bluuebunny/crossref_metadata_2025 huggingface dataset:
Neurophysiological evidence that frontoparietal connectivity and GABA-A receptor changes underpin the antidepressant response to ketamine
Authors: Sumner Rachael L. , McMillan Rebecca L. , Forsyth Anna , Muthukumaraswamy Suresh D. , Shaw Alexander D.
Published: February 2024

Revealing the acute cortical pharmacodynamics of an antidepressant dose of ketamine in humans with depression is key to determining the specific mechanism(s) of action for alleviating symptoms. While the downstream effects are characterised by increases in plasticity and reductions in depressive symptoms—it is the acute response in the brain that triggers this cascade of events. Computational modelling of cortical interlaminar and cortico-cortical connectivity and receptor dynamics provide the opportunity to interrogate this question using human electroencephalography (EEG) data recorded during a ketamine infusion. Here, resting-state EEG was recorded in a group of 30 patients with major depressive disorder (MDD) at baseline and during a 0.44 mg/kg ketamine dose comprising a bolus and infusion. Fronto-parietal connectivity was assessed using dynamic causal modelling to fit a thalamocortical model to hierarchically connected nodes in the medial prefrontal cortex and superior parietal lobule. We found a significant increase in parietal-to-frontal AMPA-mediated connectivity and a significant decrease in the frontal GABA time constant. Both parameter changes were correlated across participants with the antidepressant response to ketamine. Changes to the NMDA receptor time constant and inhibitory intraneuronal input into superficial pyramidal cells did not survive correction for multiple comparisons and were not correlated with the antidepressant response. These results provide evidence that the antidepressant effects of ketamine may be mediated by acute fronto-parietal connectivity and GABA receptor dynamics. Furthermore, it supports the large body of literature suggesting the acute mechanism underlying ketamine’s antidepressant properties is related to GABA-A and AMPA receptors rather than NMDA receptor antagonism.
Extracellular matrix abnormalities in the hippocampus of subjects with substance use disorder
Authors: Valeri Jake , Stiplosek Charlotte , O’Donovan Sinead M. , Sinclair David , Grant Kathleen A. , Bollavarapu Ratna , Platt Donna M. , Stockmeier Craig A. , Gisabella Barbara , Pantazopoulos Harry
Published: February 2024

Contextual triggers are significant factors contributing to relapse in substance use disorders (SUD). Emerging evidence points to a critical role of extracellular matrix (ECM) molecules as mediators of reward memories. Chondroitin sulfate proteoglycans (CSPGs) are a subset of ECM molecules that form perineuronal nets (PNN) around inhibitory neurons. PNNs restrict synaptic connections and help maintain synapses. Rodent models suggest that modulation of PNNs may strengthen contextual reward memories in SUD. However, there is currently a lack of information regarding PNNs in the hippocampus of people with SUD as well as how comorbidity with major depressive disorder (MDD) may affect PNNs. We used postmortem hippocampal tissues from cohorts of human and nonhuman primates with or without chronic alcohol use to test the hypothesis that PNNs are increased in subjects with SUD. We used histochemical labeling and quantitative microscopy to examine PNNs, and qRT-PCR to examine gene expression for ECM molecules, synaptic markers and related markers. We identified increased densities of PNNs and CSPG-labeled glial cells in SUD, coinciding with decreased expression of the ECM protease matrix metalloproteinase 9 (Mmp9), and increased expression for the excitatory synaptic marker vesicle associated membrane protein 2 (Vamp2). Similar increases in PNNs were observed in monkeys with chronic alcohol self-administration. Subjects with MDD displayed changes opposite to SUD, and subjects with SUD and comorbid MDD had minimal changes in any of the outcome measures examined. Our findings demonstrate that PNNs are increased in SUD, possibly contributing to stabilizing contextual reward memories as suggested by preclinical studies. Our results also point to a previously unsuspected role for CSPG expression in glial cells in SUD. Evidence for increased hippocampal PNNs in SUD suggests that targeting PNNs to weaken contextual reward memories is a promising therapeutic approach for SUD, however comorbidity with MDD is a significant consideration.
Fluoropyrimidine type, patient age, tumour sidedness and mutation status as determinants of benefit in patients with metastatic colorectal cancer treated with EGFR monoclonal antibodies: individual patient data pooled analysis of randomised trials from the ARCAD database
Authors: Karapetis C. S. , Liu H. , Sorich M. J. , Pederson L. D. , Van Cutsem E. , Maughan T. , Douillard J. Y. , O’Callaghan C. J. , Jonker D. , Bokemeyer C. , Sobrero A. , Cremolini C. , Chibaudel B. , Zalcberg J. , Adams R. , Buyse M. , Peeters M. , Yoshino T. , de Gramont A. , Shi Q.
Published: February 2024

Background

KRAS mutations in metastatic colorectal cancer (mCRC) are used as predictive biomarkers to select therapy with EGFR monoclonal antibodies (mAbs). Other factors may be significant determinants of benefit.

Methods

Individual patient data from randomised trials with a head-to-head comparison between EGFR mAb versus no EGFR mAb (chemotherapy alone or best supportive care) in mCRC, across all lines of therapy, were pooled. Overall survival (OS) and progression-free survival (PFS) were compared between groups. Treatment effects within the predefined KRAS biomarker subsets were estimated by adjusted hazard ratio (HRadj) and 95% confidence interval (CI). EGFR mAb efficacy was measured within the KRAS wild-type subgroup according to BRAF and NRAS mutation status. In both KRAS wild-type and mutant subgroups, additional factors that could impact EGFR mAb efficacy were explored including the type of chemotherapy, line of therapy, age, sex, tumour sidedness and site of metastasis.

Results

5675 patients from 8 studies were included, all with known mCRC KRAS mutation status. OS (HRadj 0.90, 95% CI 0.84–0.98, p = 0.01) and PFS benefit (HRadj 0.73, 95% CI 0.68–0.79, p < 0.001) from EGFR mAbs was observed in the KRAS wild-type group. PFS benefit was seen in patients treated with fluorouracil (HRadj 0.75, 95% CI 0.68–0.82) but not with capecitabine-containing regimens (HRadj 1.04, 95% CI 0.86–1.26) (pinteraction = 0.002). Sidedness also interacted with EGFR mAb efficacy, with survival benefit restricted to left-sided disease (pinteraction = 0.038). PFS benefits differed according to age, with benefits greater in those under 70 (pinteraction = 0.001). The survival benefit was not demonstrated in those patients with mutations found in the KRAS, NRAS or BRAF genes. The presence of liver metastases interacted with EGFR mAb efficacy in patients with KRAS mutant mCRC (pinteraction = 0.004).

Conclusion

The benefit provided by EGFR mAbs in KRAS WT mCRC is associated with left-sided primary tumour location, younger patient age and absence of NRAS or BRAF mutations. Survival benefit is observed with fluorouracil but not capecitabine. Exploratory results support further research in KRAS mutant mCRC without liver metastases.
PRMT1-mediated PGK1 arginine methylation promotes colorectal cancer glycolysis and tumorigenesis
Authors: Liu Hao , Chen Xintian , Wang Pengfei , Chen Miaolei , Deng Chuyin , Qian Xingyou , Bai Jin , Li Zhongwei , Yu Xiangyang
Published: February 2024

Many types of cancer cells, including colorectal cancer cells (CRC), can simultaneously enhance glycolysis and repress the mitochondrial tricarboxylic acid (TCA) cycle, which is called the Warburg effect. However, the detailed mechanisms of abnormal activation of the glycolysis pathway in colorectal cancer are largely unknown. In this study, we reveal that the protein arginine methyltransferase 1 (PRMT1) promotes glycolysis, proliferation, and tumorigenesis in CRC cells. Mechanistically, PRMT1-mediated arginine asymmetric dimethylation modification of phosphoglycerate kinase 1 (PGK1, the first ATP-producing enzyme in glycolysis) at R206 (meR206-PGK1) enhances the phosphorylation level of PGK1 at S203 (pS203-PGK1), which inhibits mitochondrial function and promotes glycolysis. We found that PRMT1 and meR206-PGK1 expression were positively correlated with pS203-PGK1 expression in tissues from colorectal cancer patients. Furthermore, we also confirmed that meR206-PGK1 expression is positively correlated with the poor survival of patients with colorectal cancer. Our findings show that PRMT1 and meR206-PGK1 may become promising predictive biomarkers for the prognosis of patients with CRC and that arginine methyltransferase inhibitors have great potential in colorectal cancer treatment.
DNA polymerase iota promotes EMT and metastasis of esophageal squamous cell carcinoma by interacting with USP7 to stabilize HIF-1α
Authors: Gao Aidi , Zhang Mingxia , Zhu Shuang qi , Zou Shitao , Chen Hengrui , Li Xiaoqin , He Chao , Zhou Liangsu , Mei Yan , Ding Weiqun , Zhou Jundong , Zhou Yue , Cao Yuandong
Published: February 2024

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal cancer types, with a low 5-year survival rate of ~20%. Our prior research has suggested that DNA Polymerase iota (Pol ι), a member of Y-family DNA polymerase, plays a crucial role in the invasion and metastasis of ESCC. However, the underlying mechanism is not well understood. In this study, we utilized ChIP-PCR and luciferase reporter assays to investigate the binding of HIF-1α to the promoter of the Pol ι gene. Transwell, wound healing, and mouse models were employed to assess the impact of Pol ι and HIF-1α on the motility of ESCC cells. Co-immunoprecipitation and Western blot were carried out to explore the interaction between Pol ι and HIF-1α, while qRT-PCR and Western blot were conducted to confirm the regulation of Pol ι and HIF-1α on their downstream targets. Our results demonstrate that HIF-1α activates the transcription of the Pol ι gene in ESCC cells under hypoxic conditions. Furthermore, the knockdown of Pol ι impeded HIF-1α-induced invasion and metastasis. Additionally, we found that Pol ι regulates the expression of genes involved in epithelial-mesenchymal transition (EMT) and initiates EMT through the stabilization of HIF-1α. Mechanistically, Pol ι maintains the protein stability of HIF-1α by recruiting USP7 to mediate the deubiquitination of HIF-1α, with the residues 446–578 of Pol being crucial for the interaction between Pol ι and USP7. Collectively, our findings unveil a novel feedforward molecular axis of HIF-1α- Pol ι -USP7 in ESCC that contributes to ESCC metastasis. Hence, our results present an attractive target for intervention in ESCC.
The interplay of mitophagy, autophagy, and apoptosis in cisplatin-induced kidney injury: involvement of ERK signaling pathway
Authors: Suman Iva , Šimić Lidija , Čanadi Jurešić Gordana , Buljević Sunčica , Klepac Damir , Domitrović Robert
Published: February 2024

AKI induced by CP chemotherapy remains an obstacle during patient treatments. Extracellular signal-regulated protein kinases 1/2 (ERK), key participants in CP-induced nephrotoxicity, are suggested to be involved in the regulation of mitophagy, autophagy, and apoptosis. Human renal proximal tubular cells (HK-2) and BALB/cN mice were used to determine the role of ERK in CP-induced AKI. We found that active ERK is involved in cell viability reduction during apoptotic events but exerts a protective role in the early stages of treatment. Activation of ERK acts as a maintainer of the mitochondrial population and is implicated in mitophagy initiation but has no significant role in its conduction. In the late stages of CP treatment when ATP is deprived, general autophagy that requires ERK activation is initiated as a response, in addition to apoptosis activation. Furthermore, activation of ERK is responsible for the decrease in reserve respiratory capacity and controls glycolysis regulation during CP treatment. Additionally, we found that ERK activation is also required for the induction of NOXA gene and protein expression as well as FoxO3a nuclear translocation, but not for the regular ERK-induced phosphorylation of FoxO3a on Ser294. In summary, this study gives detailed insight into the involvement of ERK activation and its impact on key cellular processes at different time points during CP-induced kidney injury. Inhibitors of ERK activation, including Mirdametinib, are important in the development of new therapeutic strategies for the treatment of AKI in patients receiving CP chemotherapy.
Fusobacterium nucleatum promotes tumor progression in KRAS p.G12D-mutant colorectal cancer by binding to DHX15
Authors: Zhu Huiyuan , Li Man , Bi Dexi , Yang Huiqiong , Gao Yaohui , Song Feifei , Zheng Jiayi , Xie Ruting , Zhang Youhua , Liu Hu , Yan Xuebing , Kong Cheng , Zhu Yefei , Xu Qian , Wei Qing , Qin Huanlong
Published: February 2024

Fusobacterium nucleatum (F. nucleatum) promotes intestinal tumor growth and its relative abundance varies greatly among patients with CRC, suggesting the presence of unknown, individual-specific effectors in F. nucleatum-dependent carcinogenesis. Here, we identify that F. nucleatum is enriched preferentially in KRAS p.G12D mutant CRC tumor tissues and contributes to colorectal tumorigenesis in Villin-Cre/KrasG12D+/- mice. Additionally, Parabacteroides distasonis (P. distasonis) competes with F. nucleatum in the G12D mouse model and human CRC tissues with the KRAS mutation. Orally gavaged P. distasonis in mice alleviates the F. nucleatum-dependent CRC progression. F. nucleatum invades intestinal epithelial cells and binds to DHX15, a protein of RNA helicase family expressed on CRC tumor cells, mechanistically involving ERK/STAT3 signaling. Knock out of Dhx15 in Villin-Cre/KrasG12D+/- mice attenuates the CRC phenotype. These findings reveal that the oncogenic effect of F. nucleatum depends on somatic genetics and gut microbial ecology and indicate that personalized modulation of the gut microbiota may provide a more targeted strategy for CRC treatment.
Intrinsic factors responsible for brittle versus ductile nature of refractory high-entropy alloys
Authors: Tsuru Tomohito , Han Shu , Matsuura Shutaro , Chen Zhenghao , Kishida Kyosuke , Iobzenko Ivan , Rao Satish I. , Woodward Christopher , George Easo P. , Inui Haruyuki
Published: February 2024

Refractory high-entropy alloys (RHEAs) are of interest for ultrahigh-temperature applications. To overcome their drawbacks — low-temperature brittleness and poor creep strength at high temperatures — improved fundamental understanding is needed. Using experiments, theory, and modeling, we investigated prototypical body-centered cubic (BCC) RHEAs, TiZrHfNbTa and VNbMoTaW. The former is compressible to 77 K, whereas the latter is not below 298 K. Hexagonal close-packed (HCP) elements in TiZrHfNbTa lower its dislocation core energy, increase lattice distortion, and lower its shear modulus relative to VNbMoTaW whose elements are all BCC. Screw dislocations dominate TiZrHfNbTa plasticity, but equal numbers of edges and screws exist in VNbTaMoW. Dislocation cores are compact in VNbTaMoW and extended in TiZrHfNbTa, and different macroscopic slip planes are activated in the two RHEAs, which we attribute to the concentration of HCP elements. Our findings demonstrate how ductility and strength can be controlled through the ratio of HCP to BCC elements in RHEAs.
Prior flavivirus immunity skews the yellow fever vaccine response to cross-reactive antibodies with potential to enhance dengue virus infection
Authors: Santos-Peral Antonio , Luppa Fabian , Goresch Sebastian , Nikolova Elena , Zaucha Magdalena , Lehmann Lisa , Dahlstroem Frank , Karimzadeh Hadi , Thorn-Seshold Julia , Winheim Elena , Schuster Ev-Marie , Dobler Gerhard , Hoelscher Michael , Kümmerer Beate M. , Endres Stefan , Schober Kilian , Krug Anne B. , Pritsch Michael , Barba-Spaeth Giovanna , Rothenfusser Simon
Published: February 2024

The yellow fever 17D vaccine (YF17D) is highly effective but is frequently administered to individuals with pre-existing cross-reactive immunity, potentially impacting their immune responses. Here, we investigate the impact of pre-existing flavivirus immunity induced by the tick-borne encephalitis virus (TBEV) vaccine on the response to YF17D vaccination in 250 individuals up to 28 days post-vaccination (pv) and 22 individuals sampled one-year pv. Our findings indicate that previous TBEV vaccination does not affect the early IgM-driven neutralizing response to YF17D. However, pre-vaccination sera enhance YF17D virus infection in vitro via antibody-dependent enhancement (ADE). Following YF17D vaccination, TBEV-pre-vaccinated individuals develop high amounts of cross-reactive IgG antibodies with poor neutralizing capacity. In contrast, TBEV-unvaccinated individuals elicit a non-cross-reacting neutralizing response. Using YF17D envelope protein mutants displaying different epitopes, we identify quaternary dimeric epitopes as the primary target of neutralizing antibodies. Additionally, TBEV-pre-vaccination skews the IgG response towards the pan-flavivirus fusion loop epitope (FLE), capable of mediating ADE of dengue and Zika virus infections in vitro. Together, we propose that YF17D vaccination conceals the FLE in individuals without prior flavivirus exposure but favors a cross-reactive IgG response in TBEV-pre-vaccinated recipients directed to the FLE with potential to enhance dengue virus infection.
How to steer active colloids up a vertical wall
Authors: Fins Carreira Adérito , Wysocki Adam , Ybert Christophe , Leocmach Mathieu , Rieger Heiko , Cottin-Bizonne Cécile
Published: February 2024

An important challenge in active matter lies in harnessing useful global work from entities that produce work locally, e.g., via self-propulsion. We investigate here the active matter version of a classical capillary rise effect, by considering a non-phase separated sediment of self-propelled Janus colloids in contact with a vertical wall. We provide experimental evidence of an unexpected and dynamic adsorption layer at the wall. Additionally, we develop a complementary numerical model that recapitulates the experimental observations. We show that an adhesive and aligning wall enhances the pre-existing polarity heterogeneity within the bulk, enabling polar active particles to climb up a wall against gravity, effectively powering a global flux. Such steady-state flux has no equivalent in a passive wetting layer.
Implications of the three-dimensional chromatin organization for genome evolution in a fungal plant pathogen
Authors: Torres David E. , Kramer H. Martin , Tracanna Vittorio , Fiorin Gabriel L. , Cook David E. , Seidl Michael F. , Thomma Bart P. H. J.
Published: February 2024

The spatial organization of eukaryotic genomes is linked to their biological functions, although it is not clear how this impacts the overall evolution of a genome. Here, we uncover the three-dimensional (3D) genome organization of the phytopathogen Verticillium dahliae, known to possess distinct genomic regions, designated adaptive genomic regions (AGRs), enriched in transposable elements and genes that mediate host infection. Short-range DNA interactions form clear topologically associating domains (TADs) with gene-rich boundaries that show reduced levels of gene expression and reduced genomic variation. Intriguingly, TADs are less clearly insulated in AGRs than in the core genome. At a global scale, the genome contains bipartite long-range interactions, particularly enriched for AGRs and more generally containing segmental duplications. Notably, the patterns observed for V. dahliae are also present in other Verticillium species. Thus, our analysis links 3D genome organization to evolutionary features conserved throughout the Verticillium genus.
KDM3B inhibitors disrupt the oncogenic activity of PAX3-FOXO1 in fusion-positive rhabdomyosarcoma
Authors: Kim Yong Yean , Gryder Berkley E. , Sinniah Ranuka , Peach Megan L. , Shern Jack F. , Abdelmaksoud Abdalla , Pomella Silvia , Woldemichael Girma M. , Stanton Benjamin Z. , Milewski David , Barchi Joseph J. , Schneekloth John S. , Chari Raj , Kowalczyk Joshua T. , Shenoy Shilpa R. , Evans Jason R. , Song Young K. , Wang Chaoyu , Wen Xinyu , Chou Hsien-Chao , Gangalapudi Vineela , Esposito Dominic , Jones Jane , Procter Lauren , O’Neill Maura , Jenkins Lisa M. , Tarasova Nadya I. , Wei Jun S. , McMahon James B. , O’Keefe Barry R. , Hawley Robert G. , Khan Javed
Published: February 2024

Fusion-positive rhabdomyosarcoma (FP-RMS) is an aggressive pediatric sarcoma driven primarily by the PAX3-FOXO1 fusion oncogene, for which therapies targeting PAX3-FOXO1 are lacking. Here, we screen 62,643 compounds using an engineered cell line that monitors PAX3-FOXO1 transcriptional activity identifying a hitherto uncharacterized compound, P3FI-63. RNA-seq, ATAC-seq, and docking analyses implicate histone lysine demethylases (KDMs) as its targets. Enzymatic assays confirm the inhibition of multiple KDMs with the highest selectivity for KDM3B. Structural similarity search of P3FI-63 identifies P3FI-90 with improved solubility and potency. Biophysical binding of P3FI-90 to KDM3B is demonstrated using NMR and SPR. P3FI-90 suppresses the growth of FP-RMS in vitro and in vivo through downregulating PAX3-FOXO1 activity, and combined knockdown of KDM3B and KDM1A phenocopies P3FI-90 effects. Thus, we report KDM inhibitors P3FI-63 and P3FI-90 with the highest specificity for KDM3B. Their potent suppression of PAX3-FOXO1 activity indicates a possible therapeutic approach for FP-RMS and other transcriptionally addicted cancers.
Elasticity-controlled jamming criticality in soft composite solids
Authors: Zhao Yiqiu , Hu Haitao , Huang Yulu , Liu Hanqing , Yan Caishan , Xu Chang , Zhang Rui , Wang Yifan , Xu Qin
Published: February 2024

Soft composite solids are made of inclusions dispersed within soft matrices. They are ubiquitous in nature and form the basis of many biological tissues. In the field of materials science, synthetic soft composites are promising candidates for building various engineering devices due to their highly programmable features. However, when the volume fraction of the inclusions increases, predicting the mechanical properties of these materials poses a significant challenge for the classical theories of composite mechanics. The difficulty arises from the inherently disordered, multi-scale interactions between the inclusions and the matrix. To address this challenge, we systematically investigated the mechanics of densely filled soft elastomers containing stiff microspheres. We experimentally demonstrate how the strain-stiffening response of the soft composites is governed by the critical scalings in the vicinity of a shear-jamming transition of the included particles. The proposed criticality framework quantitatively connects the overall mechanics of a soft composite with the elasticity of the matrix and the particles, and captures the diverse mechanical responses observed across a wide range of material parameters. The findings uncover a novel design paradigm of composite mechanics that relies on engineering the jamming properties of the embedded inclusions.
Single-molecule RNA sizing enables quantitative analysis of alternative transcription termination
Authors: Patiño-Guillén Gerardo , Pešović Jovan , Panić Marko , Savić-Pavićević Dušanka , Bošković Filip , Keyser Ulrich Felix
Published: February 2024

Transcription, a critical process in molecular biology, has found many applications in RNA synthesis, including mRNA vaccines and RNA therapeutics. However, current RNA characterization technologies suffer from amplification and enzymatic biases that lead to loss of native information. Here, we introduce a strategy to quantitatively study both transcription and RNA polymerase behaviour by sizing RNA with RNA nanotechnology and nanopores. To begin, we utilize T7 RNA polymerase to transcribe linear DNA lacking termination sequences. Surprisingly, we discover alternative transcription termination in the origin of replication sequence. Next, we employ circular DNA without transcription terminators to perform rolling circle transcription. This allows us to gain valuable insights into the processivity and transcription behaviour of RNA polymerase at the single-molecule level. Our work demonstrates how RNA nanotechnology and nanopores may be used in tandem for the direct and quantitative analysis of RNA transcripts. This methodology provides a promising pathway for accurate RNA structural mapping by enabling the study of full-length RNA transcripts at the single-molecule level.
Phage-assisted evolution of highly active cytosine base editors with enhanced selectivity and minimal sequence context preference
Authors: Zhang Emily , Neugebauer Monica E. , Krasnow Nicholas A. , Liu David R.
Published: February 2024

TadA-derived cytosine base editors (TadCBEs) enable programmable C•G-to-T•A editing while retaining the small size, high on-target activity, and low off-target activity of TadA deaminases. Existing TadCBEs, however, exhibit residual A•T-to-G•C editing at certain positions and lower editing efficiencies at some sequence contexts and with non-SpCas9 targeting domains. To address these limitations, we use phage-assisted evolution to evolve CBE6s from a TadA-mediated dual cytosine and adenine base editor, discovering mutations at N46 and Y73 in TadA that prevent A•T-to-G•C editing and improve C•G-to-T•A editing with expanded sequence-context compatibility, respectively. In E. coli, CBE6 variants offer high C•G-to-T•A editing and no detected A•T-to-G•C editing in any sequence context. In human cells, CBE6 variants exhibit broad Cas domain compatibility and retain low off-target editing despite exceeding BE4max and previous TadCBEs in on-target editing efficiency. Finally, we show that the high selectivity of CBE6 variants is well-suited for therapeutically relevant stop codon installation without creating unwanted missense mutations from residual A•T-to-G•C editing.
Direct contribution of the sensory cortex to the judgment of stimulus duration
Authors: Reinartz Sebastian , Fassihi Arash , Ravera Maria , Paz Luciano , Pulecchi Francesca , Gigante Marco , Diamond Mathew E.
Published: February 2024

Decision making frequently depends on monitoring the duration of sensory events. To determine whether, and how, the perception of elapsed time derives from the neuronal representation of the stimulus itself, we recorded and optogenetically modulated vibrissal somatosensory cortical activity as male rats judged vibration duration. Perceived duration was dilated by optogenetic excitation. A second set of rats judged vibration intensity; here, optogenetic excitation amplified the intensity percept, demonstrating sensory cortex to be the common gateway both to time and to stimulus feature processing. A model beginning with the membrane currents evoked by vibrissal and optogenetic drive and culminating in the representation of perceived time successfully replicated rats’ choices. Time perception is thus as deeply intermeshed within the sensory processing pathway as is the sense of touch itself, suggesting that the experience of time may be further investigated with the toolbox of sensory coding.
Mechanically interlocked [c2]daisy chain backbone enabling advanced shape-memory polymeric materials
Authors: Zhou Shang-Wu , Zhou Danlei , Gu Ruirui , Ma Chang-Shun , Yu Chengyuan , Qu Da-Hui
Published: February 2024

The incorporation of mechanically interlocked structures into polymer backbones has been shown to confer remarkable functionalities to materials. In this work, a [c2]daisy chain unit based on dibenzo-24-crown-8 is covalently embedded into the backbone of a polymer network, resulting in a synthetic material possessing remarkable shape-memory properties under thermal control. By decoupling the molecular structure into three control groups, we demonstrate the essential role of the [c2]daisy chain crosslinks in driving the shape memory function. The mechanically interlocked topology is found to be an essential element for the increase of glass transition temperature and consequent gain of shape memory function. The supramolecular host-guest interactions within the [c2]daisy chain topology not only ensure robust mechanical strength and good network stability of the polymer, but also impart the shape memory polymer with remarkable shape recovery properties and fatigue resistance ability. The incorporation of the [c2]daisy chain unit as a building block has the potential to lay the groundwork for the development of a wide range of shape-memory polymer materials.
A streamlined approach to structure elucidation using in cellulo crystallized recombinant proteins, InCellCryst
Authors: Schönherr Robert , Boger Juliane , Lahey-Rudolph J. Mia , Harms Mareike , Kaiser Jacqueline , Nachtschatt Sophie , Wobbe Marla , Duden Rainer , König Peter , Bourenkov Gleb , Schneider Thomas R. , Redecke Lars
Published: February 2024

With the advent of serial X-ray crystallography on microfocus beamlines at free-electron laser and synchrotron facilities, the demand for protein microcrystals has significantly risen in recent years. However, by in vitro crystallization extensive efforts are usually required to purify proteins and produce sufficiently homogeneous microcrystals. Here, we present InCellCryst, an advanced pipeline for producing homogeneous microcrystals directly within living insect cells. Our baculovirus-based cloning system enables the production of crystals from completely native proteins as well as the screening of different cellular compartments to maximize chances for protein crystallization. By optimizing cloning procedures, recombinant virus production, crystallization and crystal detection, X-ray diffraction data can be collected 24 days after the start of target gene cloning. Furthermore, improved strategies for serial synchrotron diffraction data collection directly from crystals within living cells abolish the need to purify the recombinant protein or the associated microcrystals.
High-order sensory processing nanocircuit based on coupled VO2 oscillators
Authors: Yang Ke , Wang Yanghao , Tiw Pek Jun , Wang Chaoming , Zou Xiaolong , Yuan Rui , Liu Chang , Li Ge , Ge Chen , Wu Si , Zhang Teng , Huang Ru , Yang Yuchao
Published: February 2024

Conventional circuit elements are constrained by limitations in area and power efficiency at processing physical signals. Recently, researchers have delved into high-order dynamics and coupled oscillation dynamics utilizing Mott devices, revealing potent nonlinear computing capabilities. However, the intricate yet manageable population dynamics of multiple artificial sensory neurons with spatiotemporal coupling remain unexplored. Here, we present an experimental hardware demonstration featuring a capacitance-coupled VO2 phase-change oscillatory network. This network serves as a continuous-time dynamic system for sensory pre-processing and encodes information in phase differences. Besides, a decision-making module for special post-processing through software simulation is designed to complete a bio-inspired dynamic sensory system. Our experiments provide compelling evidence that this transistor-free coupling network excels in sensory processing tasks such as touch recognition and gesture recognition, achieving significant advantages of fewer devices and lower energy-delay-product compared to conventional methods. This work paves the way towards an efficient and compact neuromorphic sensory system based on nano-scale nonlinear dynamics.
Elevated extracellular matrix protein 1 in circulating extracellular vesicles supports breast cancer progression under obesity conditions
Authors: Xu Keyang , Fu Ai , Li Zhaoyi , Miao Liangbin , Lou Zhonghan , Jiang Keying , Lau Condon , Su Tao , Tong Tiejun , Bao Jianfeng , Lyu Aiping , Kwan Hiu Yee
Published: February 2024

The cargo content in small extracellular vesicles (sEVs) changes under pathological conditions. Our data shows that in obesity, extracellular matrix protein 1 (ECM1) protein levels are significantly increased in circulating sEVs, which is dependent on integrin-β2. Knockdown of integrin-β2 does not affect cellular ECM1 protein levels but significantly reduces ECM1 protein levels in the sEVs released by these cells. In breast cancer (BC), overexpressing ECM1 increases matrix metalloproteinase 3 (MMP3) and S100A/B protein levels. Interestingly, sEVs purified from high-fat diet-induced obesity mice (D-sEVs) deliver more ECM1 protein to BC cells compared to sEVs from control diet-fed mice. Consequently, BC cells secrete more ECM1 protein, which promotes cancer cell invasion and migration. D-sEVs treatment also significantly enhances ECM1-mediated BC metastasis and growth in mouse models, as evidenced by the elevated tumor levels of MMP3 and S100A/B. Our study reveals a mechanism and suggests sEV-based strategies for treating obesity-associated BC.
The ATR inhibitor ceralasertib potentiates cancer checkpoint immunotherapy by regulating the tumor microenvironment
Authors: Hardaker Elizabeth L. , Sanseviero Emilio , Karmokar Ankur , Taylor Devon , Milo Marta , Michaloglou Chrysis , Hughes Adina , Mai Mimi , King Matthew , Solanki Anisha , Magiera Lukasz , Miragaia Ricardo , Kar Gozde , Standifer Nathan , Surace Michael , Gill Shaan , Peter Alison , Talbot Sara , Tohumeken Sehmus , Fryer Henderson , Mostafa Ali , Mulgrew Kathy , Lam Carolyn , Hoffmann Scott , Sutton Daniel , Carnevalli Larissa , Calero-Nieto Fernando J. , Jones Gemma N. , Pierce Andrew J. , Wilson Zena , Campbell David , Nyoni Lynet , Martins Carla P. , Baker Tamara , Serrano de Almeida Gilberto , Ramlaoui Zainab , Bidar Abdel , Phillips Benjamin , Boland Joseph , Iyer Sonia , Barrett J. Carl , Loembé Arsene-Bienvenu , Fuchs Serge Y. , Duvvuri Umamaheswar , Lou Pei-Jen , Nance Melonie A. , Gomez Roca Carlos Alberto , Cadogan Elaine , Critichlow Susan E. , Fawell Steven , Cobbold Mark , Dean Emma , Valge-Archer Viia , Lau Alan , Gabrilovich Dmitry I. , Barry Simon T.
Published: February 2024

The Ataxia telangiectasia and Rad3-related (ATR) inhibitor ceralasertib in combination with the PD-L1 antibody durvalumab demonstrated encouraging clinical benefit in melanoma and lung cancer patients who progressed on immunotherapy. Here we show that modelling of intermittent ceralasertib treatment in mouse tumor models reveals CD8+ T-cell dependent antitumor activity, which is separate from the effects on tumor cells. Ceralasertib suppresses proliferating CD8+ T-cells on treatment which is rapidly reversed off-treatment. Ceralasertib causes up-regulation of type I interferon (IFNI) pathway in cancer patients and in tumor-bearing mice. IFNI is experimentally found to be a major mediator of antitumor activity of ceralasertib in combination with PD-L1 antibody. Improvement of T-cell function after ceralasertib treatment is linked to changes in myeloid cells in the tumor microenvironment. IFNI also promotes anti-proliferative effects of ceralasertib on tumor cells. Here, we report that broad immunomodulatory changes following intermittent ATR inhibition underpins the clinical therapeutic benefit and indicates its wider impact on antitumor immunity.
Reducing the metabolic burden of rRNA synthesis promotes healthy longevity in Caenorhabditis elegans
Authors: Sharifi Samim , Chaudhari Prerana , Martirosyan Asya , Eberhardt Alexander Otto , Witt Finja , Gollowitzer André , Lange Lisa , Woitzat Yvonne , Okoli Eberechukwu Maryann , Li Huahui , Rahnis Norman , Kirkpatrick Joanna , Werz Oliver , Ori Alessandro , Koeberle Andreas , Bierhoff Holger , Ermolaeva Maria
Published: February 2024

Ribosome biogenesis is initiated by RNA polymerase I (Pol I)-mediated synthesis of pre-ribosomal RNA (pre-rRNA). Pol I activity was previously linked to longevity, but the underlying mechanisms were not studied beyond effects on nucleolar structure and protein translation. Here we use multi-omics and functional tests to show that curtailment of Pol I activity remodels the lipidome and preserves mitochondrial function to promote longevity in Caenorhabditis elegans. Reduced pre-rRNA synthesis improves energy homeostasis and metabolic plasticity also in human primary cells. Conversely, the enhancement of pre-rRNA synthesis boosts growth and neuromuscular performance of young nematodes at the cost of accelerated metabolic decline, mitochondrial stress and premature aging. Moreover, restriction of Pol I activity extends lifespan more potently than direct repression of protein synthesis, and confers geroprotection even when initiated late in life, showcasing this intervention as an effective longevity and metabolic health treatment not limited by aging.
Self-regulated reversal deformation and locomotion of structurally homogenous hydrogels subjected to constant light illumination
Authors: Guo Kexin , Yang Xuehan , Zhou Chao , Li Chuang
Published: February 2024

Environmentally adaptive hydrogels that are capable of reconfiguration in response to external stimuli have shown great potential toward bioinspired actuation and soft robotics. Previous efforts have focused mainly on either the sophisticated design of heterogeneously structured hydrogels or the complex manipulation of external stimuli, and achieving self-regulated reversal shape deformation in homogenous hydrogels under a constant stimulus has been challenging. Here, we report the molecular design of structurally homogenous hydrogels containing simultaneously two spiropyrans that exhibit self-regulated transient deformation reversal when subjected to constant illumination. The deformation reversal mechanism originates from the molecular sequential descending-ascending charge variation of two coexisting spiropyrans upon irradiation, resulting in a macroscale volumetric contraction-expansion of the hydrogels. Hydrogel film actuators were developed to display complex temporary bidirectional shape transformations and self-regulated reversal rolling under constant illumination. Our work represents an innovative strategy for programming complex shape transformations of homogeneous hydrogels using a single constant stimulus.
Faecal hsa-miR-7704 inhibits the growth and adhesion of Bifidobacterium longum by suppressing ProB and aggravates hepatic encephalopathy
Authors: Wang Yuchong , Li Yuyu , Lv Longxian , Zhu Liying , Hong Liang , Wang Xueyao , Zhang Yu , Wang Xin , Diao Hongyan
Published: February 2024

Both gut microbiome and microRNAs (miRNAs) play a role in the development of hepatic encephalopathy (HE). However, the functional link between the microbiome and host-derived miRNAs in faeces remains poorly understood. In the present study, patients with HE had an altered gut microbiome and faecal miRNAs compared with patients with chronic hepatitis B. Transferring faeces and faecal miRNAs from patients with HE to the recipient mice aggravated thioacetamide-induced HE. Oral gavage of hsa-miR-7704, a host-derived miRNA highly enriched in faeces from patients with HE, aggravated HE in mice in a microbiome-dependent manner. Mechanistically, hsa-miR-7704 inhibited the growth and adhesion of Bifidobacterium longum by suppressing proB. B. longum and its metabolite acetate alleviated HE by inhibiting microglial activation and ammonia production. Our findings reveal the role of miRNA–microbiome axis in HE and suggest that faecal hsa-miR-7704 are potential regulators of HE progression.
Lumpectomy without radiation for ductal carcinoma in situ of the breast: 20-year results from the ECOG-ACRIN E5194 study
Authors: Wright Jean L. , Gray Robert , Rahbar Habib , Comstock Christopher E. , Tjoe Judy A. , Badve Sunil , Recht Abram , Sparano Joseph A. , Davidson Nancy E. , Wolff Antonio C.
Published: February 2024

We report the 20-year rate of ipsilateral breast event (IBE) for patients with ductal carcinoma in situ (DCIS) treated with lumpectomy without radiation on a non-randomized prospective clinical trial. Patients were enrolled in cohort 1: low- or intermediate-grade DCIS, size ≤ 2.5 cm (n = 561); or cohort 2: high-grade DCIS, size ≤ 1 cm (n = 104). The Kaplan–Meier method was used to estimate time-to-event distributions. Cox proportional hazard methods were used to estimate hazard ratios (HRs) and tests for significance for event times. 561 patients were enrolled in cohort 1 and 104 in cohort 2. After central pathology review, 26% in cohort 1 were recategorized as high-grade and 26% in cohort 2 as low- or intermediate-grade. Mean DCIS size was similar at 7.5 mm in cohort 1 and 7.8 mm in cohort 2. Surgical margin was ≥3 mm in 96% of patients, and about 30% received tamoxifen. Median follow-up was 19.2 years. There were 104 IBEs, of which 54 (52%) were invasive. The IBE and invasive IBE rates increased in both cohorts up to 15 years, then plateaued. The 20-year IBE rates were 17.8% for cohort 1 and 28.7% for cohort 2 (p = 0.005), respectively. Invasive IBE occurred in 9.8% and 15.1% (p = 0.09), respectively. On multivariable analysis, IBE risk increased with size and was higher in cohort 2, but grade and margin width were not significantly associated with IBE. For patients with DCIS treated with excision without radiation, the rate of IBE increased with size and assigned cohort mostly in the first 15 years.
Inter-epitope spacer variation within polytopic L2-based human papillomavirus antigens affects immunogenicity
Authors: Zhang Yueru , Mariz Filipe Colaco , Sehr Peter , Spagnoli Gloria , Koenig Karl Moritz , Çelikyürekli Simay , Kreuziger Tim , Zhao Xueer , Bolchi Angelo , Ottonello Simone , Müller Martin
Published: February 2024

The human papillomavirus minor capsid protein L2 is being extensively explored in pre-clinical studies as an attractive vaccine antigen capable of inducing broad-spectrum prophylactic antibody responses. Recently, we have developed two HPV vaccine antigens – PANHPVAX and CUT-PANHPVAX- both based on heptameric nanoparticle antigens displaying polytopes of the L2 major cross-neutralizing epitopes of eight mucosal and twelve cutaneous HPV types, respectively. Prompted by the variable neutralizing antibody responses against some of the HPV types targeted by the antigens observed in previous studies, here we investigated the influence on immunogenicity of six distinct glycine-proline spacers inserted upstream to a specific L2 epitope. We show that spacer variants differentially influence antigen immunogenicity in a mouse model, with the antigen constructs M8merV6 and C12merV6 displaying a superior ability in the induction of neutralizing antibodies as determined by pseudovirus-based neutralization assays (PBNAs). L2-peptide enzyme-linked immunosorbent assay (ELISA) assessments determined the total anti-L2 antibody level for each antigen variant, showing for the majority of sera a correlation with their repective neutralizing antibody level. Surface Plasmon Resonance revealed that L2 epitope-specific, neutralizing monoclonal antibodies (mAbs) display distinct avidities to different antigen spacer variants. Furthermore, mAb affinity toward individual spacer variants was well correlated with their neutralizing antibody induction capacity, indicating that the mAb affinity assay predicts L2-based antigen immunogenicity. These observations provide insights on the development and optimization of L2-based HPV vaccines.
A simulated ‘sandbox’ for exploring the modifiable areal unit problem in aggregation and disaggregation
Authors: Nieves Jeremiah J. , Gaughan Andrea E. , Stevens Forrest R. , Yetman Greg , Gros Andreas
Published: February 2024

We present a spatial testbed of simulated boundary data based on a set of very high-resolution census-based areal units surrounding Guadalajara, Mexico. From these input areal units, we simulated 10 levels of spatial resolutions, ranging from levels with 5,515–52,388 units and 100 simulated zonal configurations for each level – totalling 1,000 simulated sets of areal units. These data facilitate interrogating various realizations of the data and the effects of the spatial coarseness and zonal configurations, the Modifiable Areal Unit Problem (MAUP), on applications such as model training, model prediction, disaggregation, and aggregation processes. Further, these data can facilitate the production of spatially explicit, non-parametric estimates of confidence intervals via bootstrapping. We provide a pre-processed version of these 1,000 simulated sets of areal units, meta- and summary data to assist in their use, and a code notebook with the means to alter and/or reproduce these data.
Robotic monitoring of dunes: a dataset from the EU habitats 2110 and 2120 in Sardinia (Italy)
Authors: Angelini Franco , Pollayil Mathew J. , Rivieccio Giovanni , Caria Maria Carmela , Bagella Simonetta , Garabini Manolo
Published: February 2024

This data descriptor presents a novel dataset collected using the quadrupedal robot ANYmal C in the Mediterranean coastal dune environment of the European Union (EU) habitats 2110 and 2120 in Sardinia, Italy. The dataset mainly consists of photos, videos, and point clouds of the coastal dunes, providing valuable information on the structure and composition of this habitat. The data was collected by a team of robotic engineers and plant scientists as result of a joint effort towards robotic habitat monitoring. The dataset is publicly available through Zenodo and can be used by researchers working in both the fields of robotics and habitat ecology and conservation. The availability of this dataset has the potential to inform future research and conservation efforts in the EU habitats 2110 and 2120, and it highlights the importance of interdisciplinary collaboration in the field of habitat monitoring. This paper serves as a comprehensive description of the dataset and the methods used to collect it, making it a valuable resource for the scientific community.
Band-by-band spectral radiative kernels based on the ERA5 reanalysis
Authors: Huang Han , Huang Yi , Wei Qiang , Hu Yongyun
Published: February 2024

Radiative kernel is a widely adopted method for diagnosing radiation variability and climate feedback. However, most of the existing radiative kernels are broadband flux kernels and lack the spectral information. Motivated by the growing interest in the spectral changes of the Earth radiation budget, we generate a new set of band-by-band radiative kernels based on the fifth generation European Center for Medium-Range Weather Forecasts (ERA5) reanalysis, which can be used for analyzing the spectrally decomposed changes in the top of atmosphere, surface and atmospheric radiation. The radiative sensitivity quantified by the ERA5 band-by-band kernel is compared to another spectral kernel and validated in a spectral radiation closure test. The use and benefits of the new ERA5 kernels are then demonstrated in an analysis of spectral feedbacks of an ensemble of global climate models (GCMs).