air temperature data from the historical and future Coupled Model Intercomparison Project Phase 6 (CMIP6) simulations for 46 land regions defined by the Intergovernmental Panel on Climate Change. Using the multimodal distribution, we found that temperature extremes, defined based on daily data in the warmest mode of the GMM distributions, are getting more frequent in all regions. Globally, a 10‐year extreme temperature event relative to 1985–2014 conditions will occur 13.6 times more frequently in the future under 3.0°C of global warming levels (GWL). The frequency increase can be even higher in tropical regions, such that 10‐year extreme temperature events will occur almost twice a week. Additionally, we analyzed the change in future temperature distributions under different GWL and found that the hot temperatures are increasing faster than cold temperatures in low latitudes, while the cold temperatures are increasing faster than the hot temperatures in high latitudes. The smallest changes in temperature distribution can be found in tropical regions, where the annual temperature range is small. Our method captures the differences in geographical regions and shows that the frequency of extreme events will be even higher than reported in previous studies.
Time‐Resolved Measurements of PM2.5 Chemical Composition and Brown Carbon Absorption in Nanjing, East China: Diurnal Variations and Organic Tracer‐Based PMF Analysis
Authors: Feng Wei , Wang Xinyue , Shao Zhijuan , Liao Hong , Wang Yuhang , Xie Mingjie
Published: September 2023

To understand diurnal variations in PM2.5 composition and aerosol extract absorption, PM2.5 samples were collected at intervals of 2 hr from 8:00 to 20:00 and 6 hr from 20:00 to 8:00 (the next day) in northern Nanjing, China, during the winter and summer of 2019–2020 and analyzed for bulk components, organic tracers, and light absorption of water and methanol extracts—a proxy measure of brown carbon (BrC). Diurnal patterns of measured species reflected the influences of primary emissions and atmospheric processes. Light absorption coefficients of water (Abs365,w) and methanol extracts (Abs365,m) at 365 nm shared a similar diurnal profile peaking at 18:00–20:00, generally following changes in biomass burning tracers. However, Abs365,w, Abs365,m, and their normalizations to organic aerosols increased at 14:00–16:00, earlier than that of levoglucosan in the late afternoon, which was attributed to secondarily formed BrC. The methanol extracts showed a less drastic decrease in light absorption at night than the water extracts and elevated absorption efficiency during 2:00–8:00. This is due to the fact that the water‐insoluble OC has a longer lifetime and stronger light absorption than the water‐soluble OC. According to the source apportionment results solved by positive matrix factorization (PMF), biomass burning and secondary formation were the major BrC sources in northern Nanjing, with an average total relative contribution of about 90%. Compared to previous studies, diurnal source cycles were added to the PMF simulations in this work by using time‐resolved speciation data, which avoided misclassification of BrC sources.
Rate, Water Pressure, and Temperature Effects in Landslide Shear Zones
Authors: Kohler Marc , Hottiger Stephanie , Puzrin Alexander M.
Published: September 2023

The behavior of slow‐moving landslides is controlled by the residual strength of the shear zone. Despite their mobile state, such slides can often withstand extreme events such as heavy rainfalls and earthquakes. A rate‐hardening in the shear zone is suspected to be one of the main stabilizing factors and has been well investigated, in particular for clayey soils. Soils from steep alpine landslides, on the other hand, are often dominated by silts and sands with various clay contents, and while understanding of their rate dependency is less advanced, it remains critical for the reliable risk assessment. In this article, an improved ring shear apparatus is presented and applied to investigate the rate, pore water pressure, and temperature effects in landslide shear zones. The testing program on samples from two alpine landslides in Switzerland revealed a moderately positive rate effect explaining their mobile state. An achieved insight into the thermo‐hydro‐mechanical processes of fast shearing provides physical evidence to the widely debated hypothesis on the generation of excess pore water pressure due to frictional heating. However, for the tested materials, this effect only occurs after extended shearing and does not lead to a complete loss of shear strength. Based on that and the observed positive rate effects, catastrophic failure seems unlikely for these landslides. At the same time, the results suggest that for less permeable soils, frictional heating may indeed be a source of negative rate effect during very rapid shearing.
DEEP-squared: deep learning powered De-scattering with Excitation Patterning
Authors: Wijethilake Navodini , Anandakumar Mithunjha , Zheng Cheng , So Peter T. C. , Yildirim Murat , Wadduwage Dushan N.
Published: September 2023

Limited throughput is a key challenge in in vivo deep tissue imaging using nonlinear optical microscopy. Point scanning multiphoton microscopy, the current gold standard, is slow especially compared to the widefield imaging modalities used for optically cleared or thin specimens. We recently introduced “De-scattering with Excitation Patterning” or “DEEP” as a widefield alternative to point-scanning geometries. Using patterned multiphoton excitation, DEEP encodes spatial information inside tissue before scattering. However, to de-scatter at typical depths, hundreds of such patterned excitations were needed. In this work, we present DEEP2, a deep learning-based model that can de-scatter images from just tens of patterned excitations instead of hundreds. Consequently, we improve DEEP’s throughput by almost an order of magnitude. We demonstrate our method in multiple numerical and experimental imaging studies, including in vivo cortical vasculature imaging up to 4 scattering lengths deep in live mice.
Overcoming the translational crisis of contemporary psychiatry – converging phenomenological and spatiotemporal psychopathology
Authors: Northoff Georg , Daub Jonas , Hirjak Dusan
Published: September 2023

Despite all neurobiological/neurocomputational progress in psychiatric research, recent authors speak about a ‘crisis of contemporary psychiatry’. Some argue that we do not yet know the computational mechanisms underlying the psychopathological symptoms (‘crisis of mechanism’) while others diagnose a neglect of subjectivity, namely first-person experience (‘crisis of subjectivity’). In this perspective, we propose that Phenomenological Psychopathology, due to its focus on first-person experience of space and time, is in an ideal position to address the crisis of subjectivity and, if extended to the brain’s spatiotemporal topographic-dynamic structure as key focus of Spatiotemporal Psychopathology, the crisis of mechanism. We demonstrate how the first-person experiences of space and time differ between schizophrenia, mood disorders and anxiety disorders allowing for their differential-diagnosis – this addresses the crisis of subjectivity. Presupposing space and time as shared features of brain, experience, and symptoms as their “common currency”, the structure of abnormal space and time experience may also serve as template for the structure of the brain’s spatiotemporal neuro-computational mechanisms – this may address the crisis of mechanism. Preliminary scientific evidence in our examples of schizophrenia, bipolar disorder, anxiety disorder, and depression support such clinically relevant spatiotemporal determination of both first-person experience (crisis of subjectivity) and the brain’s neuro-computational structure (crisis of mechanism). In conclusion, converging Phenomenological Psychopathology with Spatiotemporal Psychopathology might help to overcome the translational crisis in psychiatry by delineating more fine-grained neuro computational and -phenomenal mechanisms; this offers novel candidate biomarkers for diagnosis and therapy including both pharmacological and non-pharmacological treatment.
Amino acid metabolism in health and disease
Authors: Ling Zhe-Nan , Jiang Yi-Fan , Ru Jun-Nan , Lu Jia-Hua , Ding Bo , Wu Jian
Published: September 2023

Amino acids are the building blocks of protein synthesis. They are structural elements and energy sources of cells necessary for normal cell growth, differentiation and function. Amino acid metabolism disorders have been linked with a number of pathological conditions, including metabolic diseases, cardiovascular diseases, immune diseases, and cancer. In the case of tumors, alterations in amino acid metabolism can be used not only as clinical indicators of cancer progression but also as therapeutic strategies. Since the growth and development of tumors depend on the intake of foreign amino acids, more and more studies have targeted the metabolism of tumor-related amino acids to selectively kill tumor cells. Furthermore, immune-related studies have confirmed that amino acid metabolism regulates the function of effector T cells and regulatory T cells, affecting the function of immune cells. Therefore, studying amino acid metabolism associated with disease and identifying targets in amino acid metabolic pathways may be helpful for disease treatment. This article mainly focuses on the research of amino acid metabolism in tumor-oriented diseases, and reviews the research and clinical research progress of metabolic diseases, cardiovascular diseases and immune-related diseases related to amino acid metabolism, in order to provide theoretical basis for targeted therapy of amino acid metabolism.
RNA binding protein TIAR modulates HBV replication by tipping the balance of pgRNA translation
Authors: Zhang Ting , Zheng Huiling , Lu Danjuan , Guan Guiwen , Li Deyao , Zhang Jing , Liu Shuhong , Zhao Jingmin , Guo Ju-Tao , Lu Fengmin , Chen Xiangmei
Published: September 2023

The pregenomic RNA (pgRNA) of hepatitis B virus (HBV) serves not only as a bicistronic message RNA to translate core protein (Cp) and DNA polymerase (Pol), but also as the template for reverse transcriptional replication of viral DNA upon packaging into nucleocapsid. Although it is well known that pgRNA translates much more Cp than Pol, the molecular mechanism underlying the regulation of Cp and Pol translation efficiency from pgRNA remains elusive. In this study, we systematically profiled HBV nucleocapsid- and pgRNA-associated cellular proteins by proteomic analysis and identified TIA-1-related protein (TIAR) as a novel cellular protein that binds pgRNA and promotes HBV DNA replication. Interestingly, loss- and gain-of-function genetic analyses showed that manipulation of TIAR expression did not alter the levels of HBV transcripts nor the secretion of HBsAg and HBeAg in human hepatoma cells supporting HBV replication. However, Ribo-seq and PRM-based mass spectrometry analyses demonstrated that TIAR increased the translation of Pol but decreased the translation of Cp from pgRNA. RNA immunoprecipitation (RIP) and pulldown assays further revealed that TIAR directly binds pgRNA at the 5’ stem-loop (ε). Moreover, HBV replication or Cp expression induced the increased expression and redistribution of TIAR from the nucleus to the cytoplasm of hepatocytes. Our results thus imply that TIAR is a novel cellular factor that regulates HBV replication by binding to the 5’ ε structure of pgRNA to tip the balance of Cp and Pol translation. Through induction of TIAR translocation from the nucleus to the cytoplasm, Cp indirectly regulates the Pol translation and balances Cp and Pol expression levels in infected hepatocytes to ensure efficient viral replication.
NRP1 transduces mechanical stress inhibition via LATS1/YAP in hypertrophic scars
Authors: Li Mengzhi , Wang Peng , Li Jingting , Zhou Fei , Huang Shixin , Qi Shaohai , Shu Bin
Published: September 2023

Hypertrophic scar (HS) is an abnormal fibrous hyperplasia of the skin caused by excessive tissue repair in response to skin burns and trauma, which restricts physical function and impairs patients’ quality of life. Numerous studies have shown that pressure garment therapy (PGT) is an effective treatment for preventing hypertrophic scars. Herein, we found that mechanical stress stimulates the neuropilin 1 (NRP1) expression through screening GSE165027, GSE137210, and GSE120194 from Gene Expression Omnibus (GEO) database and bioinformatics analysis. We verified this stimulation in the human hypertrophic scar, pressure culture cell model, and rat tail-scar model. Mechanical compression increased LATS1 and pYAP enrichment, thus repressing the expression of YAP. Functionally, the knockdown of NRP1 promoted the expression of LATS1, thus decreasing the expression of YAP and inhibiting endothelial cell proliferation. Furthermore, co-immunoprecipitation analysis confirmed that NRP1 binds to YAP, and mechanical compression disrupted this binding, which resulted in the promotion of YAP relocation to nuclear. In conclusion, our results indicated that NRP1 transduces mechanical force inhibition by inhibiting YAP expression. Mechanical pressure can release YAP bound to NRP1, which explains the phenomenon that mechanical stress increases YAP in the nucleus. Strategies targeting NRP1 may promote compression therapy with optimal and comfortable pressures.
MYC Deregulation and PTEN Loss Model Tumor and Stromal Heterogeneity of Aggressive Triple-Negative Breast Cancer
Authors: Doha Zinab O. , Wang Xiaoyan , Calistri Nicholas L. , Eng Jennifer , Daniel Colin J. , Ternes Luke , Kim Eun Na , Pelz Carl , Munks Michael , Betts Courtney , Kwon Sunjong , Bucher Elmar , Li Xi , Waugh Trent , Tatarova Zuzana , Blumberg Dylan , Ko Aaron , Kirchberger Nell , Pietenpol Jennifer A. , Sanders Melinda E. , Langer Ellen M. , Dai Mu-Shui , Mills Gordon , Chin Koei , Chang Young Hwan , Coussens Lisa M. , Gray Joe W. , Heiser Laura M. , Sears Rosalie C.
Published: September 2023

Triple-negative breast cancer (TNBC) patients have a poor prognosis and few treatment options. Mouse models of TNBC are important for development of new therapies, however, few mouse models represent the complexity of TNBC. Here, we develop a female TNBC murine model by mimicking two common TNBC mutations with high co-occurrence: amplification of the oncogene MYC and deletion of the tumor suppressor PTEN. This Myc;Ptenfl model develops heterogeneous triple-negative mammary tumors that display histological and molecular features commonly found in human TNBC. Our research involves deep molecular and spatial analyses on Myc;Ptenfl tumors including bulk and single-cell RNA-sequencing, and multiplex tissue-imaging. Through comparison with human TNBC, we demonstrate that this genetic mouse model develops mammary tumors with differential survival and therapeutic responses that closely resemble the inter- and intra-tumoral and microenvironmental heterogeneity of human TNBC, providing a pre-clinical tool for assessing the spectrum of patient TNBC biology and drug response.
Global fossil fuel reduction pathways under different climate mitigation strategies and ambitions
Authors: Achakulwisut Ploy , Erickson Peter , Guivarch Céline , Schaeffer Roberto , Brutschin Elina , Pye Steve
Published: September 2023

The mitigation scenarios database of the Intergovernmental Panel on Climate Change’s Sixth Assessment Report is an important resource for informing policymaking on energy transitions. However, there is a large variety of models, scenario designs, and resulting outputs. Here we analyse the scenarios consistent with limiting warming to 2 °C or below regarding the speed, trajectory, and feasibility of different fossil fuel reduction pathways. In scenarios limiting warming to 1.5 °C with no or limited overshoot, global coal, oil, and natural gas supply (intended for all uses) decline on average by 95%, 62%, and 42%, respectively, from 2020 to 2050, but the long-term role of gas is highly variable. Higher-gas pathways are enabled by higher carbon capture and storage (CCS) and carbon dioxide removal (CDR), but are likely associated with inadequate model representation of regional CO2 storage capacity and technology adoption, diffusion, and path-dependencies. If CDR is constrained by limits derived from expert consensus, the respective modelled coal, oil, and gas reductions become 99%, 70%, and 84%. Our findings suggest the need to adopt unambiguous near- and long-term reduction benchmarks in coal, oil, and gas production and use alongside other climate mitigation targets.
CSF proteome profiling reveals biomarkers to discriminate dementia with Lewy bodies from Alzheimer´s disease
Authors: del Campo Marta , Vermunt Lisa , Peeters Carel F. W. , Sieben Anne , Hok-A-Hin Yanaika S. , Lleó Alberto , Alcolea Daniel , van Nee Mirrelijn , Engelborghs Sebastiaan , van Alphen Juliette L. , Arezoumandan Sanaz , Chen-Plotkin Alice , Irwin David J. , van der Flier Wiesje M. , Lemstra Afina W. , Teunissen Charlotte E.
Published: September 2023

Diagnosis of dementia with Lewy bodies (DLB) is challenging and specific biofluid biomarkers are highly needed. We employed proximity extension-based assays to measure 665 proteins in the cerebrospinal fluid (CSF) from patients with DLB (n = 109), Alzheimer´s disease (AD,n = 235) and cognitively unimpaired controls (n = 190). We identified over 50 CSF proteins dysregulated in DLB, enriched in myelination processes among others. The dopamine biosynthesis enzyme DDC was the strongest dysregulated protein, and could efficiently discriminate DLB from controls and AD (AUC:0.91 and 0.81 respectively). Classification modeling unveiled a 7-CSF biomarker panel that better discriminate DLB from AD (AUC:0.93). A custom multiplex panel for six of these markers (DDC, CRH, MMP-3, ABL1, MMP-10, THOP1) was developed and validated in independent cohorts, including an AD and DLB autopsy cohort. This DLB CSF proteome study identifies DLB-specific protein changes and translates these findings to a practicable biomarker panel that accurately identifies DLB patients, providing promising diagnostic and clinical trial testing opportunities.
Multifunctional human monoclonal antibody combination mediates protection against Rift Valley fever virus at low doses
Authors: Chapman Nathaniel S. , Hulswit Ruben J. G. , Westover Jonna L. B. , Stass Robert , Paesen Guido C. , Binshtein Elad , Reidy Joseph X. , Engdahl Taylor B. , Handal Laura S. , Flores Alejandra , Gowen Brian B. , Bowden Thomas A. , Crowe James E.
Published: September 2023

The zoonotic Rift Valley fever virus (RVFV) can cause severe disease in humans and has pandemic potential, yet no approved vaccine or therapy exists. Here we describe a dual-mechanism human monoclonal antibody (mAb) combination against RVFV that is effective at minimal doses in a lethal mouse model of infection. We structurally analyze and characterize the binding mode of a prototypical potent Gn domain-A-binding antibody that blocks attachment and of an antibody that inhibits infection by abrogating the fusion process as previously determined. Surprisingly, the Gn domain-A antibody does not directly block RVFV Gn interaction with the host receptor low density lipoprotein receptor-related protein 1 (LRP1) as determined by a competitive assay. This study identifies a rationally designed combination of human mAbs deserving of future investigation for use in humans against RVFV infection. Using a two-pronged mechanistic approach, we demonstrate the potent efficacy of a rationally designed combination mAb therapeutic.
Single-cell isotope tracing reveals functional guilds of bacteria associated with the diatom Phaeodactylum tricornutum
Authors: Mayali Xavier , Samo Ty J. , Kimbrel Jeff A. , Morris Megan M. , Rolison Kristina , Swink Courtney , Ramon Christina , Kim Young-Mo , Munoz-Munoz Nathalie , Nicora Carrie , Purvine Sam , Lipton Mary , Stuart Rhona K. , Weber Peter K.
Published: September 2023

Bacterial remineralization of algal organic matter fuels algal growth but is rarely quantified. Consequently, we cannot currently predict whether some bacterial taxa may provide more remineralized nutrients to algae than others. Here, we quantified bacterial incorporation of algal-derived complex dissolved organic carbon and nitrogen and algal incorporation of remineralized carbon and nitrogen in fifteen bacterial co-cultures growing with the diatom Phaeodactylum tricornutum at the single-cell level using isotope tracing and nanoSIMS. We found unexpected strain-to-strain and cell-to-cell variability in net carbon and nitrogen incorporation, including non-ubiquitous complex organic nitrogen utilization and remineralization. We used these data to identify three distinct functional guilds of metabolic interactions, which we termed macromolecule remineralizers, macromolecule users, and small-molecule users, the latter exhibiting efficient growth under low carbon availability. The functional guilds were not linked to phylogeny and could not be elucidated strictly from metabolic capacity as predicted by comparative genomics, highlighting the need for direct activity-based measurements in ecological studies of microbial metabolic interactions.
Assembly mechanism of a Tad secretion system secretin-pilotin complex
Authors: Tassinari Matteo , Rudzite Marta , Filloux Alain , Low Harry H.
Published: September 2023

The bacterial Tight adherence Secretion System (TadSS) assembles surface pili that drive cell adherence, biofilm formation and bacterial predation. The structure and mechanism of the TadSS is mostly unknown. This includes characterisation of the outer membrane secretin through which the pilus is channelled and recruitment of its pilotin. Here we investigate RcpA and TadD lipoprotein from Pseudomonas aeruginosa. Light microscopy reveals RcpA colocalising with TadD in P. aeruginosa and when heterologously expressed in Escherichia coli. We use cryogenic electron microscopy to determine how RcpA and TadD assemble a secretin channel with C13 and C14 symmetries. Despite low sequence homology, we show that TadD shares a similar fold to the type 4 pilus system pilotin PilF. We establish that the C-terminal four residues of RcpA bind TadD - an interaction essential for secretin formation. The binding mechanism between RcpA and TadD appears distinct from known secretin-pilotin pairings in other secretion systems.
Variation in spatial dependencies across the cortical mantle discriminates the functional behaviour of primary and association cortex
Authors: Leech Robert , Vos De Wael Reinder , Váša František , Xu Ting , Austin Benn R. , Scholz Robert , Braga Rodrigo M. , Milham Michael P. , Royer Jessica , Bernhardt Boris C. , Jones Emily J. H. , Jefferies Elizabeth , Margulies Daniel S. , Smallwood Jonathan
Published: September 2023

Recent theories of cortical organisation suggest features of function emerge from the spatial arrangement of brain regions. For example, association cortex is located furthest from systems involved in action and perception. Association cortex is also ‘interdigitated’ with adjacent regions having different patterns of functional connectivity. It is assumed that topographic properties, such as distance between regions, constrains their functions, however, we lack a formal description of how this occurs. Here we use variograms, a quantification of spatial autocorrelation, to profile how function changes with the distance between cortical regions. We find function changes with distance more gradually within sensory-motor cortex than association cortex. Importantly, systems within the same type of cortex (e.g., fronto-parietal and default mode networks) have similar profiles. Primary and association cortex, therefore, are differentiated by how function changes over space, emphasising the value of topographical features of a region when estimating its contribution to cognition and behaviour.
HMGB2 regulates the differentiation and stemness of exhausted CD8+ T cells during chronic viral infection and cancer
Authors: Neubert Emily N. , DeRogatis Julia M. , Lewis Sloan A. , Viramontes Karla M. , Ortega Pedro , Henriquez Monique L. , Buisson Rémi , Messaoudi Ilhem , Tinoco Roberto
Published: September 2023

Chronic infections and cancers evade the host immune system through mechanisms that induce T cell exhaustion. The heterogeneity within the exhausted CD8+ T cell pool has revealed the importance of stem-like progenitor (Tpex) and terminal (Tex) exhausted T cells, although the mechanisms underlying their development are not fully known. Here we report High Mobility Group Box 2 (HMGB2) protein expression is upregulated and sustained in exhausted CD8+ T cells, and HMGB2 expression is critical for their differentiation. Through epigenetic and transcriptional programming, we identify HMGB2 as a cell-intrinsic regulator of the differentiation and maintenance of Tpex cells during chronic viral infection and in tumors. Despite Hmgb2−/− CD8+ T cells expressing TCF-1 and TOX, these master regulators were unable to sustain Tpex differentiation and long-term survival during persistent antigen. Furthermore, HMGB2 also had a cell-intrinsic function in the differentiation and function of memory CD8+ T cells after acute viral infection. Our findings show that HMGB2 is a key regulator of CD8+ T cells and may be an important molecular target for future T cell-based immunotherapies.
Simultaneously ultrafast and robust two-dimensional flash memory devices based on phase-engineered edge contacts
Authors: Yu Jun , Wang Han , Zhuge Fuwei , Chen Zirui , Hu Man , Xu Xiang , He Yuhui , Ma Ying , Miao Xiangshui , Zhai Tianyou
Published: September 2023

As the prevailing non-volatile memory (NVM), flash memory offers mass data storage at high integration density and low cost. However, due to the ‘speed-retention-endurance’ dilemma, their typical speed is limited to ~microseconds to milliseconds for program and erase operations, restricting their application in scenarios with high-speed data throughput. Here, by adopting metallic 1T-LixMoS2 as edge contact, we show that ultrafast (10–100 ns) and robust (endurance>106 cycles, retention>10 years) memory operation can be simultaneously achieved in a two-dimensional van der Waals heterostructure flash memory with 2H-MoS2 as semiconductor channel. We attribute the superior performance to the gate tunable Schottky barrier at the edge contact, which can facilitate hot carrier injection to the semiconductor channel and subsequent tunneling when compared to a conventional top contact with high density of defects at the metal interface. Our results suggest that contact engineering can become a strategy to further improve the performance of 2D flash memory devices and meet the increasing demands of high speed and reliable data storage.
Dual hypoxia-responsive supramolecular complex for cancer target therapy
Authors: Guo Jian-Shuang , Li Juan-Juan , Wang Ze-Han , Liu Yang , Yue Yu-Xin , Li Hua-Bin , Zhao Xiu-He , Sun Yuan-Jun , Ding Ya-Hui , Ding Fei , Guo Dong-Sheng , Wang Liang , Chen Yue
Published: September 2023

The prognosis with pancreatic cancer is among the poorest of any human cancer. One of the important factors is the tumor hypoxia. Targeting tumor hypoxia is considered a desirable therapeutic option. However, it has not been translated into clinical success in the treatment of pancreatic cancer. With enhanced cytotoxicities against hypoxic pancreatic cancer cells, BE-43547A2 (BE) may serve as a promising template for hypoxia target strategy. Here, based on rational modification, a BE prodrug (NMP-BE) is encapsulated into sulfonated azocalix[5]arene (SAC5A) to generate a supramolecular dual hypoxia-responsive complex NMP-BE@SAC5A. Benefited from the selective load release within cancer cells, NMP-BE@SAC5A markedly suppresses tumor growth at low dose in pancreatic cancer cells xenograft murine model without developing systemic toxicity. This research presents a strategy for the modification of covalent compounds to achieve efficient delivery within tumors, a horizon for the realization of safe and reinforced hypoxia target therapy using a simple approach.
Arabidopsis TCP4 transcription factor inhibits high temperature-induced homeotic conversion of ovules
Authors: Lan Jingqiu , Wang Ning , Wang Yutao , Jiang Yidan , Yu Hao , Cao Xiaofeng , Qin Genji
Published: September 2023

Abnormal high temperature (HT) caused by global warming threatens plant survival and food security, but the effects of HT on plant organ identity are elusive. Here, we show that Class II TEOSINTE BRANCHED 1/CYCLOIDEA/ PCF (TCP) transcription factors redundantly protect ovule identity under HT. The duodecuple tcp2/3/4/5/10/13/17/24/1/12/18/16 (tcpDUO) mutant displays HT-induced ovule conversion into carpelloid structures. Expression of TCP4 in tcpDUO complements the ovule identity conversion. TCP4 interacts with AGAMOUS (AG), SEPALLATA3 (SEP3), and the homeodomain transcription factor BELL1 (BEL1) to strengthen the association of BEL1 with AG-SEP3. The tcpDUO mutant synergistically interacts with bel1 and the ovule identity gene seedstick (STK) mutant stk in tcpDUO bel1 and tcpDUO stk. Our findings reveal the critical roles of Class II TCPs in maintaining ovule identity under HT and shed light on the molecular mechanisms by which ovule identity is determined by the integration of internal factors and environmental temperature.
Synchronization in collectively moving inanimate and living active matter
Authors: Riedl Michael , Mayer Isabelle , Merrin Jack , Sixt Michael , Hof Björn
Published: September 2023

Whether one considers swarming insects, flocking birds, or bacterial colonies, collective motion arises from the coordination of individuals and entails the adjustment of their respective velocities. In particular, in close confinements, such as those encountered by dense cell populations during development or regeneration, collective migration can only arise coordinately. Yet, how individuals unify their velocities is often not understood. Focusing on a finite number of cells in circular confinements, we identify waves of polymerizing actin that function as a pacemaker governing the speed of individual cells. We show that the onset of collective motion coincides with the synchronization of the wave nucleation frequencies across the population. Employing a simpler and more readily accessible mechanical model system of active spheres, we identify the synchronization of the individuals’ internal oscillators as one of the essential requirements to reach the corresponding collective state. The mechanical ‘toy’ experiment illustrates that the global synchronous state is achieved by nearest neighbor coupling. We suggest by analogy that local coupling and the synchronization of actin waves are essential for the emergent, self-organized motion of cell collectives.
High performance mechano-optoelectronic molecular switch
Authors: Yang Zhenyu , Cazade Pierre-André , Lin Jin-Liang , Cao Zhou , Chen Ningyue , Zhang Dongdong , Duan Lian , Nijhuis Christian A. , Thompson Damien , Li Yuan
Published: September 2023

Highly-efficient molecular photoswitching occurs ex-situ but not to-date inside electronic devices due to quenching of excited states by background interactions. Here we achieve fully reversible in-situ mechano-optoelectronic switching in self-assembled monolayers (SAMs) of tetraphenylethylene molecules by bending their supporting electrodes to maximize aggregation-induced emission (AIE). We obtain stable, reversible switching across >1600 on/off cycles with large on/off ratio of (3.8 ± 0.1) × 103 and 140 ± 10 ms switching time which is 10-100× faster than other approaches. Multimodal characterization shows mechanically-controlled emission with UV-light enhancing the Coulomb interaction between the electrons and holes resulting in giant enhancement of molecular conductance. The best mechano-optoelectronic switching occurs in the most concave architecture that reduces ambient single-molecule conformational entropy creating artificially-tightened supramolecular assemblies. The performance can be further improved to achieve ultra-high switching ratio on the order of 105 using tetraphenylethylene derivatives with more AIE-active sites. Our results promise new applications from optimized interplay between mechanical force and optics in soft electronics.
Cell microparticles loaded with tumor antigen and resiquimod reprogram tumor-associated macrophages and promote stem-like CD8+ T cells to boost anti-PD-1 therapy
Authors: Zhang Xiaoqiong , Wei Zhaohan , Yong Tuying , Li Shiyu , Bie Nana , Li Jianye , Li Xin , Liu Haojie , Xu Hang , Yan Yuchen , Zhang Bixiang , Chen Xiaoping , Yang Xiangliang , Gan Lu
Published: September 2023

The durable response rate to immune checkpoint blockade such as anti-programmed cell death-1 (PD-1) antibody remains relatively low in hepatocellular carcinoma (HCC), mainly depending on an immunosuppressive microenvironment with limited number of CD8+ T cells, especially stem-like CD8+ T cells, in tumor tissues. Here we develop engineered microparticles (MPs) derived from alpha-fetoprotein (AFP)-overexpressing macrophages to load resiquimod (R848@M2pep-MPsAFP) for enhanced anti-PD-1 therapy in HCC. R848@M2pep-MPsAFP target and reprogram immunosuppressive M2-like tumor-associated macrophages (TAMs) into M1-like phenotype. Meanwhile, R848@M2pep-MPsAFP-reprogrammed TAMs act as antigen-presenting cells, not only presenting AFP antigen to activate CD8+ T cell-mediated antitumor immunity, but also providing an intra-tumoral niche to maintain and differentiate stem-like CD8+ T cells. Combination immunotherapy with anti-PD-1 antibody generates strong antitumor immune memory and induces abundant stem-like CD8+ T cell proliferation and differentiation to terminally exhausted CD8+ T cells for long-term immune surveillance in orthotopic and autochthonous HCC preclinical models in male mice. We also show that the R848-loaded engineered MPs derived from macrophages overexpressing a model antigen ovalbumin (OVA) can improve anti-PD-1 therapy in melanoma B16-OVA tumor-bearing mice. Our work presents a facile and generic strategy for personalized cancer immunotherapy to boost anti-PD-1 therapy.
High-throughput screening of BAM inhibitors in native membrane environment
Authors: Rath Parthasarathi , Hermann Adrian , Schaefer Ramona , Agustoni Elia , Vonach Jean-Marie , Siegrist Martin , Miscenic Christian , Tschumi Andreas , Roth Doris , Bieniossek Christoph , Hiller Sebastian
Published: September 2023

The outer membrane insertase of Gram-negative bacteria, BAM, is a key target for urgently needed novel antibiotics. Functional reconstitutions of BAM have so far been limited to synthetic membranes and with low throughput capacity for inhibitor screening. Here, we describe a BAM functional assay in native membrane environment capable of high-throughput screening. This is achieved by employing outer membrane vesicles (OMVs) to present BAM directly in native membranes. Refolding of the model substrate OmpT by BAM was possible from the chaperones SurA and Skp, with the required SurA concentration three times higher than Skp. In the OMVs, the antibiotic darobactin had a tenfold higher potency than in synthetic membranes, highlighting the need for native conditions in antibiotics development. The assay is successfully miniaturized for 1536-well plates and upscaled using large scale fermentation, resulting in high-throughput capacities to screen large commercial compound libraries. Our OMV-based assay thus lays the basis for discovery, hit validation and lead expansion of antibiotics targeting BAM.
The tectonic complex regulates membrane protein composition in the photoreceptor cilium
Authors: Truong Hanh M. , Cruz-Colón Kevin O. , Martínez-Márquez Jorge Y. , Willer Jason R. , Travis Amanda M. , Biswas Sondip K. , Lo Woo-Kuen , Bolz Hanno J. , Pearring Jillian N.
Published: September 2023

The primary cilium is a signaling organelle with a unique membrane composition maintained by a diffusional barrier residing at the transition zone. Many transition zone proteins, such as the tectonic complex, are linked to preserving ciliary composition but the mechanism remains unknown. To understand tectonic’s role, we generate a photoreceptor-specific Tctn1 knockout mouse. Loss of Tctn1 results in the absence of the entire tectonic complex and associated MKS proteins yet has minimal effects on the transition zone structure of rod photoreceptors. We find that the protein composition of the photoreceptor cilium is disrupted as non-resident membrane proteins accumulate in the cilium over time, ultimately resulting in photoreceptor degeneration. We further show that fluorescent rhodopsin moves faster through the transition zone in photoreceptors lacking tectonic, which suggests that the tectonic complex acts as a physical barrier to slow down membrane protein diffusion in the photoreceptor transition zone to ensure proper removal of non-resident membrane proteins.
Hyperactive learning for data-driven interatomic potentials
Authors: van der Oord Cas , Sachs Matthias , Kovács Dávid Péter , Ortner Christoph , Csányi Gábor
Published: September 2023

Data-driven interatomic potentials have emerged as a powerful tool for approximating ab initio potential energy surfaces. The most time-consuming step in creating these interatomic potentials is typically the generation of a suitable training database. To aid this process hyperactive learning (HAL), an accelerated active learning scheme, is presented as a method for rapid automated training database assembly. HAL adds a biasing term to a physically motivated sampler (e.g. molecular dynamics) driving atomic structures towards uncertainty in turn generating unseen or valuable training configurations. The proposed HAL framework is used to develop atomic cluster expansion (ACE) interatomic potentials for the AlSi10 alloy and polyethylene glycol (PEG) polymer starting from roughly a dozen initial configurations. The HAL generated ACE potentials are shown to be able to determine macroscopic properties, such as melting temperature and density, with close to experimental accuracy.
Bacterial pathogens deliver water- and solute-permeable channels to plant cells
Authors: Nomura Kinya , Andreazza Felipe , Cheng Jie , Dong Ke , Zhou Pei , He Sheng Yang
Published: September 2023

Many animal- and plant-pathogenic bacteria use a type III secretion system to deliver effector proteins into host cells1,2. Elucidation of how these effector proteins function in host cells is critical for understanding infectious diseases in animals and plants3–5. The widely conserved AvrE-family effectors, including DspE in Erwinia amylovora and AvrE in Pseudomonas syringae, have a central role in the pathogenesis of diverse phytopathogenic bacteria6. These conserved effectors are involved in the induction of ‘water soaking’ and host cell death that are conducive to bacterial multiplication in infected tissues. However, the exact biochemical functions of AvrE-family effectors have been recalcitrant to mechanistic understanding for three decades. Here we show that AvrE-family effectors fold into a β-barrel structure that resembles bacterial porins. Expression of AvrE and DspE in Xenopus oocytes results in inward and outward currents, permeability to water and osmolarity-dependent oocyte swelling and bursting. Liposome reconstitution confirmed that the DspE channel alone is sufficient to allow the passage of small molecules such as fluorescein dye. Targeted screening of chemical blockers based on the predicted pore size (15–20 Å) of the DspE channel identified polyamidoamine dendrimers as inhibitors of the DspE/AvrE channels. Notably, polyamidoamines broadly inhibit AvrE and DspE virulence activities in Xenopus oocytes and during E. amylovora and P. syringae infections. Thus, we have unravelled the biochemical function of a centrally important family of bacterial effectors with broad conceptual and practical implications in the study of bacterial pathogenesis.
A framework for FAIR robotic datasets
Authors: Motta Corrado , Aracri Simona , Ferretti Roberta , Bibuli Marco , Bruzzone Gabriele , Caccia Massimo , Odetti Angelo , Ferreira Fausto , de Pascalis Francesca
Published: September 2023

It is essential to publish and make available environmental data gathered by emerging robotic platforms to contribute to the Global Ocean Observing System (GOOS), supported by the United Nations - Decade of Ocean Science for Sustainable Development (2021–2030). The transparency of these unique observational datasets needs to be supported by the corresponding robotic records. The data describing the observational platform behaviour and its performance are necessary to validate the environmental data and repeat consistently the in-situ robotic deployment. The Free and Open Source Software (FOSS), proposed in this manuscript, describes how, using the established approach in Earth Sciences, the data characterising marine robotic missions can be formatted and shared following the FAIR (Findable, Accessible, Interoperable, Reusable) principles. The manuscript is a step-by-step guide to render marine robotic telemetry FAIR and publishable. State-of-the-art protocols for metadata and data formatting are proposed, applied and integrated automatically using Jupyter Notebooks to maximise visibility and ease of use. The method outlined here aims to be a first fundamental step towards FAIR interdisciplinary observational science.
Viral-like TLR3 induction of cytokine networks and α-synuclein are reduced by complement C3 blockade in mouse brain
Authors: Thomas Ria , Connolly Kyle J. , Brekk Oeystein R. , Hinrich Anthony J. , Hastings Michelle L. , Isacson Ole , Hallett Penelope J.
Published: September 2023

Inflammatory processes and mechanisms are of central importance in neurodegenerative diseases. In the brain, α-synucleinopathies such as Parkinson’s disease (PD) and Lewy body dementia (LBD) show immune cytokine network activation and increased toll like receptor 3 (TLR3) levels for viral double-stranded RNA (dsRNA). Brain inflammatory reactions caused by TLR3 activation are also relevant to understand pathogenic cascades by viral SARS-CoV-2 infection causing post- COVID-19 brain-related syndromes. In the current study, following regional brain TLR3 activation induced by dsRNA in mice, an acute complement C3 response was seen at 2 days. A C3 splice-switching antisense oligonucleotide (ASO) that promotes the splicing of a non-productive C3 mRNA, prevented downstream cytokines, such as IL-6, and α-synuclein changes. This report is the first demonstration that α-synuclein increases occur downstream of complement C3 activation. Relevant to brain dysfunction, post-COVID-19 syndromes and pathological changes leading to PD and LBD, viral dsRNA TLR3 activation in the presence of C3 complement blockade further revealed significant interactions between complement systems, inflammatory cytokine networks and α-synuclein changes.
Antimicrobial and anticarcinogenic activity of bioactive peptides derived from abalone viscera (Haliotis fulgens and Haliotis corrugata)
Authors: Rivera-Pérez Crisalejandra , Ponce González Xolotl Paloma , Hernández-Savedra Norma Yolanda
Published: September 2023

Bioactive peptides have been studied in several sources due to their valuable potential in the pharmaceutical and food industries. Abalone viscera, which are normally discarded as byproducts, are a rich source of protein. Thus, the aim of this study was to explore the potential bioactivity of peptides derived from abalone viscera (Haliotis fulgens and Haliotis corrugata) after hydrolysis with a commercial mixture of enzymes. The hydrolysates obtained were fractionated using gel filtration chromatography. The resulting hydrolysate fractions were investigated for their antimicrobial and cytotoxic activities, including the expression of gelatinases mmp-2 and mmp-9 in human prostate cancer cell lines (PC3). Results showed antimicrobial activity for protein fractions of H. corrugata against Proteus mirabilis and Pseudomona aeuroginosa (66.2–116.25 kDa), Bacillus subtilis (6.5–21.5 kDa), and Aspergillus niger (97.4–116.25 kDa), while H. fulgens peptide fractions (200–31 kDa) displayed activity against six bacterial strains, and fractions from 116.25 to 21.5 kDa had effects on the fungus A. niger, Alternaria alternata, and Aspergillus flavus. Additionally, protein fractions displayed cytotoxic activity, inhibiting 30.4–53.8% of PC3 cellular growth. Selected fractions decreased the PMA-induced and not-induced expressions of mmp-2 and mmp-9 in PC3 cells. Abalone viscera, as byproducts, can be used as a potential source of antimicrobial and anticancer peptides.
Soil water dynamics and biomass production of young rooibos (Aspalathus linearis) plants
Authors: van Schalkwyk Roeline , Hoffman J. Eduard , Hardie Ailsa G. , van Zyl Johan L.
Published: September 2023

Rooibos (Aspalathus linearis) is endemic to certain regions of the Western- and Northern Cape of South Africa, where it is also commercially grown. Being low-rainfall regions, information on the soil water balance of rooibos is essential, but such data is limited. Consequently, the effect of inorganic fertilisation and soil depth on soil water dynamics in a young rooibos plantation at Nardouwsberg, Western Cape were studied. Soil water content of plots planted to unfertilised and fertilised plants as well as that of bare soil were determined over the duration of the 2016/17 season. All treatments were replicated on shallow and deep soils sites and plant growth was determined at the end of the season. At the end of the study, the profile soil water content and evapotranspiration of the bare and planted plots were similar which prove that fallowing (water harvesting) is not an option in the sandy soils of this region. With the exception of the 20−30 cm root zone of the planted plots at the deep site, the water content decreased to levels below the permanent wilting point in the soil profile during summer. It was concluded that rooibos plants could survive through an adapted root system. A further survival method was proposed, involving moisture moved through evaporation from the deeper soil layers into the drying-front in the ~ 10−30 cm soil layer where a condensation-evaporation cycle enables rooibos to harvest small amounts of water. The highest shoot biomass with the longest taproot resulted from the unfertilised treatment on the deep soil thanks to higher soil water content, whereas the shoot and root biomass of the fertilised treatment at both sites were low due to high P soil concentration. This study revealed that unfertilised plants on deeper soils result in higher rooibos production under drought conditions.