bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractMitochondria, 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

Abstract
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

Abstract
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

AbstractStretchable 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

AbstractHepatocytes 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

Abstract5q-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

AbstractPlasmids 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

AbstractThe 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

AbstractBasal 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

AbstractThe 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

AbstractOutbreaks 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

AbstractMechanisms 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

AbstractIn 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

AbstractChemical 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

AbstractPlants 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.