bluuebunny/crossref_metadata_2025_split huggingface dataset:
SERS nanowire chip and machine learning enabled instant identification and classification of clinically relevant wild-type and antibiotic resistant bacteria at species and strain level
Authors: Das Sathi , Saxena Kanchan , Tinguely Jean-Claude , Pal Arijit , Wickramasinghe Nima L. , Khezri Abdolrahman , Dubey Vishesh , Ahmed Azeem , Vivekanandan Perumal , Ahmad Rafi , Wadduwage Dushan N. , Ahluwalia Balpreet Singh , Mehta Dalip Singh 
Published: January 2023

ABSTRACTThe world health organization considers antimicrobial resistance (AMR) to be a critical global public health problem. Conventional culture-based methods that are used to detect and identify bacterial infection are slow. Thus, there is a growing need for the development of robust, cost-effective, and fast diagnostic solutions for the identification of pathogens. Surface-enhanced Raman spectroscopy (SERS) can be used to identify target analytes with sensitivity down to the single-molecule level. Here, we developed a SERS chip by optimizing the entire fabrication pipeline of the metal-assisted chemical etching (MACE) method. The MACE approach offers a large-scale, densely packed silver (Ag) nanostructure on top of silicon nanowires (Si-NWs) with a large aspect ratio that significantly enhances the Raman signal due to localised surface plasmonic enhancement. The optimised SERS chips exhibited sensitivity down to 10-12M concentration of R6G molecule and detected reproducible Raman spectra of bacteria down to a concentration of 100 colony forming units (CFU)/ml, which is a thousand times lower than the clinical threshold of bacterial infections like UTI (105CFU/ml). A Siamese neural network model was used to classify SERS Raman spectra from bacteria specimens. The trained model identified 12 different bacterial species, including those which are causative agents for tuberculosis and urinary tract infection (UTI). Next, the SERS chips and another Siamese neural network model were used to differentiate antibiotic-resistant strains from susceptible strains ofE. coli. The enhancement offered by SERS chip enabled acquisitions of Raman spectra of bacteria directly in the synthetic urine by spiking the sample with only 103CFU/mlE. coli. Thus, the present study lays the ground for the identification and quantification of bacteria on SERS chips, thereby offering a potential future use for rapid, reproducible, label-free, and low limit detection of clinical pathogens.
A sensation for inflation: initial swim bladder inflation in larval zebrafish is mediated by the mechanosensory lateral line
Authors: Venuto Alexandra , Thibodeau-Beganny Stacey , Trapani Josef G. , Erickson Timothy 
Published: January 2023

AbstractLarval zebrafish achieve neutral buoyancy by swimming up to the surface and taking in air through their mouths to inflate their swim bladders. We define this behavior as ‘surfacing’. Little is known about the sensory basis for this underappreciated behavior of larval fish. A strong candidate is the mechanosensory lateral line, a hair cell-based sensory system that detects hydrodynamic information from sources like water currents, predators, prey, and surface waves. However, a role for the lateral line in mediating initial inflation of the swim bladder has not been reported.To explore the connection between the lateral line and surfacing, we utilized a genetic mutant (lhfpl5b-/-) that renders the zebrafish lateral line insensitive to mechanical stimuli. We observe that approximately half of these lateral line mutants over-inflate their swim bladders during initial inflation and become positively buoyant. Thus, we hypothesize that larval zebrafish use their lateral line to moderate interactions with the air-water interface during surfacing to regulate swim bladder inflation. To test the hypothesis that lateral line defects are responsible for swim bladder over-inflation, we show exogenous air is required for the hyperinflation phenotype and transgenic rescue of hair cell function restores normal inflation. We also find that chemical ablation of anterior lateral line hair cells in wild type larvae causes hyperinflation. Furthermore, we show that manipulation of lateral line sensory information results in abnormal inflation. Finally, we report spatial and temporal differences in the surfacing behavior between wild type and lateral line mutant larvae. In summary, we propose a novel sensory basis for achieving neutral buoyancy where larval zebrafish use their lateral line to sense the air-water interface and regulate initial swim bladder inflation.
Salmonellacancer therapy metabolically disrupts tumours at the collateral cost of T cell immunity
Authors: Copland Alastair , Mackie Gillian M. , Scarfe Lisa , Lecky David A.J. , Gudgeon Nancy , McQuade Riahne , Ono Masahiro , Barthel Manja , Hardt Wolf-Dietrich , Ohno Hiroshi , Dimeloe Sarah , Bending David , Maslowski Kendle M. 
Published: January 2023

SummaryBacterial cancer therapy (BCT) is a promising therapeutic for solid tumours.Salmonella entericaTyphimurium (STm) is well-studied amongst bacterial vectors due to advantages in genetic modification and metabolic adaptation. A longstanding paradox is the redundancy of T cells for treatment efficacy; instead, STm BCT depends on innate phagocytes for tumour control. Here, we used distal T cell receptor (TCR) reporter mice (Nr4a3-Tocky-Ifng-YFP) and a colorectal cancer (CRC) model to interrogate T cell activity during BCT with attenuated STm. We found that colonic TILs exhibited a variety of activation defects, including IFN-γ production decoupled from TCR signalling, decreased polyfunctionality and reduced TCMformation. Modelling of T-cell–tumour interactions with a tumour organoid platform revealed an intact TCR signalosome, but paralysed metabolic reprogramming due to inhibition of the master metabolic controller, c-Myc. Restoration of c-Myc by deletion of the bacterial asparaginaseansBreinvigorated T cell activation, but at the cost of decreased metabolic control of the tumour by STm. This work shows for the first time that T cells are metabolically defective during BCT, but also that this same phenomenon is inexorably tied to intrinsic tumour suppression by the bacterial vector.
Myricetin protected against Aβ oligomer-induced synaptic impairment, mitochondrial function and oxidative stress in SH-SY5Y cells via ERK1/2/GSK-3β pathways
Authors: Wang Li , Tang Zhi , Deng Yuxin , Peng Yaqian , Xiao Yan , Xu Jianwei , Ni Ruiqing , Qi Xiaolan 
Published: January 2023

AbstractAlzheimer’s disease is characterized by abnormal β-amyloid (Aβ) plaque accumulation, tau hyperphosphorylation, reactive oxidative stress, mitochondrial dysfunction and synaptic loss. Myricetin, a dietary flavonoid, has been shown to have neuroprotective effects in vitro and in vivo. Here, we aimed to elucidate the mechanism and pathways involved in myricetin’s protective effect on the toxicity induced by the Aβ42 oligomer. Neuronal SH-SY5Y cells were pretreated with myricetin before incubation with Aβ42 oligomer. The levels of pre- and postsynaptic proteins, mitochondrial division and fusion proteins, glycogen synthase kinase-3 β (GSK-3β) and extracellular regulated kinase (ERK) 1/2 were assessed by Western blotting. Flow cytometry assays for mitochondrial membrane potential (JC1) and reactive oxidative stress, as well immunofluorescence staining for lipid peroxidation (4-HNE) and DNA oxidation (8-OHdG), were performed. We found that myricetin prevented Aβ42 oligomer-induced tau phosphorylation and the reduction in pre/postsynaptic proteins. In addition, myricetin reduced reactive oxygen species generation, lipid peroxidation, and DNA oxidation induced by the Aβ42 oligomer. Moreover, myricetin prevented the Aβ42 oligomer-induced reduction in mitochondrial fusion proteins (mitofusin-1, mitofusin-2), fission protein (dynamin-related protein 1) phosphorylation, and mitochondrial membrane potential via the associated GSK-3β and ERK 1/2 signaling pathways. In conclusion, this study provides new insight into the neuroprotective mechanism of myricetin against Aβ42 oligomer-induced toxicity.
Reactivation of the progenitor gene Trim71 enhances the mitotic and hair cell-forming potential of cochlear supporting cells
Authors: Li Xiao-Jun , Morgan Charles , Nadar-Ponniah Prathamesh T , Kolanus Waldemar , Doetzlhofer Angelika 
Published: January 2023

AbstractCochlear hair cell loss is a leading cause of deafness in humans. Neighboring supporting cells have some capacity to regenerate hair cells. However, their regenerative potential sharply declines as supporting cells undergo maturation (postnatal day 5 in mice). We recently reported that reactivation of the RNA-binding protein LIN28B restores the hair cell-regenerative potential of P5 cochlear supporting cells. Here, we identify the LIN28B targetTrim71as a novel and equally potent enhancer of supporting cell plasticity. TRIM71 is a critical regulator of stem cell behavior and cell reprogramming, however, its role in cell regeneration is poorly understood. Employing an organoid-based assay, we show that TRIM71 reactivation increases the mitotic and hair cell-forming potential of P5 cochlear supporting cells by facilitating their de-differentiation into progenitor-like cells. Our mechanistic work indicates that TRIM71’s RNA-binding activity is essential for such ability, and our transcriptomic analysis identifies gene modules that are linked to TRIM71 and LIN28B-mediated supporting cell reprogramming. Furthermore, our study uncovers that the TRIM71-LIN28B targetHmga2is essential for supporting cell self-renewal and hair cell formation.
Heterogeneity of novel APOER2 isoforms specific to Alzheimer’s disease impact cellular and synaptic states
Authors: Gallo Christina M. , Kistler Sabrina , Natrakul Anna , Labadorf Adam T. , Beffert Uwe , Ho Angela 
Published: January 2023

SUMMARYApolipoprotein receptor 2 (APOER2) is an alternatively spliced transmembrane receptor that binds the neuroprotective ligand Reelin and Alzheimer’s disease (AD) related risk factor, APOE. Splicing of single exons in mouseApoer2regulates neuronal function and synaptic plasticity. However, the splicing landscape and function of human APOER2 isoforms in physiological and AD conditions remains unclear. Here, we identified over 200 unique humanAPOER2isoforms in the parietal cortex and hippocampus with 151 isoforms common between the two brain regions. In addition, we identified region- and AD-specificAPOER2isoforms suggestingAPOER2splicing is spatially regulated and altered in AD. We tested whether the AD-specificAPOER2transcripts have distinct functional properties, and demonstrated AD-specific APOER2 variants have altered cell surface expression, APOE-mediated receptor processing and synaptic changes which could contribute to neuronal dysfunction associated with AD pathogenesis.
Z-Flipon Variants reveal the many roles of Z-DNA and Z-RNA in health and disease
Authors: Umerenkov Dmitry , Herbert Alan , Konovalov Dmitrii , Danilova Anna , Beknazarov Nazar , Kokh Vladimir , Fedorov Aleksandr , Poptsova Maria 
Published: January 2023

AbstractIdentifying roles for Z-flipons remains challenging given their dynamic nature. Here we perform genome-wide interrogation with the DNABERT transformer algorithm trained on experimentally identified Z-DNA sequences. We show Z-flipons are enriched in promoters and telomeres and overlap quantitative trait loci for RNA expression, RNA editing, splicing and disease associated variants. Surprisingly, many effects are mediated through Z-RNA formation. We describe Z-RNA motifs present in SCARF2, SMAD1 and CACNA1 transcripts and others in non-coding RNAs. We also provide evidence for another Z-RNA motif that likely enables an adaptive anti-viral intracellular defense through alternative splicing of KRAB domain zinc finger proteins. An analysis of OMIM and gnomAD predicted loss-of-function datasets reveals an overlap of predicted and experimentally validated Z-flipons with disease causing variants in 8.6% and 2.9% of mendelian disease genes respectively, with frameshift variants present in 22% of cases. The work greatly extends the number of phenotypes mapped to Z-flipon variants.
A Real-Time Analysis of Protein Transport via the Twin Arginine Translocation Pathway in Response to Different Components of the Protonmotive Forcein vivo
Authors: Zhou Wenjie , Hao Binhan , Bricker Terry M. , Theg Steven M. 
Published: January 2023

AbstractThe twin arginine translocation (Tat) pathway transports folded protein across the cytoplasmic membrane in bacteria, archaea, and across the thylakoid membrane in plants as well as the inner membrane in some mitochondria. In plant chloroplasts, the Tat pathway utilizes the protonmotive force (PMF) to drive protein translocation. However, in bacteria, it has been shown that Tat transport depends only on the Δψ component of PMFin vitro. To investigate the comprehensive PMF requirement inEscherichia coli, we have developed the first real-time assay to monitor Tat transport utilizing the NanoLuc Binary Technology (NanoBiT) inE. colispheroplasts. This luminescence assay allows for continuous monitoring of Tat transport with high-resolution, making it possible to observe subtle changes in transport in response to different treatments. By applying the NanoLuc assay, we report that, under acidic conditions, ΔpH, in addition to Δψ, contributes energetically to Tat transportin vivoinE. colispheroplasts. These results provide novel insight into the mechanism of energy utilization by the Tat pathway.
Injured worker outcomes after compensation system overhaul: an interrupted time series study
Authors: Lane Tyler J , Donato Michael Di , Collie Alex 
Published: January 2023

ABSTRACTObjectiveIn 2015, South Australia replaced its workers’ compensation system with the aim of improving return to work rates. We tested whether time off work among injured workers changed under the new system, as well as indicators of potential mechanisms.MethodsWe conducted a controlled interrupted time series using workers’ compensation claims data. The primary outcome was mean weeks of compensated disability duration. Secondary outcomes tested explanatory mechanisms: 1) claim volumes to determine whether the new system changed the makeup of claimants, and 2) mean employer report and insurer decision times to evaluate whether there had been changes in claim processing. Outcomes were aggregated into monthly units. South Australia was compared to six other Australian workers’ compensation systems. To test for moderation by condition type, disease claims were compared to injury claims and mental health claims to physical health claims.ResultsDisability duration and insurer decision time steadily declined before the RTW Act came into effect, but flatlined afterwards. Claim volumes did not change significantly. Employer report time initially increased but gradually decreased until it was lower than the counterfactual. There were non-significant increases in disability durations among injury claims compared to disease claims, and mental health claims compared to physical claims.ConclusionsThe increase in disability duration after the RTW Act took effect may be attributable to the disruption of implementing a new compensation system or the elimination of provisional liability entitlements that incentivised early decision making and provided early intervention.KEY MESSAGESWhat is already known on this topicWorkers’ compensation systems are a major determinant of injured worker recovery.However, the specific mechanisms of how the compensation system influences outcomes are often opaque, which impedes the design of effective systems.What this study addsThis interrupted time series study evaluates the effect of a new workers’ compensation system in South Australia, which was designed specifically to improve return to work rates.Time off work increased relative to the counterfactual, which paralleled trends in the time for insurers to decide on liability.How this study might affect research, practice, or policyThe findings highlight the importance of understanding how compensation systems influence injured workers outcomes and considering the entire claims process when designing new systems.
Metabolic signature of the pathogenic 22q11.2 deletion identifies carriers and provides insight into systemic dysregulation
Authors: Courraud Julie , Russo Francesco , Themudo Gonçalo Espregueira , Laursen Susan Svane , Hougaard David M. , Cohen Arieh S. , Werge Thomas , Ernst Madeleine 
Published: January 2023

ABSTRACTBackgroundLarge deletions at chromosome 22q11.2 are known to cause severe clinical conditions collectively known as 22q11.2 deletion syndrome. Notwithstanding the pathogenicity of these deletions, affected individuals are typically diagnosed in late childhood or early adolescence, and little is known of the molecular signaling cascades and biological consequences immediately downstream of the deleted genes.MethodsHere, we used targeted metabolomics to compare neonatal dried blood spot samples from individuals clinically identified as carriers of a 3MB deletion at the chromosome 22q11.2 with unaffected individuals. A total of 173 metabolites were successfully identified and used to inform on systemic dysregulation caused by the genomic lesion and to discriminate carriers from non-carriers.ResultsWe found 84 metabolites to be differentially abundant between carriers and non-carriers of the 22q11.2 deletion. A predictive model based on all 173 metabolites achieved high Accuracy (89%), Area Under the Curve (93%), F1 (88%), Positive Predictive Value (94%) and Negative Predictive Value (84%) with tyrosine and proline having the highest individual contributions to the model as well as the highest interaction strength.ConclusionsTargeted metabolomics provides insight into the molecular consequences possibly contributing to the pathology underlying the clinical manifestations of the 22q11 deletion and is an easily applicable approach to first-pass screening for carrier status of the 22q11 to prompt subsequent verification of the genomic diagnosis.
Deep learning-based algorithm versus physician judgement for diagnosis of myopathy and neuropathy from needle electromyography
Authors: Yoo Ilhan , Yoo Jaesung , Kim Dongmin , Youn Ina , Kim Hyodong , Youn Michelle , Won Jun Hee , Cho Woosup , Myong Youho , Kim Sehoon , Yu Ri , Kim Sung-Min , Kim Kwangsoo , Lee Seung-Bo , Kim Keewon 
Published: January 2023

AbstractElectromyography is a valuable diagnostic procedure for diagnosing patients with neuromuscular diseases; however, it has some drawbacks. First, diagnosis using electromyography is subjective, and in some cases, there is the potential for inter-individual discrepancies. Second, it is a time- and effort-intensive process that requires expertise to yield accurate results. Recently, a deep learning algorithm shows effectiveness for the analysis of waveform data such as electrocardiography. To overcome limitations of electromyography, we developed a deep learning-based electromyography classification system and compared the performance of our deep learning model with that of six physicians. This study included 58 subjects who underwent electromyography and were finally confirmed as having myopathy or neuropathy, or to be in a normal state between June 2015 and July 2020 at Seoul National University Hospital. We developed a one-dimensional convolutional neural network algorithm and divide-and-vote system for diagnosing subjects. Diagnosis results with our deep learning model were compared with those of six physicians with experience in performing and interpreting electromyography. The accuracy, sensitivity, specificity, and positive predictive value of the deep learning model for diagnosis as to whether subjects have myopathy or neuropathy or normal were 0.875, 0.820, 0.904, and 0.820, respectively, whereas those for the physicians were 0.694, 0.537, 0.773, and 0.524, respectively. The area under the receiver operating characteristic curves of the deep learning model for predicting myopathy, neuropathy, and normal states was better than the averaged results of six physicians. Our study showed that deep learning could play a key role in reading electromyography and diagnosing patients with neuromuscular diseases. In the future, large prospective cohort studies incorporating diverse neuromuscular diseases can enable deep learning-based electrodiagnosis on behalf of physicians.
Single-cell Genome-and-Transcriptome sequencing without upfront whole-genome amplification reveals cell state plasticity of melanoma subclones
Authors: Theunis Koen , Vanuytven Sebastiaan , Rambow Florian , Brown Daniel , Van Der Haegen Michiel , Marin-Bejar Oskar , Rogiers Aljosja , Van Raemdonck Nina , Leucci Eleonora , Demeulemeester Jonas , Sifrim Alejandro , Marine Jean-Christophe , Voet Thierry 
Published: January 2023

ABSTRACTSingle-cell multi-omics methods are enabling the study of cell state diversity, which is largely determined by the interplay of the genome, epigenome, and transcriptome. Here, we describe Gtag&T-seq, a genome-and-transcriptome sequencing (G&T-seq) protocol of the same single cells that omits whole-genome amplification (WGA) by using direct genomic tagmentation (Gtag). Gtag drastically decreases the cost and improves coverage uniformity at both the single-cell and pseudo-bulk level when compared to WGA-based G&T-seq. We also show that transcriptome-based DNA copy number inference has limited resolution and accuracy, underlining the importance of affordable multi-omic approaches. Moreover, applying Gtag&T-seq to a melanoma xenograft model before treatment and at minimal residual disease revealed differential cell state plasticity and treatment response between cancer subclones. In summary, Gtag&T-seq is a low-cost and accurate single-cell multi-omics method enabling the exploration of genetic alterations and their functional consequences in single cells at scale.