bluuebunny/crossref_metadata_2025 huggingface dataset:
The double burden of severe mental illness and cancer: a population-based study on colorectal cancer care pathways from screening to end-of-life care
Authors: Seppänen A.-V. , Daniel F. , Houzard S. , Le Bihan C. , Coldefy M. , Gandré C.
Published: May 2024

Aims

Cancer is one of the main causes of death in persons with severe mental illness (SMI). Although their cancer incidence is similar, or sometimes even potentially lower compared to the general population, their cancer mortality remains higher. The role of healthcare provision and care equity in this mortality is increasingly being addressed in research, but available studies are limited in their scope. In this context, our aim was to compare colorectal cancer (CRC) care pathways from screening to end-of-life care in patients with and without pre-existing SMI on a national scale.

Methods

This research leverages real-world data from the French national health claims database, covering the entire population, to assess cancer screening, diagnosis, treatment and post-treatment follow-up as well as quality of care (QOC) pathways among patients with incident CRC in 2015–2018, considering whether they had pre-existing SMI. We matched patients with SMI with three patients without – on age, sex, region of residence, year of cancer incidence and cancer type and location at presentation – as well as nationally established quality of CRC care indicators and regression models adjusting for relevant socio-economic, clinical and care provider-related covariates.

Results

Among patients with incident CRC, 1,532 individuals with pre-existing SMI were matched with individuals without SMI. After adjusting for covariates, both colon and rectal cancer patients with SMI were less likely to participate in the national CRC screening programme and to receive advanced diagnostic examinations (e.g., colonoscopies and several complementary diagnostic examinations). They also had lower odds of receiving combined treatments (e.g., neoadjuvant chemotherapy, radiotherapy and excision) and of having access to targeted therapy or capecitabine but higher odds for invasive care (e.g., stoma). Colon cancer patients with SMI were also more likely to have no treatment at all, and rectal cancer patients with SMI were less likely to receive post-treatment follow-up. Suboptimal QOC was observed for both groups of patients, but to a higher extent for patients with SMI, with statistically significant differences for indicators focusing on diagnosis and post-treatment follow-up.

Conclusions

Our findings reveal discrepancies across the care continuum of CRC between individuals with and without SMI and provide initial avenues on where to focus future efforts to address them, notably at the entry and exit stages of cancer care pathways, while calling for further research on the mechanisms preventing equity of physical healthcare for individuals with SMI.
Adaptation of Wind Drag Coefficient Parameterization: Improvement of Hydrodynamic Modeling by a Wave‐Dependent Cd in Large Shallow Lakes
Authors: Zhang Chen , Chen Lingwei , Brett Michael T.
Published: May 2024

Wind is a critical driving force in hydrodynamic and water quality modeling of large shallow lakes, and is characterized by the wind drag coefficient Cd, representing the momentum transfer at the air‐water interface. Contemporary empirical formulae for Cd estimation were derived over oceans and some of which are solely wind velocity U10 dependent. These formulae were previously found to be inadequate in inland lake models often resulting in the water velocity underestimation. To address this problem, a physical scale experiment was designed, in which Cd was measured using a wind profile and eddy covariance methodology. A new wind‐induced wave‐dependent Cd parameterization was also established and validated in two lake studies. The driving force was modified by the wave‐dependent Cd formula in a hydrodynamic model of the shallow Upper Klamath Lake (UKL), OR, USA. The experimental Cd was negatively correlated to the wind velocity up until the critical U10 = 1.6 m s−1 which was 1.0~3.1 times previous empirical extrapolations at light winds. The variation partitioning results showed that wave parameters contributed to more than 30% of Cd variation combined with wind parameters. The modified wind stress field was spatially heterogeneous and the modeled water velocity was closer to the observations at two sites. Significant main circulation and outer bank circulation were modeled accompanied by higher surface vorticity, compared to the original UKL model. Overall, the wave‐dependent Cd formula provided an improvement of the surface flow field in the UKL model and will improve the management of the lake ecosystems.
Interannual Variations in Spring Snowmelt Timing of Alaskan Black Spruce Forests Using a Bulk‐Surface Energy Balance Approach
Authors: Ikawa Hiroki , Nakai Taro , Busey Robert C. , Harazono Yoshinobu , Ikeda Kyoko , Iwata Hiroki , Nagano Hirohiko , Saito Kazuyuki , Ueyama Masahito , Kobayashi Hideki
Published: May 2024

Spring snowmelt occurs for a short duration on an annual time scale, but their timings considerably affect the carbon and hydrological cycle in high‐latitude ecosystems. Here, we developed a simple snowmelt model, treating the ecosystem surface as a bulk‐surface layer. Energy fluxes across this bulk surface and the snow‐soil boundary determine snow temperature and the energy utilized for snowmelt. Parameterizing the bulk surface using decade‐long eddy covariance site data from two Alaskan open black spruce forests offered an opportunity to quantitatively evaluate meteorological drivers affecting snowmelt timings without the needs for detailed canopy information. The sensitivity analysis suggested that the total snowfall on the forest floor, ranging from 0.35 m in 2016 to about 1 m in 2018 and 2020, was the most crucial driver for snowmelt timing. This factor accounted for a 10‐day difference in the interannual variations in snow disappearance dates. The importance of the snowfall varied from year to year, and in 2013, the late snowmelt was characterized by low air temperatures, which increased sensible heat loss from the snowpack. The importance of atmospheric radiation was revealed in relatively warm years, such as 2016 and 2019. Our modeling approach necessitates adjusting one empirical parameter that reflects the heat conductivity from the bulk surface to the snow, based on observations. Nevertheless, despite this need for adjustment, the bulk‐surface approach helps identify important meteorological drivers underlying observed snowmelt within a simple theoretical framework.
Carbon Stocks and Fluxes From a Boreal Conifer Swamp: Filling a Knowledge Gap for Understanding the Boreal C Cycle
Authors: Davidson Scott J. , Davies Marissa A. , Wegener Emma , Claussen Sara , Schmidt Megan , Peacock Mike , Strack Maria
Published: May 2024

The carbon (C) dynamics of boreal coniferous swamps are a largely understudied component of wetland carbon cycling. We investigated the above‐ and below‐ground carbon stocks and growing season carbon dioxide (CO2) and methane (CH4) fluxes from a representative boreal coniferous swamp in northern Alberta, Canada in 2022. Tree inventories, understory vegetation biomass and peat cores were collected across three sub‐sites within the broader swamp, with gas flux collars placed in the dominant plant communities present. Alongside the C flux measurements, environmental variables such as water table depth, soil temperature and growing season understory green leaf phenology were measured. Our results show that these boreal coniferous swamps store large volumes of organic C in their biomass and soil (134 kg C m−2), comparable with other wetland and forest types, although 95% of the total C stock at our site was within the soil organic carbon. We also found that understory CO2 and CH4 fluxes indicated that the ground layer of the site is a source of greenhouse gases (GHGs) to the atmosphere across the growing season. However, we did not measure litterfall input, tree GHG fluxes or net primary productivity of the overstory, therefore we are not able to say whether the site is an overall source of C to the atmosphere. This study provides a much‐needed insight into the C dynamics of these under‐valued wetland ecosystems, and we highlight the need for a coordinated effort across boreal regions to try to improve inventories of C stocks and fluxes.
2-APQC, a small-molecule activator of Sirtuin-3 (SIRT3), alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis
Authors: Peng Fu , Liao Minru , Jin Wenke , Liu Wei , Li Zixiang , Fan Zhichao , Zou Ling , Chen Siwei , Zhu Lingjuan , Zhao Qian , Zhan Gu , Ouyang Liang , Peng Cheng , Han Bo , Zhang Jin , Fu Leilei
Published: May 2024

Sirtuin 3 (SIRT3) is well known as a conserved nicotinamide adenine dinucleotide+ (NAD+)-dependent deacetylase located in the mitochondria that may regulate oxidative stress, catabolism and ATP production. Accumulating evidence has recently revealed that SIRT3 plays its critical roles in cardiac fibrosis, myocardial fibrosis and even heart failure (HF), through its deacetylation modifications. Accordingly, discovery of SIRT3 activators and elucidating their underlying mechanisms of HF should be urgently needed. Herein, we identified a new small-molecule activator of SIRT3 (named 2-APQC) by the structure-based drug designing strategy. 2-APQC was shown to alleviate isoproterenol (ISO)-induced cardiac hypertrophy and myocardial fibrosis in vitro and in vivo rat models. Importantly, in SIRT3 knockout mice, 2-APQC could not relieve HF, suggesting that 2-APQC is dependent on SIRT3 for its protective role. Mechanically, 2-APQC was found to inhibit the mammalian target of rapamycin (mTOR)-p70 ribosomal protein S6 kinase (p70S6K), c-jun N-terminal kinase (JNK) and transforming growth factor-β (TGF-β)/ small mother against decapentaplegic 3 (Smad3) pathways to improve ISO-induced cardiac hypertrophy and myocardial fibrosis. Based upon RNA-seq analyses, we demonstrated that SIRT3-pyrroline-5-carboxylate reductase 1 (PYCR1) axis was closely assoiated with HF. By activating PYCR1, 2-APQC was shown to enhance mitochondrial proline metabolism, inhibited reactive oxygen species (ROS)-p38 mitogen activated protein kinase (p38MAPK) pathway and thereby protecting against ISO-induced mitochondrialoxidative damage. Moreover, activation of SIRT3 by 2-APQC could facilitate AMP-activated protein kinase (AMPK)-Parkin axis to inhibit ISO-induced necrosis. Together, our results demonstrate that 2-APQC is a targeted SIRT3 activator that alleviates myocardial hypertrophy and fibrosis by regulating mitochondrial homeostasis, which may provide a new clue on exploiting a promising drug candidate for the future HF therapeutics.
Mitochondrial dysfunction: mechanisms and advances in therapy
Authors: Zong Yao , Li Hao , Liao Peng , Chen Long , Pan Yao , Zheng Yongqiang , Zhang Changqing , Liu Delin , Zheng Minghao , Gao Junjie
Published: May 2024

Mitochondria, with their intricate networks of functions and information processing, are pivotal in both health regulation and disease progression. Particularly, mitochondrial dysfunctions are identified in many common pathologies, including cardiovascular diseases, neurodegeneration, metabolic syndrome, and cancer. However, the multifaceted nature and elusive phenotypic threshold of mitochondrial dysfunction complicate our understanding of their contributions to diseases. Nonetheless, these complexities do not prevent mitochondria from being among the most important therapeutic targets. In recent years, strategies targeting mitochondrial dysfunction have continuously emerged and transitioned to clinical trials. Advanced intervention such as using healthy mitochondria to replenish or replace damaged mitochondria, has shown promise in preclinical trials of various diseases. Mitochondrial components, including mtDNA, mitochondria-located microRNA, and associated proteins can be potential therapeutic agents to augment mitochondrial function in immunometabolic diseases and tissue injuries. Here, we review current knowledge of mitochondrial pathophysiology in concrete examples of common diseases. We also summarize current strategies to treat mitochondrial dysfunction from the perspective of dietary supplements and targeted therapies, as well as the clinical translational situation of related pharmacology agents. Finally, this review discusses the innovations and potential applications of mitochondrial transplantation as an advanced and promising treatment.
Clinical characteristics and aetiology of uveitis in a viral haemorrhagic fever zone
Authors: Balendra Shiama , Harrison-Williams Lloyd , Mustapha Jalikatu , Koroma Zikan , Kamara Alicious , Saradugu Bangi , Conteh Osman , Kanu Theophilus , Kamara Santigie , Koroma Sheku Alhaji , Vandy Matthew , Ward Laura , Wang Huachun , Fashina Tolulope , Shantha Jessica , Yeh Steven , Kennedy Alasdair
Published: May 2024

Background/Objectives

Studies on uveitis in Sierra Leone were conducted prior to the Ebola Virus Disease epidemic of 2013–16, which was associated with uveitis in 20% of survivors. They did not include imaging or investigation of tuberculosis and used laboratory services outside the country. We performed a cross-sectional study on patients presenting with uveitis to establish their clinical characteristics and identify the impact of in-country laboratory diagnoses.

Methods

We invited uveitis cases presenting to Eye Clinics in Sierra Leone from March to September 2022 to participate in the study. They underwent a diagnostic work-up, including fundus and ocular coherence tomography imaging. Active uveitis cases underwent further investigations including serology and immunological tests for syphilis, tuberculosis, herpetic viruses and HIV and chest radiographs.

Results

We recruited 128 patients. The median age was 34 (IQR 19) years and there was an equal gender split. Panuveitis was the predominant anatomical uveitis type (n = 51, 40%), followed by posterior uveitis (n = 36, 28%). Bilateral disease affected 40 patients (31%). Active uveitis was identified in 75 (59%) cases. ICD 11 definition of blindness with VA < 3/60 occurred in 55 (33%) uveitis eyes. Aetiology of uveitis from clinical and laboratory assessment demonstrated that most cases were of undifferentiated aetiology (n = 66, 52%), followed by toxoplasmosis (n = 46, 36%). Trauma contributed to eight (6%) cases, syphilis to 5 (4%) cases and Ebola to 2 (2%).

Conclusions

Uveitis was associated with high levels of visual impairment. Posterior and panuveitis contributed to the highest proportion of uveitis cases. Laboratory studies helped differentiate syphilis as a significant aetiology of uveitis.
Xq22 deletion involving TCEAL1 in a female patient with early-onset neurological disease trait
Authors: Shimojima Yamamoto Keiko , Itagaki Yusuke , Tanaka Kazuki , Okamoto Nobuhiko , Yamamoto Toshiyuki
Published: May 2024

A 3.5-Mb microdeletion in Xq22 was identified in a female patient with early-onset neurological disease trait (EONDT). The patient exhibited developmental delay but no hypomyelination despite PLP1 involvement in the deletion. However, the clinical features of the patient were consistent with those of TCEAL1 loss-of-function syndrome. The breakpoint junction was analyzed using long-read sequencing, and blunt-end fusion was confirmed.
Stretchable phosphorescent polymers by multiphase engineering
Authors: Gan Nan , Zou Xin , Qian Zhao , Lv Anqi , Wang Lan , Ma Huili , Qian Hu-Jun , Gu Long , An Zhongfu , Huang Wei
Published: May 2024

Stretchable phosphorescence materials potentially enable applications in diverse advanced fields in wearable electronics. However, achieving room-temperature phosphorescence materials simultaneously featuring long-lived emission and good stretchability is challenging because it is hard to balance the rigidity and flexibility in the same polymer. Here we present a multiphase engineering for obtaining stretchable phosphorescent materials by combining stiffness and softness simultaneously in well-designed block copolymers. Due to the microphase separation, copolymers demonstrate an intrinsic stretchability of 712%, maintaining an ultralong phosphorescence lifetime of up to 981.11 ms. This multiphase engineering is generally applicable to a series of binary and ternary initiator systems with color-tunable phosphorescence in the visible range. Moreover, these copolymers enable multi-level volumetric data encryption and stretchable afterglow display. This work provides a fundamental understanding of the nanostructures and material properties for designing stretchable materials and extends the potential of phosphorescence polymers.
Hepatocytes differentiate into intestinal epithelial cells through a hybrid epithelial/mesenchymal cell state in culture
Authors: Miura Shizuka , Horisawa Kenichi , Iwamori Tokuko , Tsujino Satoshi , Inoue Kazuya , Karasawa Satsuki , Yamamoto Junpei , Ohkawa Yasuyuki , Sekiya Sayaka , Suzuki Atsushi
Published: May 2024

Hepatocytes play important roles in the liver, but in culture, they immediately lose function and dedifferentiate into progenitor-like cells. Although this unique feature is well-known, the dynamics and mechanisms of hepatocyte dedifferentiation and the differentiation potential of dedifferentiated hepatocytes (dediHeps) require further investigation. Here, we employ a culture system specifically established for hepatic progenitor cells to study hepatocyte dedifferentiation. We found that hepatocytes dedifferentiate with a hybrid epithelial/mesenchymal phenotype, which is required for the induction and maintenance of dediHeps, and exhibit Vimentin-dependent propagation, upon inhibition of the Hippo signaling pathway. The dediHeps re-differentiate into mature hepatocytes by forming aggregates, enabling reconstitution of hepatic tissues in vivo. Moreover, dediHeps have an unexpected differentiation potential into intestinal epithelial cells that can form organoids in three-dimensional culture and reconstitute colonic epithelia after transplantation. This remarkable plasticity will be useful in the study and treatment of intestinal metaplasia and related diseases in the liver.
Cell-mediated cytotoxicity within CSF and brain parenchyma in spinal muscular atrophy unaltered by nusinersen treatment
Authors: Lu I-Na , Cheung Phyllis Fung-Yi , Heming Michael , Thomas Christian , Giglio Giovanni , Leo Markus , Erdemir Merve , Wirth Timo , König Simone , Dambietz Christine A. , Schroeter Christina B. , Nelke Christopher , Siveke Jens T. , Ruck Tobias , Klotz Luisa , Haider Carmen , Höftberger Romana , Kleinschnitz Christoph , Wiendl Heinz , Hagenacker Tim , Meyer zu Horste Gerd
Published: May 2024

5q-associated spinal muscular atrophy (SMA) is a motoneuron disease caused by mutations in the survival motor neuron 1 (SMN1) gene. Adaptive immunity may contribute to SMA as described in other motoneuron diseases, yet mechanisms remain elusive. Nusinersen, an antisense treatment, enhances SMN2 expression, benefiting SMA patients. Here we have longitudinally investigated SMA and nusinersen effects on local immune responses in the cerebrospinal fluid (CSF) - a surrogate of central nervous system parenchyma. Single-cell transcriptomics (SMA: N = 9 versus Control: N = 9) reveal NK cell and CD8+ T cell expansions in untreated SMA CSF, exhibiting activation and degranulation markers. Spatial transcriptomics coupled with multiplex immunohistochemistry elucidate cytotoxicity near chromatolytic motoneurons (N = 4). Post-nusinersen treatment, CSF shows unaltered protein/transcriptional profiles. These findings underscore cytotoxicity’s role in SMA pathogenesis and propose it as a therapeutic target. Our study illuminates cell-mediated cytotoxicity as shared features across motoneuron diseases, suggesting broader implications.
An antiplasmid system drives antibiotic resistance gene integration in carbapenemase-producing Escherichia coli lineages
Authors: Zongo Pengdbamba Dieudonné , Cabanel Nicolas , Royer Guilhem , Depardieu Florence , Hartmann Alain , Naas Thierry , Glaser Philippe , Rosinski-Chupin Isabelle
Published: May 2024

Plasmids carrying antibiotic resistance genes (ARG) are the main mechanism of resistance dissemination in Enterobacterales. However, the fitness-resistance trade-off may result in their elimination. Chromosomal integration of ARGs preserves resistance advantage while relieving the selective pressure for keeping costly plasmids. In some bacterial lineages, such as carbapenemase producing sequence type ST38 Escherichia coli, most ARGs are chromosomally integrated. Here we reproduce by experimental evolution the mobilisation of the carbapenemase blaOXA-48 gene from the pOXA-48 plasmid into the chromosome. We demonstrate that this integration depends on a plasmid-induced fitness cost, a mobile genetic structure embedding the ARG and a novel antiplasmid system ApsAB actively involved in pOXA-48 destabilization. We show that ApsAB targets high and low-copy number plasmids. ApsAB combines a nuclease/helicase protein and a novel type of Argonaute-like protein. It belongs to a family of defense systems broadly distributed among bacteria, which might have a strong ecological impact on plasmid diffusion.
Three stepwise pH progressions in stratum corneum for homeostatic maintenance of the skin
Authors: Fukuda Keitaro , Ito Yoshihiro , Furuichi Yuki , Matsui Takeshi , Horikawa Hiroto , Miyano Takuya , Okada Takaharu , van Logtestijn Mark , Tanaka Reiko J. , Miyawaki Atsushi , Amagai Masayuki
Published: May 2024

The stratum corneum is the outermost skin layer with a vital role in skin barrier function. It is comprised of dead keratinocytes (corneocytes) and is known to maintain its thickness by shedding cells, although, the precise mechanisms that safeguard stratum corneum maturation and homeostasis remain unclear. Previous ex vivo studies have suggested a neutral-to-acidic pH gradient in the stratum corneum. Here, we use intravital pH imaging at single-corneocyte resolution to demonstrate that corneocytes actually undergo differentiation to develop three distinct zones in the stratum corneum, each with a distinct pH value. We identified a moderately acidic lower, an acidic middle, and a pH-neutral upper layer in the stratum corneum, with tight junctions playing a key role in their development. The upper pH neutral zone can adjust its pH according to the external environment and has a neutral pH under steady-state conditions owing to the influence of skin microbiota. The middle acidic pH zone provides a defensive barrier against pathogens. With mathematical modeling, we demonstrate the controlled protease activation of kallikrein-related peptidases on the stratum corneum surface that results in proper corneocyte shedding in desquamation. This work adds crucial information to our understanding of how stratum corneum homeostasis is maintained.
Jag1/2 maintain esophageal homeostasis and suppress foregut tumorigenesis by restricting the basal progenitor cell pool
Authors: Huang Haidi , Jiang Yu , Liu Jiangying , Luo Dan , Yuan Jianghong , Mu Rongzi , Yu Xiang , Sun Donglei , Lin Jihong , Chen Qiyue , Li Xinjing , Jiang Ming , Xu Jianming , Chu Bo , Yin Chengqian , Zhang Lei , Ye Youqiong , Cao Bo , Wang Qiong , Zhang Yongchun
Published: May 2024

Basal progenitor cells are crucial for maintaining foregut (the esophagus and forestomach) homeostasis. When their function is dysregulated, it can promote inflammation and tumorigenesis. However, the mechanisms underlying these processes remain largely unclear. Here, we employ genetic mouse models to reveal that Jag1/2 regulate esophageal homeostasis and foregut tumorigenesis by modulating the function of basal progenitor cells. Deletion of Jag1/2 in mice disrupts esophageal and forestomach epithelial homeostasis. Mechanistically, Jag1/2 deficiency impairs activation of Notch signaling, leading to reduced squamous epithelial differentiation and expansion of basal progenitor cells. Moreover, Jag1/2 deficiency exacerbates the deoxycholic acid (DCA)-induced squamous epithelial injury and accelerates the initiation of squamous cell carcinoma (SCC) in the forestomach. Importantly, expression levels of JAG1/2 are lower in the early stages of human esophageal squamous cell carcinoma (ESCC) carcinogenesis. Collectively, our study demonstrates that Jag1/2 are important for maintaining esophageal and forestomach homeostasis and the onset of foregut SCC.
Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways
Authors: Kurmasheva Naziia , Said Aida , Wong Boaz , Kinderman Priscilla , Han Xiaoying , Rahimic Anna H. F. , Kress Alena , Carter-Timofte Madalina E. , Holm Emilia , van der Horst Demi , Kollmann Christoph F. , Liu Zhenlong , Wang Chen , Hoang Huy-Dung , Kovalenko Elina , Chrysopoulou Maria , Twayana Krishna Sundar , Ottosen Rasmus N. , Svenningsen Esben B. , Begnini Fabio , Kiib Anders E. , Kromm Florian E. H. , Weiss Hauke J. , Di Carlo Daniele , Muscolini Michela , Higgins Maureen , van der Heijden Mirte , Arulanandam Rozanne , Bardoul Angelina , Tong Tong , Ozsvar Attila , Hou Wen-Hsien , Schack Vivien R. , Holm Christian K. , Zheng Yunan , Ruzek Melanie , Kalucka Joanna , de la Vega Laureano , Elgaher Walid A. M. , Korshoej Anders R. , Lin Rongtuan , Hiscott John , Poulsen Thomas B. , O’Neill Luke A. , Roy Dominic G. , Rinschen Markus M. , van Montfoort Nadine , Diallo Jean-Simon , Farin Henner F. , Alain Tommy , Olagnier David
Published: May 2024

The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKβ independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.
Risk assessment of a highly pathogenic H5N1 influenza virus from mink
Authors: Restori Katherine H. , Septer Kayla M. , Field Cassandra J. , Patel Devanshi R. , VanInsberghe David , Raghunathan Vedhika , Lowen Anice C. , Sutton Troy C.
Published: May 2024

Outbreaks of highly pathogenic H5N1 clade 2.3.4.4b viruses in farmed mink and seals combined with isolated human infections suggest these viruses pose a pandemic threat. To assess this threat, using the ferret model, we show an H5N1 isolate derived from mink transmits by direct contact to 75% of exposed ferrets and, in airborne transmission studies, the virus transmits to 37.5% of contacts. Sequence analyses show no mutations were associated with transmission. The H5N1 virus also has a low infectious dose and remains virulent at low doses. This isolate carries the adaptive mutation, PB2 T271A, and reversing this mutation reduces mortality and airborne transmission. This is the first report of a H5N1 clade 2.3.4.4b virus exhibiting direct contact and airborne transmissibility in ferrets. These data indicate heightened pandemic potential of the panzootic H5N1 viruses and emphasize the need for continued efforts to control outbreaks and monitor viral evolution.
Post-translational modification-dependent oligomerization switch in regulation of global transcription and DNA damage repair during genotoxic stress
Authors: Talukdar Prathama , Pal Sujay , Biswas Debabrata
Published: May 2024

Mechanisms of functional cross-talk between global transcriptional repression and efficient DNA damage repair during genotoxic stress are poorly known. In this study, using human AF9 as representative of Super Elongation Complex (SEC) components, we delineate detailed mechanisms of these processes. Mechanistically, we describe that Poly-Serine domain-mediated oligomerization is pre-requisite for AF9 YEATS domain-mediated TFIID interaction-dependent SEC recruitment at the promoter-proximal region for release of paused RNA polymerase II. Interestingly, during genotoxic stress, CaMKII-mediated phosphorylation-dependent nuclear export of AF9-specific deacetylase HDAC5 enhances concomitant PCAF-mediated acetylation of K339 residue. This causes monomerization of AF9 and reduces TFIID interaction for transcriptional downregulation. Furthermore, the K339 acetylation-dependent enhanced AF9-DNA-PKc interaction leads to phosphorylation at S395 residue which reduces AF9-SEC interaction resulting in transcriptional downregulation and efficient repair of DNA damage. After repair, nuclear re-entry of HDAC5 reduces AF9 acetylation and restores its TFIID and SEC interaction to restart transcription.
Simulating BRAFV600E-MEK-ERK signalling dynamics in response to vertical inhibition treatment strategies
Authors: De Carli Alice , Kapelyukh Yury , Kursawe Jochen , Chaplain Mark A. J. , Wolf C. Roland , Hamis Sara
Published: May 2024

In vertical inhibition treatment strategies, multiple components of an intracellular pathway are simultaneously inhibited. Vertical inhibition of the BRAFV600E–MEK-ERK signalling pathway is a standard of care for treating BRAFV600E-mutated melanoma where two targeted cancer drugs, a BRAFV600E-inhibitor, and a MEK inhibitor, are administered in combination. Targeted therapies have been linked to early onsets of drug resistance, and thus treatment strategies of higher complexities and lower doses have been proposed as alternatives to current clinical strategies. However, finding optimal complex, low-dose treatment strategies is a challenge, as it is possible to design more treatment strategies than are feasibly testable in experimental settings. To quantitatively address this challenge, we develop a mathematical model of BRAFV600E–MEK-ERK signalling dynamics in response to combinations of the BRAFV600E-inhibitor dabrafenib (DBF), the MEK inhibitor trametinib (TMT), and the ERK-inhibitor SCH772984 (SCH). From a model of the BRAFV600E–MEK–ERK pathway, and a set of molecular-level drug–protein interactions, we extract a system of chemical reactions that is parameterised by in vitro data and converted to a system of ordinary differential equations (ODEs) using the law of mass action. The ODEs are solved numerically to produce simulations of how pathway-component concentrations change over time in response to different treatment strategies, i.e., inhibitor combinations and doses. The model can thus be used to limit the search space for effective treatment strategies that target the BRAFV600E–MEK–ERK pathway and warrant further experimental investigation. The results demonstrate that DBF and DBF–TMT–SCH therapies show marked sensitivity to BRAFV600E concentrations in silico, whilst TMT and SCH monotherapies do not.
Photocatalytic doping of organic semiconductors
Authors: Jin Wenlong , Yang Chi-Yuan , Pau Riccardo , Wang Qingqing , Tekelenburg Eelco K. , Wu Han-Yan , Wu Ziang , Jeong Sang Young , Pitzalis Federico , Liu Tiefeng , He Qiao , Li Qifan , Huang Jun-Da , Kroon Renee , Heeney Martin , Woo Han Young , Mura Andrea , Motta Alessandro , Facchetti Antonio , Fahlman Mats , Loi Maria Antonietta , Fabiano Simone
Published: May 2024

Chemical doping is an important approach to manipulating charge-carrier concentration and transport in organic semiconductors (OSCs)1–3 and ultimately enhances device performance4–7. However, conventional doping strategies often rely on the use of highly reactive (strong) dopants8–10, which are consumed during the doping process. Achieving efficient doping with weak and/or widely accessible dopants under mild conditions remains a considerable challenge. Here, we report a previously undescribed concept for the photocatalytic doping of OSCs that uses air as a weak oxidant (p-dopant) and operates at room temperature. This is a general approach that can be applied to various OSCs and photocatalysts, yielding electrical conductivities that exceed 3,000 S cm–1. We also demonstrate the successful photocatalytic reduction (n-doping) and simultaneous p-doping and n-doping of OSCs in which the organic salt used to maintain charge neutrality is the only chemical consumed. Our photocatalytic doping method offers great potential for advancing OSC doping and developing next-generation organic electronic devices.
The temperature sensor TWA1 is required for thermotolerance in Arabidopsis
Authors: Bohn Lisa , Huang Jin , Weidig Susan , Yang Zhenyu , Heidersberger Christoph , Genty Bernard , Falter-Braun Pascal , Christmann Alexander , Grill Erwin
Published: May 2024

Plants exposed to incidences of excessive temperatures activate heat-stress responses to cope with the physiological challenge and stimulate long-term acclimation1,2. The mechanism that senses cellular temperature for inducing thermotolerance is still unclear3. Here we show that TWA1 is a temperature-sensing transcriptional co-regulator that is needed for basal and acquired thermotolerance in Arabidopsis thaliana. At elevated temperatures, TWA1 changes its conformation and allows physical interaction with JASMONATE-ASSOCIATED MYC-LIKE (JAM) transcription factors and TOPLESS (TPL) and TOPLESS-RELATED (TPR) proteins for repressor complex assembly. TWA1 is a predicted intrinsically disordered protein that has a key thermosensory role functioning through an amino-terminal highly variable region. At elevated temperatures, TWA1 accumulates in nuclear subdomains, and physical interactions with JAM2 and TPL appear to be restricted to these nuclear subdomains. The transcriptional upregulation of the heat shock transcription factor A2 (HSFA2) and heat shock proteins depended on TWA1, and TWA1 orthologues provided different temperature thresholds, consistent with the sensor function in early signalling of heat stress. The identification of the plant thermosensors offers a molecular tool for adjusting thermal acclimation responses of crops by breeding and biotechnology, and a sensitive temperature switch for thermogenetics.
Volatile working memory representations crystallize with practice
Authors: Bellafard Arash , Namvar Ghazal , Kao Jonathan C. , Vaziri Alipasha , Golshani Peyman
Published: May 2024

Working memory, the process through which information is transiently maintained and manipulated over a brief period, is essential for most cognitive functions1–4. However, the mechanisms underlying the generation and evolution of working-memory neuronal representations at the population level over long timescales remain unclear. Here, to identify these mechanisms, we trained head-fixed mice to perform an olfactory delayed-association task in which the mice made decisions depending on the sequential identity of two odours separated by a 5 s delay. Optogenetic inhibition of secondary motor neurons during the late-delay and choice epochs strongly impaired the task performance of the mice. Mesoscopic calcium imaging of large neuronal populations of the secondary motor cortex (M2), retrosplenial cortex (RSA) and primary motor cortex (M1) showed that many late-delay-epoch-selective neurons emerged in M2 as the mice learned the task. Working-memory late-delay decoding accuracy substantially improved in the M2, but not in the M1 or RSA, as the mice became experts. During the early expert phase, working-memory representations during the late-delay epoch drifted across days, while the stimulus and choice representations stabilized. In contrast to single-plane layer 2/3 (L2/3) imaging, simultaneous volumetric calcium imaging of up to 73,307 M2 neurons, which included superficial L5 neurons, also revealed stabilization of late-delay working-memory representations with continued practice. Thus, delay- and choice-related activities that are essential for working-memory performance drift during learning and stabilize only after several days of expert performance.
Engineered CD47 protects T cells for enhanced antitumour immunity
Authors: Yamada-Hunter Sean A. , Theruvath Johanna , McIntosh Brianna J. , Freitas Katherine A. , Lin Frank , Radosevich Molly T. , Leruste Amaury , Dhingra Shaurya , Martinez-Velez Naiara , Xu Peng , Huang Jing , Delaidelli Alberto , Desai Moksha H. , Good Zinaida , Polak Roel , May Audre , Labanieh Louai , Bjelajac Jeremy , Murty Tara , Ehlinger Zach , Mount Christopher W. , Chen Yiyun , Heitzeneder Sabine , Marjon Kristopher D. , Banuelos Allison , Khan Omair , Wasserman Savannah L. , Spiegel Jay Y. , Fernandez-Pol Sebastian , Kuo Calvin J. , Sorensen Poul H. , Monje Michelle , Majzner Robbie G. , Weissman Irving L. , Sahaf Bita , Sotillo Elena , Cochran Jennifer R. , Mackall Crystal L.
Published: May 2024

Adoptively transferred T cells and agents designed to block the CD47–SIRPα axis are promising cancer therapeutics that activate distinct arms of the immune system1,2. Here we administered anti-CD47 antibodies in combination with adoptively transferred T cells with the goal of enhancing antitumour efficacy but observed abrogated therapeutic benefit due to rapid macrophage-mediated clearance of T cells expressing chimeric antigen receptors (CARs) or engineered T cell receptors. Anti-CD47-antibody-mediated CAR T cell clearance was potent and rapid enough to serve as an effective safety switch. To overcome this challenge, we engineered the CD47 variant CD47(Q31P) (47E), which engages SIRPα and provides a ‘don’t eat me’ signal that is not blocked by anti-CD47 antibodies. TCR or CAR T cells expressing 47E are resistant to clearance by macrophages after treatment with anti-CD47 antibodies, and mediate substantial, sustained macrophage recruitment to the tumour microenvironment. Although many of the recruited macrophages manifested an M2-like profile3, the combined therapy synergistically enhanced antitumour efficacy. Our study identifies macrophages as major regulators of T cell persistence and illustrates the fundamental challenge of combining T-cell-directed therapeutics with those designed to activate macrophages. It delivers a therapeutic approach that is capable of simultaneously harnessing the antitumour effects of T cells and macrophages, offering enhanced potency against solid tumours.
Synthesis and evaluation of pyridine-3-carboxamide analogs as effective agents against bacterial wilt in tomatoes
Authors: Mohammed Yasser Hussein Issa , Shamkh Israa M. , Shntaif Ahmed Hassen , Sufyan Muhammad , Rehman Md Tabish , AlAjmi Mohamed F. , Shahwan Moayad , Alghamdi Saad , Abd El-Lateef Amal Ezzat , Khidir Elshiekh B. , Abouzied Amr S. , Khalifa Nasrin E. , A. Khojali Weam M. , Huwaimel Bader , Al Farraj Dunia A. , Almutairi Saeedah Musaed
Published: May 2024

This study focused on developing novel pyridine-3-carboxamide analogs to treat bacterial wilt in tomatoes caused by Ralstonia solanacearum. The analogs were synthesized through a multistep process and their structures confirmed using spectroscopy. Molecular docking studies identified the most potent analog from the series. A specific analog, compound 4a, was found to significantly enhance disease resistance in tomato plants infected with R. solanacearum. The structure–activity relationship analysis showed the positions and types of substituents on the aromatic rings of compounds 4a–i strongly influenced their biological activity. Compound 4a, with a chloro group at the para position on ring C and hydroxyl group at the ortho position on ring A, was exceptionally effective against R. solanacearum. When used to treat seeds, the analogs displayed remarkable efficacy, especially compound 4a which had specific activity against bacterial wilt pathogens. Compound 4a also promoted vegetative and reproductive growth of tomato plants, increasing seed germination and seedling vigor. In plants mechanically infected with bacteria, compound 4a substantially reduced the percentage of infection, pathogen quantity in young tissue, and disease progression. The analogs were highly potent due to their amide linkage. Molecular docking identified the best compounds with strong binding affinities. Overall, the strategic design and synthesis of these pyridine-3-carboxamide analogs offers an effective approach to targeting and controlling R. solanacearum and bacterial wilt in tomatoes.
A dual fusion recognition model for sleep posture based on air mattress pressure detection
Authors: Li Zebo , Zhou Yipeng , Zhou Guoping
Published: May 2024

In order to solve the difficult portability problem of traditional non-invasive sleeping posture recognition algorithms arising from the production cost and computational cost, this paper proposes a sleeping posture recognition model focusing on human body structural feature extraction and integration of feature space and algorithms based on a specific air-spring mattress structure, called SPR-DE (SPR-DE is the Sleep Posture Recognition-Data Ensemble acronym form). The model combines SMR (SMR stands for Principle of Spearman Maximal Relevance) with horizontal and vertical division based on the barometric pressure signals in the human body’s backbone region to reconstruct the raw pressure data into strongly correlated non-image features of the sleep postures in different parts and directions and construct the feature set. Finally, the recognit-ion of the two sleep postures is accomplished using the AdaBoost-SVM integrated classifier. SPR-DE is compared with the base and integrated classifiers to verify its performance. The experimental results show that the amount of significant features helps the algorithm to classify different sleeping patterns more accurately, and the f1 score of the SPR-DE model determined by the comparison experiments is 0.998, and the accuracy can reach 99.9%. Compared with other models, the accuracy is improved by 2.9% ~ 7.7%, and the f1-score is improved by 0.029 ~ 0.076. Therefore, it is concluded that the SMR feature extraction strategy in the SPR-DE model and the AdaBoost-SVM can achieve high accuracy and strong robustness in the task of sleep posture recognition in a small area, low-density air-pressure mattress, taking into account the comfort of the mattress structural design and the sleep posture recognition, integrated with the mattress adaptive adjustment system.
Multi-channel polarization manipulation based on graphene for encryption communication
Authors: Farzin Parsa , Hajiahmadi Mohammad Javad , Soleimani Mohammad
Published: May 2024

Wave-based cryptography, at the vanguard of advancing technologies in advanced information science, is essential for establishing a diverse array of secure cryptographic platforms. The realization of these platforms hinges on the intelligent application of multiplexing techniques, seamlessly combined with appropriate metasurface technology. Nevertheless, existing multi-channel encryption technologies based on metasurfaces face challenges related to information leakage during partial channel decoding processes. In this paper, we present a reprogrammable metasurface for polarization modulation. This metasurface not only allows for the arbitrary customization of linearly polarized reflected waves but also enables real-time amplitude modulation. Here, relying on polarization amplitude control, a fully secure communication protocol is developed precisely in the terahertz (THz) spectrum to achieve real-time information encryption based on polarization modulation metasurfaces where access to information is highly restricted. The proposed metasurface employs the double random phase encryption (DRPE) algorithm for information encryption. It transmits the encrypted data through different polarization channels using two graphene nanoribbons, exclusively controlled by external biasing conditions. Various encryption scenarios have been outlined to fortify information protection against potential eavesdroppers. The simulated results show that this unique technology for hiding images by manipulating the polarization of the reflected wave provides new opportunities for various applications, including encryption, THz communications, THz secure data storage, and imaging.
Chemical and biophysical characterization of novel potassium channel blocker 3-fluoro-5-methylpyridin-4-amine
Authors: Sun Yang , Rodríguez-Rangel Sofia , Zhang Lauren L. , Sánchez-Rodríguez Jorge E. , Brugarolas Pedro
Published: May 2024

4-aminopyridine (4AP) is a potassium (K+) channel blocker used clinically to improve walking in people with multiple sclerosis (MS). 4AP binds to exposed K+ channels in demyelinated axons, reducing the leakage of intracellular K+ and enhancing impulse conduction. Multiple derivatives of 4AP capable of blocking K+ channels have been reported including three radiolabeled with positron emitting isotopes for imaging demyelinated lesions using positron emission tomography (PET). However, there remains a demand for novel molecules with suitable physicochemical properties and binding affinity that can potentially be radiolabeled and used as PET radiotracers. In this study, we introduce 3-fluoro-5-methylpyridin-4-amine (5Me3F4AP) as a novel trisubstituted K+ channel blocker with potential application in PET. 5Me3F4AP has comparable potency to 4AP and the PET tracer 3-fluoro-4-aminopyridine (3F4AP). Compared to 3F4AP, 5Me3F4AP exhibits comparable basicity (pKa = 7.46 ± 0.01 vs. 7.37 ± 0.07, P-value = 0.08), greater lipophilicity (logD = 0.664 ± 0.005 vs. 0.414 ± 0.002, P-value < 0.0001) and higher permeability to an artificial brain membrane (Pe = 88.1 ± 18.3 vs. 31.1 ± 2.9 nm/s, P-value = 0.03). 5Me3F4AP is also more stable towards oxidation in vitro by the cytochrome P450 enzyme CYP2E1 (IC50 = 36.2 ± 2.5 vs. 15.4 ± 5.1, P-value = 0.0003); the enzyme responsible for the metabolism of 4AP and 3F4AP. Taken together, 5Me3F4AP has promising properties as a candidate for PET imaging warranting additional investigation.
A constrained machine learning surrogate model to predict the distribution of water-in-oil emulsions in electrostatic fields
Authors: Kooti Ghazal , Dabir Bahram , Butscher Christoph , Taherdangkoo Reza
Published: May 2024

Accurately describing the evolution of water droplet size distribution in crude oil is fundamental for evaluating the water separation efficiency in dehydration systems. Enhancing the separation of an aqueous phase dispersed in a dielectric oil phase, which has a significantly lower dielectric constant than the dispersed phase, can be achieved by increasing the water droplet size through the application of an electrostatic field in the pipeline. Mathematical models, while being accurate, are computationally expensive. Herein, we introduced a constrained machine learning (ML) surrogate model developed based on a population balance model. This model serves as a practical alternative, facilitating fast and accurate predictions. The constrained ML model, utilizing an extreme gradient boosting (XGBoost) algorithm tuned with a genetic algorithm (GA), incorporates the key parameters of the electrostatic dehydration process, including droplet diameter, voltage, crude oil properties, temperature, and residence time as input variables, with the output being the number of water droplets per unit volume. Furthermore, we modified the objective function of the XGBoost algorithm by incorporating two penalty terms to ensure the model’s predictions adhere to physical principles. The constrained model demonstrated accuracy on the test set, with a mean squared error of 0.005 and a coefficient of determination of 0.998. The efficiency of the model was validated through comparison with the experimental data and the results of the population balance mathematical model. The analysis shows that the initial droplet diameter and voltage have the highest influence on the model, which aligns with the observed behaviour in the real-world process.