bluuebunny/crossref_metadata_2025 huggingface dataset:
Closing the Reactive Carbon Flux Budget: Observations From Dual Mass Spectrometers Over a Coniferous Forest
Authors: Vermeuel Michael P. , Millet Dylan B. , Farmer Delphine K. , Pothier Matson A. , Link Michael F. , Riches Mj , Williams Sara , Garofalo Lauren A.
Published: July 2023

We use observations from dual high‐resolution mass spectrometers to characterize ecosystem‐atmosphere fluxes of reactive carbon across an extensive range of volatile organic compounds (VOCs) and test how well that exchange is represented in current chemical transport models. Measurements combined proton‐transfer reaction mass spectrometry (PTRMS) and iodide chemical ionization mass spectrometry (ICIMS) over a Colorado pine forest; together, these techniques have been shown to capture the majority of ambient VOC abundance and reactivity. Total VOC mass and associated OH reactivity fluxes were dominated by emissions of 2‐methyl‐3‐buten‐2‐ol, monoterpenes, and small oxygenated VOCs, with a small number of compounds detected by PTRMS driving the majority of both net and upward exchanges. Most of these dominant species are explicitly included in chemical models, and we find here that GEOS‐Chem accurately simulates the net and upward VOC mass and OH reactivity fluxes under clear sky conditions. However, large upward terpene fluxes occurred during sustained rainfall, and these are not captured by the model. Far more species contributed to the downward fluxes than are explicitly modeled, leading to a major underestimation of this key sink of atmospheric reactive carbon. This model bias mainly reflects missing and underestimated concentrations of depositing species, though inaccurate deposition velocities also contribute. The deposition underestimate is particularly large for assumed isoprene oxidation products, organic acids, and nitrates—species that are primarily detected by ICIMS. Net ecosystem‐atmosphere fluxes of ozone reactivity were dominated by sesquiterpenes and monoterpenes, highlighting the importance of these species for predicting near‐surface ozone, oxidants, and aerosols.
Neonatal brain MRI and short-term outcomes after acute provoked seizures
Authors: Li Yi , Scheffler Aaron , Barkovich Anthony James , Chang Taeun , Chu Catherine J. , Massey Shavonne L. , Abend Nicholas S. , Lemmon Monica E. , Thomas Cameron , Numis Adam , Franck Linda S. , Rogers Elizabeth , Callen Andrew , McCulloch Charles E. , Shellhaas Renée A. , Glass Hannah C.
Published: July 2023

Objective

We investigated how diagnosis and injury location on neonatal brain MRI following onset of acute provoked seizures was associated with short term outcome.

Study design

A multicenter cohort of neonates with acute provoked seizures enrolled in the Neonatal Seizure Registry. MRIs were centrally evaluated by a neuroradiologist for location of injury and radiologic diagnosis. Clinical outcomes were determined by chart review. Multivariate logistic regression was used to examine the association between MRI findings and outcomes.

Results

Among 236 newborns with MRI at median age 4 days (IQR 3–8), 91% had abnormal MRI. Radiologic diagnoses of intracranial hemorrhage (OR 3.2 [1.6–6.5], p < 0.001) and hypoxic-ischemic encephalopathy (OR 2.7 [1.4–5.4], p < 0.003) were associated with high seizure burden. Radiologic signs of intracranial infection were associated with abnormal neurologic examination at discharge (OR 3.9 [1.3–11.6], p < 0.01).

Conclusion

Findings on initial MRI can help with expectant counseling on short-term outcomes following acute provoked neonatal seizures.
Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions: reevaluation of the defining characteristics in a registry-based cohort
Authors: Metzgeroth Georgia , Steiner Laurenz , Naumann Nicole , Lübke Johannes , Kreil Sebastian , Fabarius Alice , Haferlach Claudia , Haferlach Torsten , Hofmann Wolf-Karsten , Cross Nicholas C. P. , Schwaab Juliana , Reiter Andreas
Published: July 2023

In a registry-based analysis of 135 patients with “myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions” (MLN-TK; FIP1L1::PDGFRA, n = 78; PDGFRB, diverse fusions, n = 26; FGFR1, diverse, n = 9; JAK2, diverse, n = 11; ETV6::ABL1, n = 11), we sought to evaluate the disease-defining characteristics. In 81/135 (60%) evaluable patients, hypereosinophilia (>1.5 × 109/l) was observed in 40/44 (91%) FIP1L1::PDGFRA and 7/7 (100%) ETV6::ABL1 positive patients but only in 13/30 (43%) patients with PDGFRB, FGFR1, and JAK2 fusion genes while 9/30 (30%) patients had no eosinophilia. Monocytosis >1 × 109/l was identified in 27/81 (33%) patients, most frequently in association with hypereosinophilia (23/27, 85%). Overall, a blast phase (BP) was diagnosed in 38/135 (28%) patients (myeloid, 61%; lymphoid, 39%), which was at extramedullary sites in 18 (47%) patients. The comparison between patients with PDGFRA/PDGFRB vs. FGFR1, JAK2, and ETV6::ABL1 fusion genes revealed a similar occurrence of primary BP (17/104, 16% vs. 8/31 26%, p = 0.32), a lower frequency (5/87, 6% vs. 8/23, 35%, p = 0.003) of and a later progression (median 87 vs. 19 months, p = 0.053) into secondary BP, and a better overall survival from diagnosis of BP (17.1 vs. 1.7 years, p < 0.0008). We conclude that hypereosinophilia with or without monocytosis and various phenotypes of BP occur at variable frequencies in MLN-TK.
Resistance to immune checkpoint therapies by tumour-induced T-cell desertification and exclusion: key mechanisms, prognostication and new therapeutic opportunities
Authors: Wang Mona Meng , Coupland Sarah E. , Aittokallio Tero , Figueiredo Carlos R.
Published: July 2023

Immune checkpoint therapies (ICT) can reinvigorate the effector functions of anti-tumour T cells, improving cancer patient outcomes. Anti-tumour T cells are initially formed during their first contact (priming) with tumour antigens by antigen-presenting cells (APCs). Unfortunately, many patients are refractory to ICT because their tumours are considered to be ‘cold’ tumours—i.e., they do not allow the generation of T cells (so-called ‘desert’ tumours) or the infiltration of existing anti-tumour T cells (T-cell-excluded tumours). Desert tumours disturb antigen processing and priming of T cells by targeting APCs with suppressive tumour factors derived from their genetic instabilities. In contrast, T-cell-excluded tumours are characterised by blocking effective anti-tumour T lymphocytes infiltrating cancer masses by obstacles, such as fibrosis and tumour-cell-induced immunosuppression. This review delves into critical mechanisms by which cancer cells induce T-cell ‘desertification’ and ‘exclusion’ in ICT refractory tumours. Filling the gaps in our knowledge regarding these pro-tumoral mechanisms will aid researchers in developing novel class immunotherapies that aim at restoring T-cell generation with more efficient priming by APCs and leukocyte tumour trafficking. Such developments are expected to unleash the clinical benefit of ICT in refractory patients.
Flt1 produced by lung endothelial cells impairs ATII cell transdifferentiation and repair in pulmonary fibrosis
Authors: Volpe Maria Concetta , Ciucci Giulio , Zandomenego Giulia , Vuerich Roman , Ring Nadja Anneliese Ruth , Vodret Simone , Salton Francesco , Marchesan Pietro , Braga Luca , Marcuzzo Thomas , Bussani Rossana , Colliva Andrea , Piazza Silvano , Confalonieri Marco , Zacchigna Serena
Published: July 2023

Pulmonary fibrosis is a devastating disease, in which fibrotic tissue progressively replaces lung alveolar structure, resulting in chronic respiratory failure. Alveolar type II cells act as epithelial stem cells, being able to transdifferentiate into alveolar type I cells, which mediate gas exchange, thus contributing to lung homeostasis and repair after damage. Impaired epithelial transdifferentiation is emerging as a major pathogenetic mechanism driving both onset and progression of fibrosis in the lung. Here, we show that lung endothelial cells secrete angiocrine factors that regulate alveolar cell differentiation. Specifically, we build on our previous data on the anti-fibrotic microRNA-200c and identify the Vascular Endothelial Growth Factor receptor 1, also named Flt1, as its main functional target in endothelial cells. Endothelial-specific knockout of Flt1 reproduces the anti-fibrotic effect of microRNA-200c against pulmonary fibrosis and results in the secretion of a pool of soluble factors and matrix components able to promote epithelial transdifferentiation in a paracrine manner. Collectively, these data indicate the existence of a complex endothelial-epithelial paracrine crosstalk in vitro and in vivo and position lung endothelial cells as a relevant therapeutic target in the fight against pulmonary fibrosis.
HSPB1 facilitates chemoresistance through inhibiting ferroptotic cancer cell death and regulating NF-κB signaling pathway in breast cancer
Authors: Liang Yiran , Wang Yajie , Zhang Yan , Ye Fangzhou , Luo Dan , Li Yaming , Jin Yuhan , Han Dianwen , Wang Zekun , Chen Bing , Zhao Wenjing , Wang Lijuan , Chen Xi , Ma Tingting , Kong Xiaoli , Yang Qifeng
Published: July 2023

Chemoresistance is one of the major causes of therapeutic failure and poor prognosis for breast cancer patients, especially for triple-negative breast cancer patients. However, the underlying mechanism remains elusive. Here, we identified novel functional roles of heat shock protein beta-1 (HSPB1), regulating chemoresistance and ferroptotic cell death in breast cancer. Based on TCGA and GEO databases, HSPB1 expression was upregulated in breast cancer tissues and associated with poor prognosis of breast cancer patients, which was considered an independent prognostic factor for breast cancer. Functional assays revealed that HSPB1 could promote cancer growth and metastasis in vitro and in vivo. Furthermore, HSPB1 facilitated doxorubicin (DOX) resistance through protecting breast cancer cells from drug-induced ferroptosis. Mechanistically, HSPB1 could bind with Ikβ-α and promote its ubiquitination-mediated degradation, leading to increased nuclear translocation and activation of NF-κB signaling. In addition, HSPB1 overexpression led to enhanced secretion of IL6, which further facilitated breast cancer progression. These findings revealed that HSPB1 upregulation might be a key driver to progression and chemoresistance through regulating ferroptosis in breast cancer while targeting HSPB1 could be an effective strategy against breast cancer.
miR-221/222 induce instability of p53 By downregulating deubiquitinase YOD1 in acute myeloid leukemia
Authors: Pei Han Zhong , Peng Zhiyong , Zhuang Xiaomei , Wang Xiaobo , Lu Bo , Guo Yao , Zhao Yuming , Zhang Dengyang , Xiao Yunjun , Gao Tianshun , Yu Liuting , He Chunxiao , Wu Shunjie , Baek Suk-Hwan , Zhao Zhizhuang Joe , Xu Xiaojun , Chen Yun
Published: July 2023

Acute myeloid leukemia (AML) is a hematological malignancy characterized by the impaired differentiation and uncontrolled proliferation of myeloid blasts. Tumor suppressor p53 is often downregulated in AML cells via ubiquitination-mediated degradation. While the role of E3 ligase MDM2 in p53 ubiquitination is well-accepted, little is known about the involvement of deubiquitinases (DUBs). Herein, we found that the expression of YOD1, among several DUBs, is substantially reduced in blood cells from AML patients. We identified that YOD1 deubiqutinated and stabilized p53 through interaction via N-terminus of p53 and OTU domain of YOD1. In addition, expression levels of YOD1 were suppressed by elevated miR-221/222 in AML cells through binding to the 3′ untranslated region of YOD1, as verified by reporter gene assays. Treatment of cells with miR-221/222 mimics and inhibitors yielded the expected effects on YOD1 expressions, in agreement with the negative correlation observed between the expression levels of miR-221/222 and YOD1 in AML cells. Finally, overexpression of YOD1 stabilized p53, upregulated pro-apoptotic p53 downstream genes, and increased the sensitivity of AML cells to FLT3 inhibitors remarkably. Collectively, our study identified a pathway connecting miR-221/222, YOD1, and p53 in AML. Targeting miR-221/222 and stimulating YOD1 activity may improve the therapeutic effects of FLT3 inhibitors in patients with AML.
Loss of PML nuclear bodies in familial amyotrophic lateral sclerosis-frontotemporal dementia
Authors: Antoniani Francesco , Cimino Marco , Mediani Laura , Vinet Jonathan , Verde Enza M. , Secco Valentina , Yamoah Alfred , Tripathi Priyanka , Aronica Eleonora , Cicardi Maria E. , Trotti Davide , Sterneckert Jared , Goswami Anand , Carra Serena
Published: July 2023

Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are two neurodegenerative disorders that share genetic causes and pathogenic mechanisms. The critical genetic players of ALS and FTD are the TARDBP, FUS and C9orf72 genes, whose protein products, TDP-43, FUS and the C9orf72-dipeptide repeat proteins, accumulate in form of cytoplasmic inclusions. The majority of the studies focus on the understanding of how cells control TDP-43 and FUS aggregation in the cytoplasm, overlooking how dysfunctions occurring at the nuclear level may influence the maintenance of protein solubility outside of the nucleus. However, protein quality control (PQC) systems that maintain protein homeostasis comprise a cytoplasmic and a nuclear arm that are interconnected and share key players. It is thus conceivable that impairment of the nuclear arm of the PQC may have a negative impact on the cytoplasmic arm of the PQC, contributing to the formation of the cytoplasmic pathological inclusions. Here we focused on two stress-inducible condensates that act as transient deposition sites for misfolding-prone proteins: Promyelocytic leukemia protein (PML) nuclear bodies (PML-NBs) and cytoplasmic stress granules (SGs). Upon stress, PML-NBs compartmentalize misfolded proteins, including defective ribosomal products (DRiPs), and recruit chaperones and proteasomes to promote their nuclear clearance. SGs transiently sequester aggregation-prone RNA-binding proteins linked to ALS-FTD and mRNAs to attenuate their translation. We report that PML assembly is impaired in the human brain and spinal cord of familial C9orf72 and FUS ALS-FTD cases. We also show that defective PML-NB assembly impairs the compartmentalization of DRiPs in the nucleus, leading to their accumulation inside cytoplasmic SGs, negatively influencing SG dynamics. Although it is currently unclear what causes the decrease of PML-NBs in ALS-FTD, our data highlight the existence of a cross-talk between the cytoplasmic and nuclear PQC systems, whose alteration can contribute to SG accumulation and cytoplasmic protein aggregation in ALS-FTD.
Soft corrugated channel with synergistic exclusive discrimination gating for CO2 recognition in gas mixture
Authors: Gu Yifan , Zheng Jia-Jia , Otake Ken-ichi , Sakaki Shigeyoshi , Ashitani Hirotaka , Kubota Yoshiki , Kawaguchi Shogo , Yao Ming-Shui , Wang Ping , Wang Ying , Li Fengting , Kitagawa Susumu
Published: July 2023

Developing artificial porous systems with high molecular recognition performance is critical but very challenging to achieve selective uptake of a particular component from a mixture of many similar species, regardless of the size and affinity of these competing species. A porous platform that integrates multiple recognition mechanisms working cooperatively for highly efficient guest identification is desired. Here, we designed a flexible porous coordination polymer (PCP) and realised a corrugated channel system that cooperatively responds to only target gas molecules by taking advantage of its stereochemical shape, location of binding sites, and structural softness. The binding sites and structural deformation act synergistically, exhibiting exclusive discrimination gating (EDG) effect for selective gate-opening adsorption of CO2 over nine similar gas molecules, including N2, CH4, CO, O2, H2, Ar, C2H6, and even higher-affinity gases such as C2H2 and C2H4. Combining in-situ crystallographic experiments with theoretical studies, it is clear that this unparalleled ability to decipher the CO2 molecule is achieved through the coordination of framework dynamics, guest diffusion, and interaction energetics. Furthermore, the gas co-adsorption and breakthrough separation performance render the obtained PCP an efficient adsorbent for CO2 capture from various gas mixtures.
Inheritance of associative memories and acquired cellular changes in C. elegans
Authors: Deshe Noa , Eliezer Yifat , Hoch Lihi , Itskovits Eyal , Bokman Eduard , Ben-Ezra Shachaf , Zaslaver Alon
Published: July 2023

Experiences have been shown to modulate behavior and physiology of future generations in some contexts, but there is limited evidence for inheritance of associative memory in different species. Here, we trained C. elegans nematodes to associate an attractive odorant with stressful starvation conditions and revealed that this associative memory was transmitted to the F1 progeny who showed odor-evoked avoidance behavior. Moreover, the F1 and the F2 descendants of trained animals exhibited odor-evoked cellular stress responses, manifested by the translocation of DAF-16/FOXO to cells’ nuclei. Sperm, but not oocytes, transmitted these odor-evoked cellular stress responses which involved H3K9 and H3K36 methylations, the small RNA pathway machinery, and intact neuropeptide secretion. Activation of a single chemosensory neuron sufficed to induce a serotonin-mediated systemic stress response in both the parental trained generation and in its progeny. Moreover, inheritance of the cellular stress responses increased survival chances of the progeny as exposure to the training odorant allowed the animals to prepare in advance for an impending adversity. These findings suggest that in C. elegans associative memories and cellular changes may be transferred across generations.
Complementarity in Allen’s and Bergmann’s rules among birds
Authors: Baldwin Justin W. , Garcia-Porta Joan , Botero Carlos A.
Published: July 2023

Biologists have long noted that endotherms tend to have larger bodies (Bergmann’s rule) and shorter appendages (Allen’s rule) in colder environments. Nevertheless, many taxonomic groups appear not to conform to these ‘rules’, and general explanations for these frequent exceptions are currently lacking. Here we note that by combining complementary changes in body and extremity size, lineages could theoretically respond to thermal gradients with smaller changes in either trait than those predicted by either Bergmann’s or Allen’s rule alone. To test this idea, we leverage geographic, ecological, phylogenetic, and morphological data on 6,974 non-migratory terrestrial bird species, and show that stronger family-wide changes in bill size over thermal gradients are correlated with more muted changes in body size. Additionally, we show that most bird families exhibit weak but appropriately directed changes in both traits, supporting the notion of complementarity in Bergmann’s and Allen’s rules. Finally, we show that the few families that exhibit significant gradients in either bill or body size, tend to be more speciose, widely distributed, or ecologically constrained. Our findings validate Bergmann’s and Allen’s logic and remind us that body and bill size are simply convenient proxies for their true quantity of interest: the surface-to-volume ratio.
The structural basis of divalent cation block in a tetrameric prokaryotic sodium channel
Authors: Irie Katsumasa , Oda Yoshinori , Sumikama Takashi , Oshima Atsunori , Fujiyoshi Yoshinori
Published: July 2023

Divalent cation block is observed in various tetrameric ion channels. For blocking, a divalent cation is thought to bind in the ion pathway of the channel, but such block has not yet been directly observed. So, the behaviour of these blocking divalent cations remains still uncertain. Here, we elucidated the mechanism of the divalent cation block by reproducing the blocking effect into NavAb, a well-studied tetrameric sodium channel. Our crystal structures of NavAb mutants show that the mutations increasing the hydrophilicity of the inner vestibule of the pore domain enable a divalent cation to stack on the ion pathway. Furthermore, non-equilibrium molecular dynamics simulation showed that the stacking calcium ion repel sodium ion at the bottom of the selectivity filter. These results suggest the primary process of the divalent cation block mechanism in tetrameric cation channels.
Carbene-catalyzed chemoselective reaction of unsymmetric enedials for access to Furo[2,3-b]pyrroles
Authors: Fan Guodong , Wang Qingyun , Xu Jun , Zheng Pengcheng , Chi Yonggui Robin
Published: July 2023

A carbene-catalyzed chemoselective reaction of unsymmetric enedials is disclosed. The reaction provides a concise access to bicyclic furo[2,3-b]pyrroles derivatives in excellent selectivity. A main challenge in this reaction is chemoselective reaction of the two aldehyde moieties in the enedial substrates. Mechanistic studies via experiments suggest that our chemoselectivity controls are mostly achieved on the reducing properties of different sited Breslow intermediates. Several side reactions processes and the corresponding side adducts are also studied by high resolution mass spectroscopy analysis. Our method allows for efficient assembly of the furo[2,3-b]pyrrole structural moieties and their analogues widely found in natural products and pharmaceuticals.
Cooperative microbial interactions drive spatial segregation in porous environments
Authors: Wu Yichao , Fu Chengxia , Peacock Caroline L. , Sørensen Søren J. , Redmile-Gordon Marc A. , Xiao Ke-Qing , Gao Chunhui , Liu Jun , Huang Qiaoyun , Li Zixue , Song Peiyi , Zhu Yongguan , Zhou Jizhong , Cai Peng
Published: July 2023

The role of microbial interactions and the underlying mechanisms that shape complex biofilm communities are poorly understood. Here we employ a microfluidic chip to represent porous subsurface environments and show that cooperative microbial interactions between free-living and biofilm-forming bacteria trigger active spatial segregation to promote their respective dominance in segregated microhabitats. During initial colonization, free-living and biofilm-forming microbes are segregated from the mixed planktonic inoculum to occupy the ambient fluid and grain surface. Contrary to spatial exclusion through competition, the active spatial segregation is induced by cooperative interactions which improves the fitness of both biofilm and planktonic populations. We further show that free-living Arthrobacter induces the surface colonization by scavenging the biofilm inhibitor, D-amino acids and receives benefits from the public goods secreted by the biofilm-forming strains. Collectively, our results reveal how cooperative microbial interactions may contribute to microbial coexistence in segregated microhabitats and drive subsurface biofilm community succession.
Photothermal recycling of waste polyolefin plastics into liquid fuels with high selectivity under solvent-free conditions
Authors: Miao Yingxuan , Zhao Yunxuan , Waterhouse Geoffrey I. N. , Shi Run , Wu Li-Zhu , Zhang Tierui
Published: July 2023

The widespread use of polyolefin plastics in modern societies generates huge amounts of plastic waste. With a view toward sustainability, researchers are now seeking novel and low-cost strategies for recycling and valorizing polyolefin plastics. Herein, we report the successful development of a photothermal catalytic recycling system for transforming polyolefin plastics into liquid/waxy fuels under concentrated sunlight or xenon lamp irradiation. Photothermal heating of a Ru/TiO2 catalyst to 200–300 °C in the presence of polyolefin plastics results in intimate catalyst-plastic contact and controllable hydrogenolysis of C-C and C-H bonds in the polymer chains (mediated by Ru sites). By optimizing the reaction temperature and pressure, the complete conversion of waste polyolefins into valuable liquid fuels (86% gasoline- and diesel-range hydrocarbons, C5-C21) is possible in short periods (3 h). This work demonstrates a simple and efficient strategy for recycling waste polyolefin plastics using abundant solar energy.
In vitro and in vivo characterization of SARS-CoV-2 resistance to ensitrelvir
Authors: Kiso Maki , Yamayoshi Seiya , Iida Shun , Furusawa Yuri , Hirata Yuichiro , Uraki Ryuta , Imai Masaki , Suzuki Tadaki , Kawaoka Yoshihiro
Published: July 2023

Ensitrelvir, an oral antiviral agent that targets a SARS-CoV-2 main protease (3CLpro or Nsp5), is clinically useful against SARS-CoV-2 including its omicron variants. Since most omicron subvariants have reduced sensitivity to most monoclonal antibody therapies, SARS-CoV-2 resistance to other antivirals including main protease inhibitors such as ensitrelvir is a major public health concern. Here, repeating passages of SARS-CoV-2 in the presence of ensitrelvir revealed that the M49L and E166A substitutions in Nsp5 are responsible for reduced sensitivity to ensitrelvir. Both substitutions reduced in vitro virus growth in the absence of ensitrelvir. The combination of the M49L and E166A substitutions allowed the virus to largely evade the suppressive effect of ensitrelvir in vitro. The virus possessing Nsp5-M49L showed similar pathogenicity to wild-type virus, whereas the virus possessing Nsp5-E166A or Nsp5-M49L/E166A slightly attenuated. Ensitrelvir treatment of hamsters infected with the virus possessing Nsp5-M49L/E166A was ineffective; however, nirmatrelvir or molnupiravir treatment was effective. Therefore, it is important to closely monitor the emergence of ensitrelvir-resistant SARS-CoV-2 variants to guide antiviral treatment selection.
Mass spectrometry imaging for biosolids characterization to assess ecological or health risks before reuse
Authors: Villette Claire , Maurer Loïc , Zumsteg Julie , Mutterer Jérôme , Wanko Adrien , Heintz Dimitri
Published: July 2023

Biosolids are byproducts of wastewater treatment. With the increasing global population, the amounts of wastewater to be treated are expanding, along with the amounts of biosolids generated. The reuse of biosolids is now accepted for diversified applications in fields such as agriculture, engineering, agro-forestry. However, biosolids are known to be potential carriers of compounds that can be toxic to living beings or alter the environment. Therefore, biosolid reuse is subject to regulations, mandatory analyses are performed on heavy metals, persistent organic pollutants or pathogens. Conventional methods for the analysis of heavy metals and persistent organic pollutants are demanding, lengthy, and sometimes unsafe. Here, we propose mass spectrometry imaging as a faster and safer method using small amounts of material to monitor heavy metals and persistent organic pollutants in different types of biosolids, allowing for ecological and health risk assessment before reuse. Our methodology can be extended to other soil-like matrices.
A large-scale Boolean model of the rheumatoid arthritis fibroblast-like synoviocytes predicts drug synergies in the arthritic joint
Authors: Singh Vidisha , Naldi Aurelien , Soliman Sylvain , Niarakis Anna
Published: July 2023

Rheumatoid arthritis (RA) is a complex autoimmune disease with an unknown aetiology. However, rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) play a significant role in initiating and perpetuating destructive joint inflammation by expressing immuno-modulating cytokines, adhesion molecules, and matrix remodelling enzymes. In addition, RA-FLS are primary drivers of inflammation, displaying high proliferative rates and an apoptosis-resistant phenotype. Thus, RA-FLS-directed therapies could become a complementary approach to immune-directed therapies by predicting the optimal conditions that would favour RA-FLS apoptosis, limit inflammation, slow the proliferation rate and minimise bone erosion and cartilage destruction. In this paper, we present a large-scale Boolean model for RA-FLS that consists of five submodels focusing on apoptosis, cell proliferation, matrix degradation, bone erosion and inflammation. The five-phenotype-specific submodels can be simulated independently or as a global model. In silico simulations and perturbations reproduced the expected biological behaviour of the system under defined initial conditions and input values. The model was then used to mimic the effect of mono or combined therapeutic treatments and predict novel targets and drug candidates through drug repurposing analysis.
Altered neutrophil-to-lymphocyte ratio in patients with non-affective first episode psychosis and its relationship with symptom severity and cognitive impairment
Authors: Leung Kwan Keung , Wong Yip Chau , Shea Ka Sin , Chan Sheung Chun , Chang Wing Chung , Mo Yi Man Flora , Chan Sau Man Sandra
Published: July 2023

Signatures of immune dysregulation as clinical biomarker for psychosis have remained unclear. We aimed to compare the Neutrophil-to-lymphocyte ratio (NLR) of patients with acute non-affective first-episode psychosis (FEP) with healthy controls after accounting for emotional states. We also explored the associations of NLR with symptom severity, onset profile and cognitive functions. The NLR was enumerated from complete blood count taken within a week of assessment. All FEP patients were rated on the Positive and Negative Syndrome Scale (PANSS) and the Clinician Global Impression-Severity (CGI-S) with verbal memory and executive functions assessed with the Cambridge Neuropsychological Test Automated Battery. Prevailing emotional state was measured with Beck Depression Inventory-II and Beck Anxiety Inventory. Out of seventy-nine consecutive FEP patients presenting to the study site, twenty-seven subjects were eligible and recruited. Twenty-seven age-/sex-matched controls were recruited. FEP patients had an NLR of 1.886 over the controls after accounting for scores on emotional states. The NLR of FEP patients was positively associated with CGI-S scores, PANSS positive symptom, disorganization and excitation scores. There was no significant correlation between NLR with the duration of untreated psychosis and cognitive performances. These findings support using NLR as a clinical biomarker in FEP, purporting further prospective study to measure NLR changes in the course of treatment.
Advantages and potential limitations of applying AFM kymograph analysis to pharmaceutically relevant membrane proteins in lipid bilayers
Authors: Schaefer Katherine G. , Roberts Arthur G. , King Gavin M.
Published: July 2023

Membrane proteins play critical roles in disease and in the disposition of many pharmaceuticals. A prime example is P-glycoprotein (Pgp) which moves a diverse range of drugs across membranes and out of the cell before a therapeutic payload can be delivered. Conventional structural biology methods have provided a valuable framework for comprehending the complex conformational changes underlying Pgp function, which also includes ATPase activity, but the lack of real-time information hinders understanding. Atomic force microscopy (AFM) is a single-molecule technique that is well-suited for studying active membrane proteins in bilayers and is poised to advance the field beyond static snapshots. After verifying Pgp activity in surface-support bilayers, we used kymograph analysis in conjunction with AFM imaging and simulations to study structural transitions at the 100 ms timescale. Though kymographs are frequently employed to boost temporal resolution, the limitations of the method have not been well characterized, especially for sparse non-crystalline distributions of pharmaceutically relevant membrane proteins like Pgp. Common experimental challenges are analyzed, including protein orientation, instrument noise, and drift. Surprisingly, a lateral drift of 75% of the protein dimension leads to only a 12% probability of erroneous state transition detection; average dwell time error achieves a maximum value of 6%. Rotational drift of proteins like Pgp, with azimuthally-dependent maximum heights, can lead to artifactual transitions. Torsional constraints can alleviate this potential pitfall. Confidence in detected transitions can be increased by adding conformation-altering ligands such as non-hydrolysable analogs. Overall, the data indicate that AFM kymographs are a viable method to access conformational dynamics for Pgp, but generalizations of the method should be made with caution.
The benefits of mind wandering on a naturalistic prospective memory task
Authors: Girardeau J. C. , Ledru R. , Gaston-Bellegarde A. , Blondé P. , Sperduti M. , Piolino P.
Published: July 2023

Mind wandering (MW) occurs when our attention spontaneously shifts from the task at hand to inner thoughts. MW is often future-oriented and may help people remember to carry out their planned actions (Prospective Memory, PM). Past-oriented MW might also play a critical role in boosting PM performance. Sixty participants learned 24 PM items and recalled them during an immersive virtual walk in a town. The items were divided into event-based—EB and time-based—TB. During the PM retention phase, participants were randomly assigned to a high or a low cognitive load condition, in order to manipulate MW frequency. Some PM items were encoded before this MW manipulation (pre-PM) and some during the virtual walk (post-PM). A high MW frequency was linked with better global PM performances. Spontaneous past-oriented MW predicted better pre-EB retrospective PM retrieval, while spontaneous future-oriented MW predicted better Pre-EB prospective PM retrieval. Voluntary future-oriented MW predicted better post-EB retrospective retrieval. We highlighted, for the first time, a differential impact of spontaneous MW content depending on the PM component (retrospective or prospective). Past‐oriented MW is crucial for (re)consolidating PM intentions, and episodic future thinking MW for the execution of PM intentions. We discuss the twofold functional role of MW, namely, to consolidate an already programmed intention and to plan future actions.
Chemical doping to control the in-situ formed doping structure in light-emitting electrochemical cells
Authors: Huseynova Gunel , Ràfols-Ribé Joan , Auroux Etienne , Huang Ping , Tang Shi , Larsen Christian , Edman Ludvig
Published: July 2023

The initial operation of a light-emitting electrochemical cell (LEC) constitutes the in-situ formation of a p–n junction doping structure in the active material by electrochemical doping. It has been firmly established that the spatial position of the emissive p–n junction in the interelectrode gap has a profound influence on the LEC performance because of exciton quenching and microcavity effects. Hence, practical strategies for a control of the position of the p–n junction in LEC devices are highly desired. Here, we introduce a “chemical pre-doping” approach for the rational shifting of the p–n junction for improved performance. Specifically, we demonstrate, by combined experiments and simulations, that the addition of a strong chemical reductant termed “reduced benzyl viologen” to a common active-material ink during LEC fabrication results in a filling of deep electron traps and an associated shifting of the emissive p–n junction from the center of the active material towards the positive anode. We finally demonstrate that this chemical pre-doping approach can improve the emission efficiency and stability of a common LEC device.
Investigation of the therapeutic role of native plant compounds against colorectal cancer based on system biology and virtual screening
Authors: Alibakhshi Abbas , Malekzadeh Rahim , Hosseini Sayedeh Azimeh , Yaghoobi Hajar
Published: July 2023

This study investigated the anticancer effects of compounds extracted from native plants on colon cancer following drug–target-network analysis and molecular docking. Based on the ChEBI database, compounds were identified in medicinal plants and weeds in the Chaharmahal and Bakhtiari provinces of Iran. A drug–target network was constructed based on candidate colon cancer protein targets and selective compounds. Network pharmacology analysis was conducted against the identified compounds and subjected to molecular docking studies. Based on molecular dynamics simulations, the most efficient compounds were evaluated for their anticancer effects. Our study suggests that TREM1, MAPK1, MAPK8, CTSB, MIF, and DPP4 proteins may be targeted by compounds in medicinal plants for their anti-cancer effects. Multiorthoquinone, Liquiritin, Isoliquiritin, Hispaglabridin A, Gibberellin A98, Cyclomulberrin, Cyclomorusin A, and Cudraflavone B are effective anticancer compounds found in targeted medicinal plants and play an important role in the regulation of important pathways in colon cancer. Compounds that inhibit MIF, CTSB, and MAPK8-16 appear to be more effective. Additional in vitro and in vivo experiments will be helpful in validating and optimizing the findings of this study.
Organic electrochemical transistors printed from degradable materials as disposable biochemical sensors
Authors: Fumeaux Nicolas , Almeida Claudio Pinto , Demuru Silvia , Briand Danick
Published: July 2023

Transient electronics hold promise in reducing electronic waste, especially in applications that require only a limited lifetime. While various degradable electronic and physical sensing devices have been proposed, there is growing interest in the development of degradable biochemical sensors. In this work, we present the development of an organic electrochemical transistor (OECT) with degradable electrodes, printed on an eco- and bioresorbable substrate. The influence of the design and materials for the contacts, channel and gate of the transducer, namely poly(3,4-ethylene dioxythiophene):polystyrene sulfonate (PEDOT:PSS) and carbon, is systematically evaluated for the development of OECT-based transient biosensors. The sensing capabilities of the electrochemical transistors are demonstrated with ionic solutions as well as for the enzyme-based detection of glucose. The disposable OECTs show comparable performance to their non-degradable counterparts. Their integration with highly conductive degradable and printable zinc tracks is studied for the realization of interconnects. These eco-friendly OECTs may find applications as disposable and sustainable biochemical sensors, and constitute a step towards bioresorbable biosensors.
A randomized clinical trial of omega-3 fatty acid and vitamin D supplementation on electrocardiographic risk profiles
Authors: Tikkanen Jani T. , Soliman Elsayed Z. , Pester Julie , Danik Jacqueline S. , Gomelskya Natalia , Copeland Trisha , Lee I.-Min , Buring Julie E. , Manson JoAnn E. , Cook Nancy R. , Albert Christine M.
Published: July 2023

Beneficial and adverse associations with arrhythmias have been reported for omega-3 fatty acids (omega-3 FA) and Vitamin D. The 12 lead electrocardiogram (ECG) contains quantitative measures reflecting diverse aspects of electrophysiology that might provide insights into mechanisms underlying these associations. In a pre-specified ancillary study of the VITaminD and omegA-3 (VITAL) trial, we examined the effect of 1 g of marine omega-3 FA per day, comprised of 460 mg eicosapentanoic acid and 380 mg of docosahexaenoic acid, and 2000 IU VitaminD3 per day on ECG characteristics associated with atrial and ventricular arrhythmias among individuals age 50 years or greater. A total of 911 study participants underwent ECGs at baseline and again at 2 years after the randomization. Individuals randomized to active omega-3 FA demonstrated significant net increase in PR-interval duration (p = 0.005) and P-wave duration (p = 0.03) as well significant net decrease in P-wave amplitude (p = 0.037) as compared to placebo. RMSSD increased to a greater extent in the omega-3 FA arm compared to placebo (p = 0.040). For Vitamin D3, the Cornell voltage increased to a lesser extent in the participants assigned to active treatment as compared to placebo (p = 0.044). There were no other significant differences in QRS, QTc, Cornell voltage or heart rate. Thus, randomized treatment with omega-3 FA supplements resulted in changes on the ECG that are potentially reflective of heightened vagal tone and/or slowing of intraatrial and AV conduction. Vitamin D3 supplementation resulted in modest reductions in progressive LV voltage suggestive of a potential antihypertrophic effect.

Trial registration ClinicalTrials.gov Identifiers: NCT01169259, NCT02178410 (06/26/2010 and 06/30/2014).
Preliminary experience of CT imaging of the ischaemic brain penumbra through spectral processing of multiphasic CTA datasets
Authors: Duprez T. , Vlassenbroek A. , Peeters A. , Poncelet P. A. , Levecque E. , Austein F. , Pahn G. , Nae Y. , Abdallah S. , Coche E.
Published: July 2023

To assess ischaemic penumbra through the post-processing of the spectral multiphasic CT Angiography (mCTA) data in acute ischaemic stroke (AIS) patients. Thirty one consecutive patients strongly suspected of severe Middle Cerebral Artery AIS presenting less than 6 h after onset of symptoms or with unknown time of onset of symptoms underwent a standardized CT protocol in spectral mode including Non Contrast CT, mCTA, and Perfusion CT (CTP) on a dual-layer MDCT system. Areas disclosing delayed enhancement on iodine density (ID) maps were highlighted by subtraction of the serial mCTA datasets. Two neuroradiologists independently rated the correspondence between delayed enhancing areas at mCTA and the penumbral/infarcted areas delineated by two validated CTP applications using a 5-levels scoring scale. Interobserver agreement between observers was evaluated by kappa statistics. Dose delivery was recorded for each acquisition. Averaged correspondence score between penumbra delineation using subtracted mCTA-derived ID maps and CTP ones was 2.76 for one application and 2.9 for the other with best interobserver agreement kappa value at 0.59. All 6 stroke mimics out of the 31 patients’ cohort were correctly identified. Average dose delivery was 7.55 mSv for the whole procedure of which CTP accounted for 39.7%. Post-processing of spectral mCTA data could allow clinically relevant assessment of the presence or absence of ischaemic penumbra in AIS-suspected patients if results of this proof-of-concept study should be confirmed in larger patients’series.
Association of killer cell immunoglobulin-like receptors and their cognate HLA class I ligands with susceptibility to acute myeloid leukemia in Iranian patients
Authors: Mirzazadeh Sara , Bemani Peyman , Halimi Hossein , Sanaee Mohammad Nabi , Karami Narges , Ramzi Mani , Farjadian Shirin
Published: July 2023

Acute myeloid leukemia (AML) is one of the most prevalent leukemia in adults. Among the various NK receptors, killer immunoglobulin-like receptors (KIRs) carry out indispensable roles in NK cell development and function through engaging with class I human leukocyte antigens (HLA-I) as their ligands. Besides divergent KIR and HLA loci, KIR/HLA-I combinations have a significant effect on NK cell response. In this case–control study, we aimed to verify the association of KIR/HLA-I combinations with susceptibility to AML in the Southwestern Iranian population. KIR and HLA genotyping was performed with PCR-SSP by some novel primers for 181 patients with AML and 181 healthy controls. According to our results, the frequencies of KIR3DS1 (p = 0.0001, OR = 2.32, 95% CI 1.51–3.58), KIR2DS4fl (p = 0.02, OR = 1.53, 95% CI 1.05–2.21), CxT4 genotypes (p = 0.03, OR = 2.0, 95% CI 1.05–3.82), and T4 gene cluster (p = 0.01, OR = 1.99, 95% CI 1.17–3.41) were significantly higher in patients than controls, while C1/C2 genotype (p = 0.00002, OR = 0.39, 95% CI 0.25–0.61), HLA-A Bw4 (p = 0.02, OR = 0.6, 95% CI 0.38–0.94), and HLA-A*11 (p = 0.03, OR = 0.57, 95% CI 0.34–0.95) alleles were more frequent in controls. In addition, inhibitory (i)KIR/HLA-I combinations analysis revealed higher frequencies of KIR2DL1( +)/HLA-C2( +), KIR2DL2/3( +)/HLA-C1( +), KIR3DL1( +)/HLA-A Bw4( +), and KIR3DL2( +)/HLA-A*03/11( +) in the control group (p = 0.002, OR = 0.49, 95% CI 0.3–0.78; p = 0.04, OR = 0.62, 95% CI 0.39–0.99; p = 0.04, OR = 0.63, 95% CI 0.4–0.99; and p = 0.03, OR = 0.62, 95% CI 0.4–0.95, respectively). Overall, the number of iKIR/HLA-I combinations was more in the control group. Moreover, KIR3DS1( +)/HLA-B Bw4Ile80( +) and the sum of HLA-B Bw4/A Bw4 combined with KIR3DS1 as activating KIR/HLA-I combinations were more frequent among patients than controls (p = 0.01, OR = 1.99, 95% CI 1.14–3.49 and p = 0.005, OR = 1.97, 95% CI 1.22–3.19, respectively). In conclusion, our results postulate that inhibitory combinations play a protective role against AML by developing potent NK cells during education. It is noteworthy that KIR/HLA-I combination studies can be applicable in donor selection for allogeneic NK cell therapy in hematological malignancies.
Long-term effects of subthalamic nucleus deep brain stimulation on speech in Parkinson’s disease
Authors: Gessani Annalisa , Cavallieri Francesco , Fioravanti Valentina , Campanini Isabella , Merlo Andrea , Di Rauso Giulia , Damiano Benedetta , Scaltriti Sara , Bardi Elisa , Corni Maria Giulia , Antonelli Francesca , Cavalleri Francesca , Molinari Maria Angela , Contardi Sara , Menozzi Elisa , Fraternali Alessandro , Versari Annibale , Biagini Giuseppe , Fraix Valérie , Pinto Serge , Moro Elena , Budriesi Carla , Valzania Franco
Published: July 2023

Bilateral subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment in advanced Parkinson’s Disease (PD). However, the effects of STN-DBS on speech are still debated, particularly in the long-term follow-up. The objective of this study was to evaluate the long-term effects of bilateral STN-DBS on speech in a cohort of advanced PD patients treated with bilateral STN-DBS. Each patient was assessed before surgery through a neurological evaluation and a perceptual-acoustic analysis of speech and re-assessed in the long-term in different stimulation and drug conditions. The primary outcome was the percentage change of speech intelligibility obtained by comparing the postoperative on-stimulation/off-medication condition with the preoperative off-medication condition. Twenty-five PD patients treated with bilateral STN-DBS with a 5-year follow-up were included. In the long-term, speech intelligibility stayed at the same level as preoperative values when compared with preoperative values. STN-DBS induced a significant acute improvement of speech intelligibility (p < 0.005) in the postoperative assessment when compared to the on-stimulation/off-medication and off-stimulation/off-medication conditions. These results highlight that STN-DBS may handle speech intelligibility even in the long-term.
Quantum range-migration-algorithm for synthetic aperture radar applications
Authors: Waller Erik H. , Keil Andreas , Friederich Fabian
Published: July 2023

The 3D range-migration algorithm (RMA) and its 2D equivalent, the omega-k algorithm, are employed in a wide range of applications where reconstruction of synthetic aperture data is required, from satellite radar imaging of planets over seismic imaging of the earth crust, down to phased-array ultrasound and ultrasonic application, and recently in-line synthetic aperture radar for non-destructive testing. These algorithms are based on Fourier transforms and share their time-complexity. This limits highly-resolved measurement data to be processed at high speeds which would be advantageous for modern production feed lines. In this publication, we present the development and implementation of the RMA on a quantum computer that scales favourably compared to the time complexity of the classical RMA. We compare reconstruction results of simulated and measured data of the classical and quantum RMA. Hereby, the quantum RMA is run on a quantum simulator backend as well as on IBM’s Q System One quantum computer. The results show that real world applications and testing tasks may benefit from future quantum computers.