bluuebunny/crossref_metadata_2025 huggingface dataset:
THE MANY FACES OF DIONYSUS IN THE HEXAMETERS OF THE SINAI PALIMPSEST (SIN. AR. NF 66)
Authors: Edmonds Radcliffe G.
Published: March 2023

The fragments of a hexameter poem about Dionysus recently discovered in a palimpsest (Sin. Ar. NF 66) reveal some different faces of Dionysus, including an Adonis-figure at the heart of a dispute between two goddesses (Persephone and Aphrodite), and a personified wine-god, Oinos, threatened by the machinations of his enemies in the court of Zeus. These palimpsest texts help to illuminate some of the allusions to the early life of the god that have long puzzled scholars, especially in some of the early Christian apologists and the collection of OrphicHymns.
Finite point configurations in products of thick Cantor sets and a robust nonlinear Newhouse Gap Lemma
Authors: MCDONALD ALEX , TAYLOR KRYSTAL
Published: March 2023

In this paper we prove that the set
$\{|x^1-x^2|,\dots,|x^k-x^{k+1}|\,{:}\,x^i\in E\}$
has non-empty interior in
$\mathbb{R}^k$
when
$E\subset \mathbb{R}^2$
is a Cartesian product of thick Cantor sets
$K_1,K_2\subset\mathbb{R}$
. We also prove more general results where the distance map
$|x-y|$
is replaced by a function
$\phi(x,y)$
satisfying mild assumptions on its partial derivatives. In the process, we establish a nonlinear version of the classic Newhouse Gap Lemma, and show that if
$K_1,K_2, \phi$
are as above then there exists an open set S so that
$\bigcap_{x \in S} \phi(x,K_1\times K_2)$
has non-empty interior.
Predictors of prolonged pleural effusion after Fontan operation
Authors: Çınar Betül , Atik Sezen Ugan , Gökalp Selman , Çilsal Erman , Şahin Murat , Kamalı Hacer , Onan İsmihan Selen , Genç Serhat Bahadır , Yıldız Okan , Haydin Sertaç , Baydili Kürşad Nuri , Ergül Yakup , Güzeltaş Alper
Published: March 2023

Prolonged pleural effusion is a fairly common condition which has considerable impact on complicated and longer hospital stays after Fontan surgery. Identifying the patient population prone to have pleural effusions is still seeking for an answer. This study is to determine the variables that may predict prolonged pleural effusion according to the data of 69 patients who underwent Fontan operation between June 2018 and December 2020 and survived to date. Prolonged pleural effusion was defined as the need for a chest tube for more than 7 days. Two patient groups, with and without prolonged effusion, were compared in terms of pre-, peri-, and post-operative variables. The patients were subdivided into "high-risk" and "low-risk" groups based on the pre-operative catheterisation data. The most frequent main diagnosis was tricuspid atresia (n: 13, 19%). Among 69 patients, 28 (40%) had prolonged pleural effusion whereas 11 (16%) had effusions that lasted longer than 14 days. Ten patients among prolonged effusion group (35%) had pulmonary atresia coexistent with the main diagnosis. Fontan operation was performed in 6 patients (8.7%) over the age of 10, and 4 of these patients (67%) had prolonged pleural effusion. Among numerous variables, statistical significance between the two groups was achieved in pre-operative mean pulmonary artery pressure, post-operative albumin, C-reactive protein levels, length of hospital stay, duration of chest tube drainage, and amount of effusion per day. Early recognition and treatment strategies with routine medical protocol use remain to be the cornerstone for the management of post-operative prolonged pleural effusions after Fontan surgery.
Food for Thought: A Survey on the Nature of Work Precarity in Platform-Based On-Demand Work
Authors: Parwez Sazzad
Published: March 2023

This study aims to empirically understand the precarity of food delivery work at online platforms particularly during the COVID-19-led devastations. Food delivery workers are the new form of the global phenomenon in the labour market. This is a result of access to cheap internet and smartphones among customers, which has enabled the platform to create a new form of labour market. Platform-based food aggregators use the terminology of 'delivery partners’ for these workers which alters the traditional employer-employee relationships, allowing corporations to evade labour-related responsibilities. This makes working conditions at digital platforms highly precarious and is reflected by low income and the non-existence of labour welfare measures. The COVID-19 pandemic and resultant lockdowns have worsened the precarious nature of on-demand work. It has caused a massive loss of livelihoods and erosion of income, showing the importance of traditional employer-employee relationships. These precarious working conditions call for affirmative actions in the form of regulations.
AN ALGORITHMIC IMPOSSIBLE-WORLDS MODEL OF BELIEF AND KNOWLEDGE
Authors: SOYSAL ZEYNEP
Published: March 2023

In this paper, I develop an algorithmic impossible-worlds model of belief and knowledge that provides a middle ground between models that entail that everyone is logically omniscient and those that are compatible with even the most egregious kinds of logical incompetence. In outline, the model entails that an agent believes (knows)$\phi $just in case she can easily (and correctly) compute that$\phi $is true and thus has the capacity to make her actions depend on whether$\phi $. The model thereby captures the standard view that belief and knowledge ground are constitutively connected to dispositions to act. As I explain, the model improves upon standard algorithmic models developed by Parikh, Halpern, Moses, Vardi, and Duc, among other ways, by integrating them into an impossible-worlds framework. The model also avoids some important disadvantages of recent candidate middle-ground models based on dynamic epistemic logic or step logic, and it can subsume their most important advantages.
Generation of the Internal Pycnocline in the Subpolar Southern Ocean by Wintertime Sea Ice Melting
Authors: Klocker A. , Naveira Garabato A. C. , Roquet F. , de Lavergne C. , Rintoul S. R.
Published: March 2023

The ocean's internal pycnocline is a layer of elevated stratification that separates the well‐ventilated upper ocean from the more slowly renewed deep ocean. Despite its pivotal role in organizing ocean circulation, the processes governing the formation of the internal pycnocline remain little understood. Classical theories on pycnocline formation have been couched in terms of temperature and it is not clear how the theory applies in the high‐latitude Southern Ocean, where stratification is dominated by salinity. Here we assess the mechanisms generating the internal pycnocline at southern high latitudes through the analysis of a high‐resolution, realistic, global sea ice–ocean model. We show evidence suggesting that the internal pycnocline's formation is associated with sea ice‐ocean interactions in two distinct ice‐covered regions, fringing the Antarctic continental slope and the winter sea‐ice edge. In both areas, winter‐persistent sea‐ice melt creates strong, salinity‐based stratification at the base of the winter mixed layer. The resulting sheets of high stratification subsequently descend into the ocean interior at fronts of the Antarctic Circumpolar Current, and connect seamlessly to the internal pycnocline in areas further north in which pycnocline stratification is determined by temperature. Our findings thus suggest an important role of localized sea ice‐ocean interactions in configuring the vertical structure of the Southern Ocean.
Relative Humidity Dependence of Growth Factor and Real Refractive Index for Sea Salt/Malonic Acid Internally Mixed Aerosols
Authors: Liu Huichao , Pei Xiangyu , Zhang Fei , Song Yao , Kuang Binyu , Xu Zhengning , Wang Zhibin
Published: March 2023

Sea salt aerosols (SSAs) often mix with organic matter via sea‐to‐air emission, photochemical oxidation, and atmospheric transport, which change particle hygroscopicity and real refractive index (RRI), thereby the radiative effects. However, the influence of water uptake and organic matters on radiative effects is not well understood. In this study, relative humidity (RH)‐dependent growth factor (GF), light scattering enhancement factor, RRI (nmea), and radiative forcing efficiency (RFE) in the visible spectrum of SSAs/malonic acid (MA) internally mixed aerosols were investigated. Our results showed that MA‐mediated SSAs readily absorbed water even at low RH but suppressed hygroscopic growth at high RH. The discrepancy between Zdanovskii‐Stokes‐Robinson predictions and measured GF indicated that the suppressing effect on size caused by produced malonate salts in chloride depletion became more evident as MA content increased. RRI in the visible spectrum decreased as MA got enriched and approached toward water's RRI at high RH, resulting in a less cooling effect. The increasing RH reduced RFE both by decreasing RRI and increasing particle size substantially. Ignoring the effect of MA on particle size and RRI under varied RH, errors in RFE at 525 nm up to 25% could be induced. Volume mixing rule performs well in predicting the RRI of mixed aerosols in dry conditions, while the retrieved difference of 0.061 between volume mixing RRI nvol and nmea would make the error in RFE up to 1.15 W·m−2·Aerosol optical depth−1 at 87% RH. Our study helps understand the impact of water content and dicarboxylic acids on the direct radiative effects of SSAs.
Sub‐Seasonal Variability of ENSO Teleconnections in Western North America and Its Prediction Skill
Authors: Park Chang‐Hyun , Choi Jung , Son Seok‐Woo , Kim Daehyun , Yeh Sang‐Wook , Kug Jong‐Seong
Published: March 2023

The El Niño–Southern Oscillation (ENSO) significantly affects the wintertime surface climate in western North America (WNA) via the Pacific/North American‐like teleconnection pattern. Here, we show that the ENSO teleconnections over the WNA have significant sub‐seasonal variation despite the persistence of ENSO‐related tropical sea surface temperature anomalies throughout the entire winter. The ENSO–WNA teleconnections become substantially weakened in mid‐winter, considerably weaker than those in early and late winter. This mid‐winter weakening of the ENSO–WNA teleconnections is attributable to the convection over the equatorial Indian Ocean. In mid‐December of El Niño winters, the anomalously‐enhanced convection develops over the equatorial Indian Ocean and excites the teleconnection pattern with a 2‐week time lag. This teleconnection largely opposes the Pacific/North American‐like teleconnection pattern that is induced by anomalous convection over the equatorial central Pacific. Such sub‐seasonal variation of ENSO teleconnections is poorly predicted by multi‐model hindcasts, affecting the mid‐latitude prediction skill. It particularly results in a poorer prediction skill of WNA surface air temperature in mid‐winter than in late winter. This result highlights a need to better simulate the ENSO‐related tropical convection and the associated teleconnections in the model to improve the long‐lead prediction of the WNA surface climate.
Levosimendan inhibits disulfide tau oligomerization and ameliorates tau pathology in TauP301L-BiFC mice
Authors: Lim Sungsu , Shin Seulgi , Sung Yoonsik , Lee Ha Eun , Kim Kyu Hyeon , Song Ji Yeon , Lee Gwan-Ho , Aziz Hira , Lukianenko Nataliia , Kang Dong Min , Boesen Nicolette , Jeong Hyeanjeong , Abdildinova Aizhan , Lee Junghee , Yu Byung-Yong , Lim Sang Min , Lee Jun-Seok , Ryu Hoon , Pae Ae Nim , Kim Yun Kyung
Published: March 2023

Tau oligomers play critical roles in tau pathology and are responsible for neuronal cell death and transmitting the disease in the brain. Accordingly, preventing tau oligomerization has become an important therapeutic strategy to treat tauopathies, including Alzheimer’s disease. However, progress has been slow because detecting tau oligomers in the cellular context is difficult. Working toward tau-targeted drug discovery, our group has developed a tau-BiFC platform to monitor and quantify tau oligomerization. By using the tau-BiFC platform, we screened libraries with FDA-approved and passed phase I drugs and identified levosimendan as a potent anti-tau agent that inhibits tau oligomerization. 14C-isotope labeling of levosimendan revealed that levosimendan covalently bound to tau cysteines, directly inhibiting disulfide-linked tau oligomerization. In addition, levosimendan disassembles tau oligomers into monomers, rescuing neurons from aggregation states. In comparison, the well-known anti-tau agents methylene blue and LMTM failed to protect neurons from tau-mediated toxicity, generating high-molecular-weight tau oligomers. Levosimendan displayed robust potency against tau oligomerization and rescued cognitive declines induced by tauopathy in the TauP301L-BiFC mouse model. Our data present the potential of levosimendan as a disease-modifying drug for tauopathies.
Single-cell sequencing reveals that endothelial cells, EndMT cells and mural cells contribute to the pathogenesis of cavernous malformations
Authors: Ren Jian , Xiao Xiao , Li Ruofei , Lv Cheng , Zhang Yu , Wang Leiming , Hong Tao , Zhang Hongqi , Wang Yibo
Published: March 2023

Cavernous malformations (CMs) invading the central nervous system occur in ~0.16–0.4% of the general population, often resulting in hemorrhages and focal neurological deficits. Further understanding of disease mechanisms and therapeutic strategies requires a deeper knowledge of CMs in humans. Herein, we performed single-cell RNA sequencing (scRNA-seq) analysis on unselected viable cells from twelve human CM samples and three control samples. A total of 112,670 high-quality cells were clustered into 11 major cell types, which shared a number of common features in CMs harboring different genetic mutations. A new EC subpopulation marked with PLVAP was uniquely identified in lesions. The cellular ligand‒receptor network revealed that the PLVAP-positive EC subcluster was the strongest contributor to the ANGPT and VEGF signaling pathways in all cell types. The PI3K/AKT/mTOR pathway was strongly activated in the PLVAP-positive subcluster even in non-PIK3CA mutation carriers. Moreover, endothelial-to-mesenchymal transition (EndMT) cells were identified for the first time in CMs at the single-cell level, which was accompanied by strong immune activation. The transcription factor SPI1 was predicted to be a novel key driver of EndMT, which was confirmed by in vitro and in vivo studies. A specific fibroblast-like phenotype was more prevalent in lesion smooth muscle cells, hinting at the role of vessel reconstructions and repairs in CMs, and we also confirmed that TWIST1 could induce SMC phenotypic switching in vitro and in vivo. Our results provide novel insights into the pathomechanism decryption and further precise therapy of CMs.
UHRF1/UBE2L6/UBR4-mediated ubiquitination regulates EZH2 abundance and thereby melanocytic differentiation phenotypes in melanoma
Authors: Kuser-Abali Gamze , Zhang Youfang , Szeto Pacman , Zhao Peinan , Masoumi-Moghaddam Samar , Fedele Clare G. , Leece Isobel , Huang Cheng , Cheung Jen G. , Ameratunga Malaka , Noguchi Fumihito , Andrews Miles C. , Wong Nicholas C. , Schittenhelm Ralf B. , Shackleton Mark
Published: March 2023

Cellular heterogeneity in cancer is linked to disease progression and therapy response, although mechanisms regulating distinct cellular states within tumors are not well understood. We identified melanin pigment content as a major source of cellular heterogeneity in melanoma and compared RNAseq data from high-pigmented (HPCs) and low-pigmented melanoma cells (LPCs), suggesting EZH2 as a master regulator of these states. EZH2 protein was found to be upregulated in LPCs and inversely correlated with melanin deposition in pigmented patient melanomas. Surprisingly, conventional EZH2 methyltransferase inhibitors, GSK126 and EPZ6438, had no effect on LPC survival, clonogenicity and pigmentation, despite fully inhibiting methyltransferase activity. In contrast, EZH2 silencing by siRNA or degradation by DZNep or MS1943 inhibited growth of LPCs and induced HPCs. As the proteasomal inhibitor MG132 induced EZH2 protein in HPCs, we evaluated ubiquitin pathway proteins in HPC vs LPCs. Biochemical assays and animal studies demonstrated that in LPCs, the E2-conjugating enzyme UBE2L6 depletes EZH2 protein in cooperation with UBR4, an E3 ligase, via ubiquitination at EZH2’s K381 residue, and is downregulated in LPCs by UHRF1-mediated CpG methylation. Targeting UHRF1/UBE2L6/UBR4-mediated regulation of EZH2 offers potential for modulating the activity of this oncoprotein in contexts in which conventional EZH2 methyltransferase inhibitors are ineffective.
Activation of immune signals during organ transplantation
Authors: Li Qingwen , Lan Peixiang
Published: March 2023

The activation of host’s innate and adaptive immune systems can lead to acute and chronic graft rejection, which seriously impacts graft survival. Thus, it is particularly significant to clarify the immune signals, which are critical to the initiation and maintenance of rejection generated after transplantation. The initiation of response to graft is dependent on sensing of danger and stranger molecules. The ischemia and reperfusion of grafts lead to cell stress or death, followed by releasing a variety of damage-associated molecular patterns (DAMPs), which are recognized by pattern recognition receptors (PRRs) of host immune cells to activate intracellular immune signals and induce sterile inflammation. In addition to DAMPs, the graft exposed to ‘non-self’ antigens (stranger molecules) are recognized by the host immune system, stimulating a more intense immune response and further aggravating the graft damage. The polymorphism of MHC genes between different individuals is the key for host or donor immune cells to identify heterologous ‘non-self’ components in allogeneic and xenogeneic organ transplantation. The recognition of ‘non-self’ antigen by immune cells mediates the activation of immune signals between donor and host, resulting in adaptive memory immunity and innate trained immunity to the graft, which poses a challenge to the long-term survival of the graft. This review focuses on innate and adaptive immune cells receptor recognition of damage-associated molecular patterns, alloantigens and xenoantigens, which is described as danger model and stranger model. In this review, we also discuss the innate trained immunity in organ transplantation.
Vitamin B12 is not shared by all marine prototrophic bacteria with their environment
Authors: Sultana Sabiha , Bruns Stefan , Wilkes Heinz , Simon Meinhard , Wienhausen Gerrit
Published: March 2023

Vitamin B12 (cobalamin, herein B12) is an essential cofactor involved in amino acid synthesis and carbon resupply to the TCA cycle for most prokaryotes, eukaryotic microorganisms, and animals. Despite being required by most, B12 is produced by only a minor fraction of prokaryotes and therefore leads to complex interaction between prototrophs and auxotrophs. However, it is unknown how B12 is provided by prototrophs to auxotrophs. In this study, 33 B12 prototrophic alphaproteobacterial strains were grown in co-culture with Thalassiosira pseudonana, a B12 auxotrophic diatom, to determine the bacterial ability to support the growth of the diatom by sharing B12. Among these strains, 18 were identified to share B12 with the diatom, while nine were identified to retain B12 and not support growth of the diatom. The other bacteria either shared B12 with the diatom only with the addition of substrate or inhibited the growth of the diatom. Extracellular B12 measurements of B12-provider and B12-retainer strains confirmed that the cofactor could only be detected in the environment of the tested B12-provider strains. Intracellular B12 was measured by LC-MS and showed that the concentrations of the different B12-provider as well as B12-retainer strains differed substantially. Although B12 is essential for the vast majority of microorganisms, mechanisms that export this essential cofactor are still unknown. Our results suggest that a large proportion of bacteria that can synthesise B12de novo cannot share the cofactor with their environment.
Protein dynamics at invadopodia control invasion–migration transitions in melanoma cells
Authors: Legrand Marlène , Mousson Antoine , Carl Philippe , Rossé Léa , Justiniano Hélène , Gies Jean-Pierre , Bouvard Daniel , Sick Emilie , Dujardin Denis , Rondé Philippe
Published: March 2023

Cell invasion is a highly complex process that requires the coordination of cell migration and degradation of the extracellular matrix. In melanoma cells, as in many highly invasive cancer cell types these processes are driven by the regulated formation of adhesives structures such as focal adhesions and invasive structures like invadopodia. Structurally, focal adhesion and invadopodia are quite distinct, yet they share many protein constituents. However, quantitative understanding of the interaction of invadopodia with focal adhesion is lacking, and how invadopodia turn-over is associated with invasion-migration transition cycles remains unknown. In this study, we investigated the role of Pyk2, cortactin and Tks5 in invadopodia turnover and their relation with focal adhesions. We found that active Pyk2 and cortactin are localised at both focal adhesions and invadopodia. At invadopodia, localisation of active Pyk2 is correlated with ECM degradation. During invadopodia disassembly, Pyk2 and cortactin but not Tks5 are often relocated at nearby nascent adhesions. We also show that during ECM degradation, cell migration is reduced which is likely related to the sharing of common molecules within the two structures. Finally, we found that the dual FAK/Pyk2 inhibitor PF-431396 inhibits both focal adhesion and invadopodia activities thereby reducing both migration and ECM degradation.
PDIA4 confers resistance to ferroptosis via induction of ATF4/SLC7A11 in renal cell carcinoma
Authors: Kang Lichun , Wang Dekun , Shen Tianyu , Liu Xuan , Dai Bo , Zhou Donghui , Shen Huan , Gong Junbo , Li Gang , Hu Yuanjing , Wang Peng , Mi Xue , Zhang Yuying , Tan Xiaoyue
Published: March 2023

The prognosis of renal cell carcinoma (RCC) remains poor due to metastases and resistance to chemotherapy. Salinomycin (Sal) exhibits the potential of antitumor, while the underlying mechanism is not completely clear. Here, we found that Sal induced ferroptosis in RCCs and identified Protein Disulfide Isomerase Family A Member 4 (PDIA4) as a mediator of Sal’s effect on ferroptosis. Sal suppressed PDIA4 by increasing its autophagic degradation. Downregulation of PDIA4 increased the sensitivity to ferroptosis, while ectopic overexpression of PDIA4 conferred ferroptosis resistance to RCCs. Our data showed that downregulation of PDIA4 suppressed activating transcription factor 4 (ATF4) and its downstream protein SLC7A11 (solute carrier family 7 member 11), thereby aggravating ferroptosis. In vivo, the administration of Sal promoted ferroptosis and suppressed tumor progress in the xenograft mouse model of RCC. Bioinformatical analyses based on clinical tumor samples and database indicated a positive correlation exists between PDIA4 and PERK/ATF4/SLC7A11 signaling pathway, as well as the malignant prognosis of RCCs. Together, our findings reveal that PDIA4 promotes ferroptosis resistance in RCCs. Treatment of Sal sensitizes RCC to ferroptosis via suppressing PDIA4, suggesting the potential therapeutical application in RCCs.
Emerging roles of TFE3 in metabolic regulation
Authors: Li Xingyu , Chen Yongming , Gong Siqiao , Chen Huixia , Liu Huafeng , Li Xiaoyu , Hao Junfeng
Published: March 2023

TFE3 is a member of the MiT family of the bHLH-leucine zipper transcription factor. We previously focused on the role of TFE3 in autophagy and cancer. Recently, an increasing number of studies have revealed that TFE3 plays an important role in metabolic regulation. TFE3 participates in the metabolism of energy in the body by regulating pathways such as glucose and lipid metabolism, mitochondrial metabolism, and autophagy. This review summarizes and discusses the specific regulatory mechanisms of TFE3 in metabolism. We determined both the direct regulation of TFE3 on metabolically active cells, such as hepatocytes and skeletal muscle cells, and the indirect regulation of TFE3 through mitochondrial quality control and the autophagy–lysosome pathway. The role of TFE3 in tumor cell metabolism is also summarized in this review. Understanding the diverse roles of TFE3 in metabolic processes can provide new avenues for the treatment of some metabolism-related disorders.
Acidic graphene organocatalyst for the superior transformation of wastes into high-added-value chemicals
Authors: Cheruvathoor Poulose Aby , Medveď Miroslav , Bakuru Vasudeva Rao , Sharma Akashdeep , Singh Deepika , Kalidindi Suresh Babu , Bares Hugo , Otyepka Michal , Jayaramulu Kolleboyina , Bakandritsos Aristides , Zbořil Radek
Published: March 2023

Our dependence on finite fossil fuels and the insecure energy supply chains have stimulated intensive research for sustainable technologies. Upcycling glycerol, produced from biomass fermentation and as a biodiesel formation byproduct, can substantially contribute in circular carbon economy. Here, we report glycerol’s solvent-free and room-temperature conversion to high-added-value chemicals via a reusable graphene catalyst (G-ASA), functionalized with a natural amino acid (taurine). Theoretical studies unveil that the superior performance of the catalyst (surpassing even homogeneous, industrial catalysts) is associated with the dual role of the covalently linked taurine, boosting the catalyst’s acidity and affinity for the reactants. Unlike previous catalysts, G-ASA exhibits excellent activity (7508 mmol g−1 h−1) and selectivity (99.9%) for glycerol conversion to solketal, an additive for improving fuels’ quality and a precursor of commodity and fine chemicals. Notably, the catalyst is also particularly active in converting oils to biodiesel, demonstrating its general applicability.
Mammalian-brain-inspired neuromorphic motion-cognition nerve achieves cross-modal perceptual enhancement
Authors: Jiang Chengpeng , Liu Jiaqi , Ni Yao , Qu Shangda , Liu Lu , Li Yue , Yang Lu , Xu Wentao
Published: March 2023

Perceptual enhancement of neural and behavioral response due to combinations of multisensory stimuli are found in many animal species across different sensory modalities. By mimicking the multisensory integration of ocular-vestibular cues for enhanced spatial perception in macaques, a bioinspired motion-cognition nerve based on a flexible multisensory neuromorphic device is demonstrated. A fast, scalable and solution-processed fabrication strategy is developed to prepare a nanoparticle-doped two-dimensional (2D)-nanoflake thin film, exhibiting superior electrostatic gating capability and charge-carrier mobility. The multi-input neuromorphic device fabricated using this thin film shows history-dependent plasticity, stable linear modulation, and spatiotemporal integration capability. These characteristics ensure parallel, efficient processing of bimodal motion signals encoded as spikes and assigned with different perceptual weights. Motion-cognition function is realized by classifying the motion types using mean firing rates of encoded spikes and postsynaptic current of the device. Demonstrations of recognition of human activity types and drone flight modes reveal that the motion-cognition performance match the bio-plausible principles of perceptual enhancement by multisensory integration. Our system can be potentially applied in sensory robotics and smart wearables.
BET inhibitor trotabresib in heavily pretreated patients with solid tumors and diffuse large B-cell lymphomas
Authors: Moreno Victor , Vieito Maria , Sepulveda Juan Manuel , Galvao Vladimir , Hernández-Guerrero Tatiana , Doger Bernard , Saavedra Omar , Carlo-Stella Carmelo , Michot Jean-Marie , Italiano Antoine , Magagnoli Massimo , Carpio Cecilia , Pinto Antonio , Sarmiento Rafael , Amoroso Barbara , Aronchik Ida , Filvaroff Ellen , Hanna Bishoy , Wei Xin , Nikolova Zariana , Braña Irene
Published: March 2023

Bromodomain and extraterminal proteins (BET) play key roles in regulation of gene expression, and may play a role in cancer-cell proliferation, survival, and oncogenic progression. CC-90010-ST-001 (NCT03220347) is an open-label phase I study of trotabresib, an oral BET inhibitor, in heavily pretreated patients with advanced solid tumors and relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Primary endpoints were the safety, tolerability, maximum tolerated dose, and RP2D of trotabresib. Secondary endpoints were clinical benefit rate (complete response [CR] + partial response [PR] + stable disease [SD] of ≥4 months’ duration), objective response rate (CR + PR), duration of response or SD, progression-free survival, overall survival, and the pharmacokinetics (PK) of trotabresib. In addition, part C assessed the effects of food on the PK of trotabresib as a secondary endpoint. The dose escalation (part A) showed that trotabresib was well tolerated, had single-agent activity, and determined the recommended phase 2 dose (RP2D) and schedule for the expansion study. Here, we report long-term follow-up results from part A (N = 69) and data from patients treated with the RP2D of 45 mg/day 4 days on/24 days off or an alternate RP2D of 30 mg/day 3 days on/11 days off in the dose-expansion cohorts (parts B [N = 25] and C [N = 41]). Treatment-related adverse events (TRAEs) are reported in almost all patients. The most common severe TRAEs are hematological. Toxicities are generally manageable, allowing some patients to remain on treatment for ≥2 years, with two patients receiving ≥3 years of treatment. Trotabresib monotherapy shows antitumor activity, with an ORR of 13.0% (95% CI, 2.8–33.6) in patients with R/R DLBCL (part B) and an ORR of 0.0% (95% CI, 0.0–8.6) and a CBR of 31.7% (95% CI, 18.1–48.1) in patients with advanced solid tumors (part C). These results support further investigation of trotabresib in combination with other anticancer agents.
Cryo-EM structures of human Cx36/GJD2 neuronal gap junction channel
Authors: Lee Seu-Na , Cho Hwa-Jin , Jeong Hyeongseop , Ryu Bumhan , Lee Hyuk-Joon , Kim Minsoo , Yoo Jejoong , Woo Jae-Sung , Lee Hyung Ho
Published: March 2023

Connexin 36 (Cx36) is responsible for signal transmission in electrical synapses by forming interneuronal gap junctions. Despite the critical role of Cx36 in normal brain function, the molecular architecture of the Cx36 gap junction channel (GJC) is unknown. Here, we determine cryo-electron microscopy structures of Cx36 GJC at 2.2–3.6 Å resolutions, revealing a dynamic equilibrium between its closed and open states. In the closed state, channel pores are obstructed by lipids, while N-terminal helices (NTHs) are excluded from the pore. In the open state with pore-lining NTHs, the pore is more acidic than those in Cx26 and Cx46/50 GJCs, explaining its strong cation selectivity. The conformational change during channel opening also includes the α-to-π-helix transition of the first transmembrane helix, which weakens the protomer-protomer interaction. Our structural analyses provide high resolution information on the conformational flexibility of Cx36 GJC and suggest a potential role of lipids in the channel gating.
Rapid protection induced by a single-shot Lassa vaccine in male cynomolgus monkeys
Authors: Mateo Mathieu , Reynard Stéphanie , Pietrosemoli Natalia , Perthame Emeline , Journeaux Alexandra , Noy Kodie , Germain Clara , Carnec Xavier , Picard Caroline , Borges-Cardoso Virginie , Hortion Jimmy , Lopez-Maestre Hélène , Regnard Pierrick , Fellmann Lyne , Vallve Audrey , Barron Stéphane , Jourjon Ophélie , Lacroix Orianne , Duthey Aurélie , Dirheimer Manon , Daniau Maïlys , Legras-Lachuer Catherine , Carbonnelle Caroline , Raoul Hervé , Tangy Frédéric , Baize Sylvain
Published: March 2023

Lassa fever hits West African countries annually in the absence of licensed vaccine to limit the burden of this viral hemorrhagic fever. We previously developed MeV-NP, a single-shot vaccine protecting cynomolgus monkeys against divergent strains one month or more than a year before Lassa virus infection. Given the limited dissemination area during outbreaks and the risk of nosocomial transmission, a vaccine inducing rapid protection could be useful to protect exposed people during outbreaks in the absence of preventive vaccination. Here, we test whether the time to protection can be reduced after immunization by challenging measles virus pre-immune male cynomolgus monkeys sixteen or eight days after a single shot of MeV-NP. None of the immunized monkeys develop disease and they rapidly control viral replication. Animals immunized eight days before the challenge are the best controllers, producing a strong CD8 T-cell response against the viral glycoprotein. A group of animals was also vaccinated one hour after the challenge, but was not protected and succumbed to the disease as the control animals. This study demonstrates that MeV-NP can induce a rapid protective immune response against Lassa fever in the presence of MeV pre-existing immunity but can likely not be used as therapeutic vaccine.
Effects of acidification on nitrification and associated nitrous oxide emission in estuarine and coastal waters
Authors: Zhou Jie , Zheng Yanling , Hou Lijun , An Zhirui , Chen Feiyang , Liu Bolin , Wu Li , Qi Lin , Dong Hongpo , Han Ping , Yin Guoyu , Liang Xia , Yang Yi , Li Xiaofei , Gao Dengzhou , Li Ye , Liu Zhanfei , Bellerby Richard , Liu Min
Published: March 2023

In the context of an increasing atmospheric carbon dioxide (CO2) level, acidification of estuarine and coastal waters is greatly exacerbated by land-derived nutrient inputs, coastal upwelling, and complex biogeochemical processes. A deeper understanding of how nitrifiers respond to intensifying acidification is thus crucial to predict the response of estuarine and coastal ecosystems and their contribution to global climate change. Here, we show that acidification can significantly decrease nitrification rate but stimulate generation of byproduct nitrous oxide (N2O) in estuarine and coastal waters. By varying CO2concentration and pH independently, an expected beneficial effect of elevated CO2on activity of nitrifiers (“CO2-fertilization” effect) is excluded under acidification. Metatranscriptome data further demonstrate that nitrifiers could significantly up-regulate gene expressions associated with intracellular pH homeostasis to cope with acidification stress. This study highlights the molecular underpinnings of acidification effects on nitrification and associated greenhouse gas N2O emission, and helps predict the response and evolution of estuarine and coastal ecosystems under climate change and human activities.
Determinants of anemia severity levels among children aged 6–59 months in Ethiopia: Multilevel Bayesian statistical approach
Authors: Alamneh Tesfa Sewunet , Melesse Alemakef Wagnew , Gelaye Kassahun Alemu
Published: March 2023

Anemia is a widespread public health problem that affects all stages of life particularly preschool children and pregnant mothers. Anemia among children had significant impact on their growth, development, school performance and mortality. Different strategies like deworming of young children, vitamin A supplementation for children aged 6–59 months, and ferrous sulphate supplementation and provision of insecticide treated bed net for pregnant women were designed to control and prevent anemia. Also, previous studies on anemia factors were conducted but they were not considering the ordered nature of anemia. Therefore, this study aimed to identify the factors of anemia severity levels among children aged 6–59 months in Ethiopia by using ordinal analysis based on Bayesian hierarchical statistical approach. A secondary data analysis was conducted using the 2016 Ethiopian Demographic and Health Survey data. A total of 8483 weighted children were included. Due to the ordered nature of the anemia and nested nature of DHS data, ordinal logistic regression model based on hierarchical Bayesian statistical approach was employed to identify the determinants of anemia severity levels. In this study, moderate anemia level was found to be the commonest type which accounts around 29.4%. Female children, poorer, middle, and richest wealth index, primary maternal education and having ANC visit had lower risk of having higher order of anemia. Moderate maternal anemia and stunted children had higher chance of having higher order of anemia. Children age had significant different effect on mild and moderate anemia. Meanwhile, multiple birth/s and deworming had effect on moderate anemia. In addition, normal birth weight had also significant and different effect on mild and severe anemia and history of feverlike illness on mild anemia. The prevalence of anemia among children aged 6–59 months anemia was found to be a severe public health problem. Children age, sex, maternal education, child stunting, history of fever, multiple birth, birth weight, provision of deworming and maternal anemia was found to be the most important factors for child anemia severity levels. Therefore, intervention efforts to control and prevent anemia in Ethiopia requires targeting of these hindering factors.
Improving the robustness and stability of a machine learning model for breast cancer prognosis through the use of multi-modal classifiers
Authors: Arya Nikhilanand , Saha Sriparna , Mathur Archana , Saha Snehanshu
Published: March 2023

Breast cancer is a deadly disease with a high mortality rate among PAN cancers. The advancements in biomedical information retrieval techniques have been beneficial in developing early prognosis and diagnosis systems for cancer patients. These systems provide the oncologist with plenty of information from several modalities to make the correct and feasible treatment plan for breast cancer patients and protect them from unnecessary therapies and their toxic side effects. The cancer patient’s related information can be collected using various modalities like clinical, copy number variation, DNA-methylation, microRNA sequencing, gene expression, and histopathological whole slide images. High dimensionality and heterogeneity in these modalities demand the development of some intelligent systems to understand related features to the prognosis and diagnosis of diseases and make correct predictions. In this work, we have studied some end-to-end systems having two main components : (a) dimensionality reduction techniques applied to original features from different modalities and (b) classification techniques applied to the fusion of reduced feature vectors from different modalities for automatic predictions of breast cancer patients into two categories: short-time and long-time survivors. Principal component analysis (PCA) and variational auto-encoders (VAEs) are used as the dimensionality reduction techniques, followed by support vector machines (SVM) or random forest as the machine learning classifiers. The study utilizes raw, PCA, and VAE extracted features of the TCGA-BRCA dataset from six different modalities as input to the machine learning classifiers. We conclude this study by suggesting that adding more modalities to the classifiers provides complementary information to the classifier and increases the stability and robustness of the classifiers. In this study, the multimodal classifiers have not been validated on primary data prospectively.
Top-down and bottom-up effects modulate species co-existence in a context of top predator restoration
Authors: Burgos Tamara , Salesa Javier , Fedriani Jose María , Escribano-Ávila Gema , Jiménez José , Krofel Miha , Cancio Inmaculada , Hernández-Hernández Javier , Rodríguez-Siles Javier , Virgós Emilio
Published: March 2023

Mesopredators abundance is often limited by top-order predators and also by key food resources. However, the contribution of these bidirectional forces to structure carnivore community is still unclear. Here, we studied how the presence and absence of an apex predator which is currently recovering its former distribution range, the Iberian lynx (Lynx pardinus), determined the absolute abundance and fine-scale spatiotemporal avoidance mechanisms of two sympatric mesocarnivores (stone marten Martes foina and common genet Genetta genetta) with different dietary plasticity. We hypothesized that the lynx causes a mesopredator suppression and subordinate predators develop segregation strategies in respect to their trophic niche breadth. We placed 120 camera-traps in Southern Spain for 8 months in two consecutive years to estimate mesocarnivore abundances by using SCR Bayesian models, prey availability and assess spatio-temporal patterns. We found that the lynx reduced mesocarnivore abundance up to 10 times. Stone marten, a mesopredator with a broad food resources spectrum, showed a total spatial exclusion with the apex predator. Meanwhile, fine-scale avoidance mechanisms allowed the genet to persist in low density inside lynx territories, probably taking advantage of high availability of its preferred prey. Thus, the strength of these top-down and bottom-up effects was rather species-specific. Given the recent recovery of large carnivore populations worldwide, variation in suppression levels on different mesopredator species could modify ecosystem functions provided by the carnivore community in contrasting ways.
Spinach (Spinacia oleracea) as green manure modifies the soil nutrients and microbiota structure for enhanced pepper productivity
Authors: Kim Ryeong-Hui , Tagele Setu Bazie , Jeong Minsoo , Jung Da-Ryung , Lee Dokyung , Park TaeHyung , Tino Bashizi Flory , Lim Kyeongmo , Kim Min A. , Park Yeong-Jun , Shin Jae-Ho
Published: March 2023

Spinach has been suggested as a potential rotation crop for increasing crop yield by enhancing beneficial fungal microbes in continuous monocropping. However, no research on the use of spinach as a green manure has been reported. Thus, we tested the effects of spinach and Korean mustard cultivars (green and red mustards) (10 g pot −1) as green manure on soil chemical properties, pepper productivity, and soil microbiome of long-year pepper-monocropped soil. Spinach improved the soil nutrition (e.g., pH, SOM, TN, NH4+, and K), weed suppression, and pepper growth. Spinach had by far the highest fruit yield, over 100% pepper fruit yield increment over the mustard green manures and control. Our study showed that the major influencing factors to cause a shift in both bacterial and fungal community assemblies were soil pH, TC TN, and K. Following green manure amendment Bacillota, especially Clostridium, Bacillus and Sedimentibacter, were enriched, whereas Chloroflexi and Acidobacteriota were reduced. In addition, spinach highly reduced the abundance of Leotiomycetes and Fusarium but enriched Papiliotrema. FAPROTAX and FUNGuild analysis revealed that predicted functional profiles of bacterial and fungal communities in spinach-amended soil were changed. Spinach-treated soil was differentially abundant in function related to hydrocarbon degradation and functional guilds of symbiotrophs and ectomycorrhizal. This study contributes significantly to our understanding of how the soil fertility and soil microbiome alteration via spinach green manure application as a pre-plant soil treatment might help alleviate continuous cropping obstacles.
High-performance glass filters for capturing and culturing circulating tumor cells and cancer-associated fibroblasts
Authors: Tanaka Hiromasa , Iwata Daijiro , Shibata Yuki , Hase Tetsunari , Onoshima Daisuke , Yogo Naoyuki , Shibata Hirofumi , Sato Mitsuo , Ishikawa Kenji , Nagasawa Ikuo , Hasegawa Yoshinori , Ishii Makoto , Baba Yoshinobu , Hori Masaru
Published: March 2023

Various liquid biopsy methods have been developed for the non-invasive and early detection of diseases. In particular, the detection of circulating tumor cells (CTCs) and cancer-associated fibroblasts (CAFs) in blood has been receiving a great deal of attention. We have been developing systems and materials to facilitate such liquid biopsies. In this study, we further developed glass filters (with various patterns of holes, pitches, and non-adhesive coating) that can capture CTCs, but not white blood cells. We optimized the glass filters to capture CTCs, and demonstrated that they could be used to detect CTCs from lung cancer patients. We also used the optimized glass filters for detecting CAFs. Additionally, we further developed a system for visualizing the captured cells on the glass filters. Finally, we demonstrated that we could directly culture the captured cells on the glass filters. Based on these results, our high-performance glass filters appear to be useful for capturing and culturing CTCs and CAFs for further examinations.
CSF tau phosphorylation occupancies at T217 and T205 represent improved biomarkers of amyloid and tau pathology in Alzheimer’s disease
Authors: Barthélemy Nicolas R. , Saef Benjamin , Li Yan , Gordon Brian A. , He Yingxin , Horie Kanta , Stomrud Erik , Salvadó Gemma , Janelidze Shorena , Sato Chihiro , Ovod Vitaliy , Henson Rachel L. , Fagan Anne M. , Benzinger Tammie L. S. , Xiong Chengjie , Morris John C. , Hansson Oskar , Bateman Randall J. , Schindler Suzanne E.
Published: March 2023

Cerebrospinal fluid (CSF) amyloid-β peptide (Aβ)42/Aβ40 and the concentration of tau phosphorylated at site 181 (p-tau181) are well-established biomarkers of Alzheimer’s disease (AD). The present study used mass spectrometry to measure concentrations of nine phosphorylated and five nonphosphorylated tau species and phosphorylation occupancies (percentage phosphorylated/nonphosphorylated) at ten sites. In the present study we show that, in 750 individuals with a median age of 71.2 years, CSF pT217/T217 predicted the presence of brain amyloid by positron emission tomography (PET) slightly better than Aβ42/Aβ40 (P = 0.02). Furthermore, for individuals with positive brain amyloid by PET (n = 263), CSF pT217/T217 was more strongly correlated with the amount of amyloid (Spearman’sρ = 0.69) than Aβ42/Aβ40 (ρ = −0.42,P < 0.0001). In two independent cohorts of participants with symptoms of AD dementia (n = 55 andn = 90), CSF pT217/T217 and pT205/T205 were better correlated with tau PET measures than CSF p-tau181 concentration. These findings suggest that CSF pT217/T217 and pT205/T205 represent improved CSF biomarkers of amyloid and tau pathology in AD.
Characterization of a bloom-associated alphaproteobacterial lineage, ‘Candidatus Phycosocius’: insights into freshwater algal-bacterial interactions
Authors: Tanabe Yuuhiko , Yamaguchi Haruyo , Yoshida Masaki , Kai Atsushi , Okazaki Yusuke
Published: March 2023

Marine bacterial lineages associated with algal blooms, such as the Roseobacter clade, have been well characterized in ecological and genomic contexts, yet such lineages have rarely been explored in freshwater blooms. This study performed phenotypic and genomic analyses of an alphaproteobacterial lineage ‘Candidatus Phycosocius’ (denoted the CaP clade), one of the few lineages ubiquitously associated with freshwater algal blooms, and described a novel species: ‘Ca. Phycosocius spiralis.’ Phylogenomic analyses indicated that the CaP clade is a deeply branching lineage in the Caulobacterales. Pangenome analyses revealed characteristic features of the CaP clade: aerobic anoxygenic photosynthesis and essential vitamin B auxotrophy. Genome size varies widely among members of the CaP clade (2.5–3.7 Mb), likely a result of independent genome reductions at each lineage. This includes a loss of tight adherence pilus genes (tad) in ‘Ca. P. spiralis’ that may reflect its adoption of a unique spiral cell shape and corkscrew-like burrowing activity at the algal surface. Notably, quorum sensing (QS) proteins showed incongruent phylogenies, suggesting that horizontal transfers of QS genes and QS-involved interactions with specific algal partners might drive CaP clade diversification. This study elucidates the ecophysiology and evolution of proteobacteria associated with freshwater algal blooms.
Laser defined and driven bio-inspired soft robots toward complex motion control
Authors: Liu Monan , Wang Qing , Li Ai-Wu , Sun Hong-Bo
Published: March 2023

The design and actuation of soft robots are targeted at extreme motion control as well as high functionalization.