bluuebunny/crossref_metadata_2025 huggingface dataset:
PET assessment of acute gastrointestinal graft versus host disease
Authors: Scott Ashleigh P. , Henden Andrea , Kennedy Glen A. , Tey Siok-Keen
Published: August 2023

Acute gastrointestinal graft versus host disease (GI-GVHD) is a common complication following allogeneic haematopoietic cell transplantation (HCT), and is characterised by severe morbidity, frequent treatment-refractoriness, and high mortality. Early, accurate identification of GI-GVHD could allow for therapeutic interventions to ameliorate its severity, improve response rates and survival; however, standard endoscopic biopsy is inadequately informative in terms of diagnostic sensitivity or outcome prediction. In an era where rapid technological and laboratory advances have dramatically expanded our understanding of GI-GVHD biology and potential therapeutic targets, there is substantial scope for novel investigations that can precisely guide GI-GVHD management. In particular, the combination of tissue-based biomarker assessment (plasma cytokines, faecal microbiome) and molecular imaging by positron emission tomography (PET) offers the potential for non-invasive, real-time in vivo assessment of donor:recipient immune activity within the GI tract for GI-GVHD prediction or diagnosis. In this article, we review the evidence regarding GI-GVHD diagnosis, and examine the potential roles and translational opportunities posed by these novel diagnostic tools, with a focus on the evolving role of PET.
A Phase Ib/II study of IGF-neutralising antibody xentuzumab with enzalutamide in metastatic castration-resistant prostate cancer
Authors: Macaulay Valentine M. , Lord Simon , Hussain Syed , Maroto José Pablo , Jones Robert Hugh , Climent Miguel Ángel , Cook Natalie , Lin Chia-Chi , Wang Shian-Shiang , Bianchini Diletta , Bailey Mark , Schlieker Laura , Bogenrieder Thomas , de Bono Johann
Published: August 2023

Background

This multicentre, open-label, Phase Ib/II trial evaluated the insulin-like growth factor (IGF) 1/2 neutralising antibody xentuzumab plus enzalutamide in metastatic castrate-resistant prostate cancer (mCRPC).

Methods

The trial included Phase Ib escalation and expansion parts and a randomised Phase II part versus enzalutamide alone. Primary endpoints in the Phase Ib escalation, Phase Ib expansion and Phase II parts were maximum tolerated dose (MTD), prostate-specific antigen response and investigator-assessed progression-free survival (PFS), respectively. Patients in the Phase Ib escalation and Phase II parts had progressed on/after docetaxel/abiraterone.

Results

In the Phase Ib escalation (n = 10), no dose-limiting toxicities were reported, and xentuzumab 1000 mg weekly plus enzalutamide 160 mg daily (Xe1000 + En160) was defined as the MTD and recommended Phase 2 dose. In the Phase Ib expansion (n = 24), median PFS was 8.2 months, and one patient had a confirmed, long-term response. In Phase II (n = 86), median PFS for the Xe1000 + En160 and En160 arms was 7.4 and 6.2 months, respectively. Subgroup analysis suggested trends towards benefit with Xe1000 + En160 in patients whose tumours had high levels of IGF1 mRNA or PTEN protein. Overall, the combination was well tolerated.

Conclusions

Xentuzumab plus enzalutamide was tolerable but lacked antitumour activity in unselected patients with mCRPC.

Clinical trial registration

EudraCT number 2013-004011-41.
Simultaneously discovering the fate and biochemical effects of pharmaceuticals through untargeted metabolomics
Authors: Bowen Tara J. , Southam Andrew D. , Hall Andrew R. , Weber Ralf J. M. , Lloyd Gavin R. , Macdonald Ruth , Wilson Amanda , Pointon Amy , Viant Mark R.
Published: August 2023

Untargeted metabolomics is an established approach in toxicology for characterising endogenous metabolic responses to xenobiotic exposure. Detecting the xenobiotic and its biotransformation products as part of the metabolomics analysis provides an opportunity to simultaneously gain deep insights into its fate and metabolism, and to associate the internal relative dose directly with endogenous metabolic responses. This integration of untargeted exposure and response measurements into a single assay has yet to be fully demonstrated. Here we assemble a workflow to discover and analyse pharmaceutical-related measurements from routine untargeted UHPLC-MS metabolomics datasets, derived from in vivo (rat plasma and cardiac tissue, and human plasma) and in vitro (human cardiomyocytes) studies that were principally designed to investigate endogenous metabolic responses to drug exposure. Our findings clearly demonstrate how untargeted metabolomics can discover extensive biotransformation maps, temporally-changing relative systemic exposure, and direct associations of endogenous biochemical responses to the internal dose.
Gain-of-function mutant p53 together with ERG proto-oncogene drive prostate cancer by beta-catenin activation and pyrimidine synthesis
Authors: Ding Donglin , Blee Alexandra M. , Zhang Jianong , Pan Yunqian , Becker Nicole A. , Maher L. James , Jimenez Rafael , Wang Liguo , Huang Haojie
Published: August 2023

Whether TMPRSS2-ERG fusion and TP53 gene alteration coordinately promote prostate cancer (PCa) remains unclear. Here we demonstrate that TMPRSS2-ERG fusion and TP53 mutation / deletion co-occur in PCa patient specimens and this co-occurrence accelerates prostatic oncogenesis. p53 gain-of-function (GOF) mutants are now shown to bind to a unique DNA sequence in the CTNNB1 gene promoter and transactivate its expression. ERG and β-Catenin co-occupy sites at pyrimidine synthesis gene (PSG) loci and promote PSG expression, pyrimidine synthesis and PCa growth. β-Catenin inhibition by small molecule inhibitors or oligonucleotide-based PROTAC suppresses TMPRSS2-ERG- and p53 mutant-positive PCa cell growth in vitro and in mice. Our study identifies a gene transactivation function of GOF mutant p53 and reveals β-Catenin as a transcriptional target gene of p53 GOF mutants and a driver and therapeutic target of TMPRSS2-ERG- and p53 GOF mutant-positive PCa.
Droplet-based bisulfite sequencing for high-throughput profiling of single-cell DNA methylomes
Authors: Zhang Qiang , Ma Sai , Liu Zhengzhi , Zhu Bohan , Zhou Zirui , Li Gaoshan , Meana J. Javier , González-Maeso Javier , Lu Chang
Published: August 2023

The genome-wide DNA methylation profile, or DNA methylome, is a critical component of the overall epigenomic landscape that modulates gene activities and cell fate. Single-cell DNA methylomic studies offer unprecedented resolution for detecting and profiling cell subsets based on methylomic features. However, existing single-cell methylomic technologies are based on use of tubes or well plates and these platforms are not easily scalable for handling a large number of single cells. Here we demonstrate a droplet-based microfluidic technology, Drop-BS, to construct single-cell bisulfite sequencing libraries for DNA methylome profiling. Drop-BS takes advantage of the ultrahigh throughput offered by droplet microfluidics to prepare bisulfite sequencing libraries of up to 10,000 single cells within 2 days. We apply the technology to profile mixed cell lines, mouse and human brain tissues to reveal cell type heterogeneity. Drop-BS offers a promising solution for single-cell methylomic studies requiring examination of a large cell population.
Molecular basis of the pleiotropic effects by the antibiotic amikacin on the ribosome
Authors: Seely Savannah M. , Parajuli Narayan P. , De Tarafder Arindam , Ge Xueliang , Sanyal Suparna , Gagnon Matthieu G.
Published: August 2023

Aminoglycosides are a class of antibiotics that bind to ribosomal RNA and exert pleiotropic effects on ribosome function. Amikacin, the semisynthetic derivative of kanamycin, is commonly used for treating severe infections with multidrug-resistant, aerobic Gram-negative bacteria. Amikacin carries the 4-amino-2-hydroxy butyrate (AHB) moiety at the N1 amino group of the central 2-deoxystreptamine (2-DOS) ring, which may confer amikacin a unique ribosome inhibition profile. Here we use in vitro fast kinetics combined with X-ray crystallography and cryo-EM to dissect the mechanisms of ribosome inhibition by amikacin and the parent compound, kanamycin. Amikacin interferes with tRNA translocation, release factor-mediated peptidyl-tRNA hydrolysis, and ribosome recycling, traits attributed to the additional interactions amikacin makes with the decoding center. The binding site in the large ribosomal subunit proximal to the 3’-end of tRNA in the peptidyl (P) site lays the groundwork for rational design of amikacin derivatives with improved antibacterial properties.
Latent evolution of biofilm formation depends on life-history and genetic background
Authors: Nucci Amandine , Rocha Eduardo P. C. , Rendueles Olaya
Published: August 2023

Adaptation to one environment can often generate phenotypic and genotypic changes which impact the future ability of an organism to thrive in other environmental conditions. In the context of host-microbe interactions, biofilm formation can increase survival rates in vivo upon exposure to stresses, like the host’s immune system or antibiotic therapy. However, how the generic process of adaptation impacts the ability to form biofilm and how it may change through time has seldomly been studied. To do so, we used a previous evolution experiment with three strains of theKlebsiella pneumoniaespecies complex, in which we specifically did not select for biofilm formation. We observed that changes in the ability to form biofilm happened very fast at first and afterwards reverted to ancestral levels in many populations. Biofilm changes were associated to changes in population yield and surface polysaccharide production. Genotypically, mutations in the tip adhesin of type III fimbriae (mrkD) or thefimswitch of type I fimbriae were shaped by nutrient availability during evolution, and their impact on biofilm formation was dependent on capsule production. Analyses of natural isolates revealed similar mutations inmrkD, suggesting that such mutations also play an important role in adaptation outside the laboratory. Our work reveals that the latent evolution of biofilm formation, and its temporal dynamics, depend on nutrient availability, the genetic background and other intertwined phenotypic and genotypic changes. Ultimately, it suggests that small differences in the environment can alter an organism’s fate in more complex niches like the host.
Soliton pulse pairs at multiple colours in normal dispersion microresonators
Authors: Yuan Zhiquan , Gao Maodong , Yu Yan , Wang Heming , Jin Warren , Ji Qing-Xin , Feshali Avi , Paniccia Mario , Bowers John , Vahala Kerry
Published: August 2023

Soliton microcombs are helping to advance the miniaturization of a range of comb systems. These combs mode lock through the formation of short temporal pulses in anomalous dispersion resonators. Here, a new microcomb is demonstrated that mode locks through the formation of pulse pairs in coupled normal dispersion resonators. Unlike conventional microcombs, pulses in this system cannot exist alone, and instead phase lock in pairs wherein pulses in each pair feature different optical spectra. The pairwise mode-locking modality extends to multiple pulse pairs and beyond two rings, and it greatly constrains mode-locking states. Two- (bipartite) and three-ring (tripartite) states containing many pulse pairs are demonstrated, including crystal states. Pulse pairs can also form at recurring spectral windows. We obtained the results using an ultra-low-loss Si3N4 platform that has not previously produced bright solitons on account of its inherent normal dispersion. The ability to generate multicolour pulse pairs over multiple rings is an important new feature for microcombs. It can extend the concept of all-optical soliton buffers and memories to multiple storage rings that multiplex pulses with respect to soliton colour and that are spatially addressable. The results also suggest a new platform for the study of topological photonics and quantum combs.
Design of a mucin-selective protease for targeted degradation of cancer-associated mucins
Authors: Pedram Kayvon , Shon D. Judy , Tender Gabrielle S. , Mantuano Natalia R. , Northey Jason J. , Metcalf Kevin J. , Wisnovsky Simon P. , Riley Nicholas M. , Forcina Giovanni C. , Malaker Stacy A. , Kuo Angel , George Benson M. , Miller Caitlyn L. , Casey Kerriann M. , Vilches-Moure José G. , Ferracane Michael J. , Weaver Valerie M. , Läubli Heinz , Bertozzi Carolyn R.
Published: August 2023

Targeted protein degradation is an emerging strategy for the elimination of classically undruggable proteins. Here, to expand the landscape of targetable substrates, we designed degraders that achieve substrate selectivity via recognition of a discrete peptide and glycan motif and achieve cell-type selectivity via antigen-driven cell-surface binding. We applied this approach to mucins, O-glycosylated proteins that drive cancer progression through biophysical and immunological mechanisms. Engineering of a bacterial mucin-selective protease yielded a variant for fusion to a cancer antigen-binding nanobody. The resulting conjugate selectively degraded mucins on cancer cells, promoted cell death in culture models of mucin-driven growth and survival, and reduced tumor growth in mouse models of breast cancer progression. This work establishes a blueprint for the development of biologics that degrade specific protein glycoforms on target cells.
Somatic mutations in facial skin from countries of contrasting skin cancer risk
Authors: King Charlotte , Fowler Joanna C. , Abnizova Irina , Sood Roshan K. , Hall Michael W. J. , Szeverényi Ildikó , Tham Muly , Huang Jingxiang , Young Stephanie Ming , Hall Benjamin A. , Birgitte Lane E. , Jones Philip H.
Published: August 2023

The incidence of keratinocyte cancer (basal cell and squamous cell carcinomas of the skin) is 17-fold lower in Singapore than the UK1–3, despite Singapore receiving 2–3 times more ultraviolet (UV) radiation4,5. Aging skin contains somatic mutant clones from which such cancers develop6,7. We hypothesized that differences in keratinocyte cancer incidence may be reflected in the normal skin mutational landscape. Here we show that, compared to Singapore, aging facial skin from populations in the UK has a fourfold greater mutational burden, a predominant UV mutational signature, increased copy number aberrations and increased mutant TP53 selection. These features are shared by keratinocyte cancers from high-incidence and low-incidence populations8–13. In Singaporean skin, most mutations result from cell-intrinsic processes; mutant NOTCH1 and NOTCH2 are more strongly selected than in the UK. Aging skin in a high-incidence country has multiple features convergent with cancer that are not found in a low-risk country. These differences may reflect germline variation in UV-protective genes.
Transcription modulates chromatin dynamics and locus configuration sampling
Authors: Forte Giada , Buckle Adam , Boyle Shelagh , Marenduzzo Davide , Gilbert Nick , Brackley Chris A.
Published: August 2023

In living cells, the 3D structure of gene loci is dynamic, but this is not revealed by 3C and FISH experiments in fixed samples, leaving a notable gap in our understanding. To overcome these limitations, we applied the highly predictive heteromorphic polymer (HiP-HoP) model to determine chromatin fiber mobility at the Pax6 locus in three mouse cell lines with different transcription states. While transcriptional activity minimally affects movement of 40-kbp regions, we observed that motion of smaller 1-kbp regions depends strongly on local disruption to chromatin fiber structure marked by H3K27 acetylation. This also substantially influenced locus configuration dynamics by modulating protein-mediated promoter-enhancer loops. Importantly, these simulations indicate that chromatin dynamics are sufficiently fast to sample all possible locus conformations within minutes, generating wide dynamic variability within single cells. This combination of simulation and experimental validation provides insight into how transcriptional activity influences chromatin structure and gene dynamics.
DIPS-Plus: The enhanced database of interacting protein structures for interface prediction
Authors: Morehead Alex , Chen Chen , Sedova Ada , Cheng Jianlin
Published: August 2023

In this work, we expand on a dataset recently introduced for protein interface prediction (PIP), the Database of Interacting Protein Structures (DIPS), to present DIPS-Plus, an enhanced, feature-rich dataset of 42,112 complexes for machine learning of protein interfaces. While the original DIPS dataset contains only the Cartesian coordinates for atoms contained in the protein complex along with their types, DIPS-Plus contains multiple residue-level features including surface proximities, half-sphere amino acid compositions, and new profile hidden Markov model (HMM)-based sequence features for each amino acid, providing researchers a curated feature bank for training protein interface prediction methods. We demonstrate through rigorous benchmarks that training an existing state-of-the-art (SOTA) model for PIP on DIPS-Plus yields new SOTA results, surpassing the performance of some of the latest models trained on residue-level and atom-level encodings of protein complexes to date.
Chromosome-scale genomes of commercial timber trees (Ochroma pyramidale, Mesua ferrea, and Tectona grandis)
Authors: Sahu Sunil Kumar , Liu Min , Chen Yewen , Gui Jinshan , Fang Dongming , Chen Xiaoli , Yang Ting , He Chengzhong , Cheng Le , Yang Jinlong , Sahu Durgesh Nandini , Li Linzhou , Wang Hongli , Mu Weixue , Wei Jinpu , Liu Jie , Zhao Yuxian , Zhang Shouzhou , Lisby Michael , Liu Xin , Xu Xun , Li Laigeng , Wang Sibo , Liu Huan
Published: August 2023

Wood is the most important natural and endlessly renewable source of energy. Despite the ecological and economic importance of wood, many aspects of its formation have not yet been investigated. We performed chromosome-scale genome assemblies of three timber trees (Ochroma pyramidale, Mesua ferrea, and Tectona grandis) which exhibit different wood properties such as wood density, hardness, growth rate, and fiber cell wall thickness. The combination of 10X, stLFR, Hi-Fi sequencing and HiC data led us to assemble high-quality genomes evident by scaffold N50 length of 55.97 Mb (O. pyramidale), 22.37 Mb (M. ferrea) and 14.55 Mb (T. grandis) with >97% BUSCO completeness of the assemblies. A total of 35774, 24027, and 44813 protein-coding genes were identified in M. ferrea, T. grandis and O. pyramidale, respectively. The data generated in this study is anticipated to serve as a valuable genetic resource and will promote comparative genomic analyses, and it is of practical importance in gaining a further understanding of the wood properties in non-model woody species.
Seafood label quality and mislabelling rates hamper consumer choices for sustainability in Australia
Authors: Cundy Megan E. , Santana-Garcon Julia , McLennan Alexander G. , Ayad Marcelle E. , Bayer Philipp E. , Cooper Madalyn , Corrigan Shannon , Harrison Emily , Wilcox Chris
Published: August 2023

Seafood mislabelling and species substitution, compounded by a convoluted seafood supply chain with significant traceability challenges, hinder efforts towards more sustainable, responsible, and ethical fishing and business practices. We conducted the largest evaluation of the quality and accuracy of labels for 672 seafood products sold in Australia, assessing six seafood groups (i.e., hoki, prawns, sharks and rays, snapper, squid and cuttlefish, and tuna) from fishmongers, restaurants, and supermarkets, including domestically caught and imported products. DNA barcoding revealed 11.8% of seafood tested did not match their label with sharks and rays, and snappers, having the highest mislabelling rate. Moreover, only 25.5% of products were labelled at a species-level, while most labels used vague common names or umbrella terms such as ‘flake’ and ‘snapper’. These poor-quality labels had higher rates of mislabelling than species-specific labels and concealed the sale of threatened or overfished taxa, as well as products with lower nutritional quality, reduced economic value, or potential health risks. Our results highlight Australia’s weak seafood labelling regulations and ambiguous non-mandatory naming conventions, which impede consumer choice for accurately represented, sustainable, and responsibly sourced seafood. We recommend strengthening labelling regulations to mitigate seafood mislabelling and substitution, ultimately improving consumer confidence when purchasing seafood.
An examination of the design for a prefabricated housing unit in Cyprus in terms of energy, daylighting and cost
Authors: Savvides Andreas , Michael Aimilios , Vassiliades Constantinos , Parpa Despina , Triantafyllidou Elina , Englezou Maria
Published: August 2023

Housing prefabrication emerged as an energy and cost-saving solution, which can also be linked to the reduction of environmental impacts, as well as to the development of green construction practices. In the first part of this study, a comprehensive literature review of the prefabricated assembly methods and their inherent potential, in terms of both design and construction are presented. Design strategies that incorporate the integration of environmental systems are also considered. A classification and taxonomy of archetypes is included, based on key design principles pertaining to environmental design. Based on the conclusions drawn from the assessment of these considerations, this paper revisits the realm of design and construction techniques used in energy efficient and environmentally compatible prefabricated housing unit in a Cypriot context. Cost-saving strategies are proposed, as well as architectural design and fabrication recommendations. Consequently, the research aims to contribute to existing literature by drawing results from an actual demonstration project in Cyprus. It goes on to outline considerations affecting the front end of the design and construction processes based on criteria for efficient prefabrication and modular construction. Findings are then related to simulations for energy and daylighting performance supplemented by a techno-economic analysis, aiming to demonstrate the viability of this enterprise. In this way it is hoped that stakeholders considering the adoption of this approach to design and construction may make better informed and more appropriate decisions.
Ramifications of POU4F3 variants associated with autosomal dominant hearing loss in various molecular aspects
Authors: Lee Sang-Yeon , Kim Min Young , Han Jin Hee , Park Sang Soo , Yun Yejin , Jee Seung-Cheol , Han Jae Joon , Lee Jun Ho , Seok Heeyoung , Choi Byung Yoon
Published: August 2023

POU4F3, a member of the POU family of transcription factors, commonly causes autosomal dominant deafness. Exome sequencing was used to identify four novel variants in POU4F3 (NM_002700.2), including c.564dupA: p.Ala189SerfsTer26, c.743T > C:p.Leu248Pro, c.879C > A:p.Phe293Leu, and c.952G > A:p.Val318Met, and diverse aspects of the molecular consequences of their protein expression, stability, subcellular localization, and transcriptional activity were investigated. The expression of three mutant proteins, encoded by missense variants, was reduced compared to the wild-type protein, demonstrating that the mutants were unstable and vulnerable to degradation. Additionally, all the mutant proteins had distinct subcellular localization patterns. A mutant protein carrying p.Ala189SerfsTer26, in which both mono- and bi-partite nuclear localization signals were disrupted, showed abnormal subcellular localization. Resultantly, all the mutant proteins significantly reduced the transcriptional activity required to regulate the downstream target gene expression. Furthermore, we identified the altered expression of 14 downstream target genes associated with inner ear development using patient-derived lymphoblastoid cell lines. There was a significant correlation of the expression profile between patient-derived cells and the cochlear hair cells, which provided a breakthrough for cases where the collection of human cochlear samples for transcriptome studies was unfeasible. This study expanded the genotypic spectrum of POU4F3 in DFNA15, and further refined the molecular mechanisms underlying POU4F3-associated DFNA15.
Delhi urbanization footprint and its effect on the earth’s subsurface state-of-stress through decadal seismicity modulation
Authors: Tiwari Deepak K. , Hari Manoj , Kundu Bhaskar , Jha Birendra , Tyagi Bhishma , Malik Kapil
Published: August 2023

Urban land and its expansion have profoundly impacted the global environment, including the stress change in the earth’s subsurface, even though urban land is a small fraction of the global land surface. Divulging such effects has never been more important, given the role of stress in determining the safety of the urban population against earthquakes. However, knowledge of this time-dependent non-linear effect of urbanization on the subsurface remains in the gray area. This study focuses on the area surrounding Delhi, the capital city of India, to understand the relative contribution of the building load created by rapid urbanization in exacerbating the subsurface state-of-stress. The results highlight that, since 2010, the modulation in the seismicity rate and the stability of basement thrust faults is linked not only to urbanization but also to decadal groundwater storage. Mounting evidence suggests that the rapid urbanization, and the resulting non-tectonic horizontal compression, stabilize faults in the Aravalli Delhi belt, which are destabilized due to the extensive groundwater extraction. This affects the decadal seismicity trend around the Aravalli Delhi fold belt. Nonetheless, the magnitude of this time-dependent deformation influence on the seismicity modulation remains uncertain. The findings from this study quantify the geomechanical impacts of urbanization in the Delhi area for the first time.
Phase field modelling of hopper crystal growth in alloys
Authors: Bollada P. C. , Jimack P. K. , Mullis A. M.
Published: August 2023

Here we use phase field to model and simulate “hopper” crystals, so named because of their underlying cubic structure but with a hopper-like depression on each of the six faces. Over the past three decades simulations of single phase solidification have successfully explored dendritic structures, in two and three dimensions, formed under high undercooling from a slight perturbation in anisotropy. More recently we see the modelling of faceted structures at near equilibrium, and also, under high undercooling, the formation of dendritic-like structures in two dimensions which retain some faceting in the dendrite arms. A cubic hopper crystal appears to be a hybrid structure, somewhere between a perfect cube and a dendrite, and, to date, has not appeared in the modelling literature. In this paper we describe a model for faceted cubic growth and explore results, necessarily in three dimensions, that include perfect cube, hopper and dendritic. We also touch briefly on one other morphology—octahedral.
Effects of repeated sprinting on hamstring shear modulus pattern and knee flexor neuromuscular parameters
Authors: Pimenta Ricardo , Lopes Tomás , Correia José Pedro , Veloso António Prieto
Published: August 2023

The purpose of the present study was to examine the acute effects of a maximum repeated sprint protocol on (1) hamstring shear modulus and (2) knee flexor neuromuscular parameters such as peak torque (PT) and rate of torque development (RTD). Muscle shear modulus was assessed in 18 healthy males using shear wave elastography at rest and during 30° isometric knee flexion at 20% of maximal voluntary isometric contraction, before and after a 10 × 30 m repeated sprint protocol. There was a 9% decrease in average speed between the fastest and slowest sprint (p < 0.001; d = 2.27). A pre-post decrease was observed in PT (p = 0.004; η2p = 0.399) and in the 0–50 ms (p = 0.042; η2p = 0.222), and 50–100 ms (p = 0.028; η2p = 0.254) RTD periods. For the active shear modulus, the only significant change after the sprint task was in the biceps femoris long head (BFlh) with an increase of 10% (Pre: 26.29 ± 8.89 kPa; Post: 28.93 ± 8.31 kPa; p = 0.015; d = 0.31). The present study provides evidence that repeated sprinting leads to significant decreases in average speed, PT, early RTD (0–50 ms; 50–100 ms), and to an increase in BFlh active shear modulus without changing the shear modulus of the other hamstrings muscles.
Transient power equalization control strategy of virtual synchronous generator in isolated island microgrid with heterogeneous power supply
Authors: Gao Changwei , Sun Yongchang , Zheng Weiqiang , Wang Wei
Published: August 2023

In the parallel supply system of synchronous generator and virtual synchronous generator, the physical structure and control structure of the two kinds of power supply are quite different, and it is difficult to distribute the transient power of the two kinds of power supply evenly when the load changes abruptly. Especially in the case of sudden load increase, virtual synchronous generator bears too much load in the transient process because of its fast adjustment speed, and even causes short-term overload, which makes the capacity of virtual synchronous generator can not be fully utilized. In view of this problem, firstly, the mechanism of transient power uneven distribution of two heterogeneous power sources is explained from the differences of frequency modulation, voltage regulation and output impedance. Secondly, virtual speed regulation, virtual excitation and dynamic virtual impedance are added to the traditional virtual synchronous generator control to simulate the speed regulation characteristics and electromagnetic transient characteristics of the synchronous generator, so as to realize the transient and steady-state power equalization between heterogeneous power supplies when the virtual synchronous generator and the synchronous generator run in parallel. Thirdly, in order to ensure the fast dynamic response characteristics of the virtual synchronous generator in independent operation mode, the traditional virtual synchronous generator control algorithm is still maintained in independent operation mode, and the mode switching control link based on state tracking is designed to realize smooth switching between the two working modes. Finally, the hardware in loop experiment results based on RT-LAB show that the proposed control method can realize the transient and steady-state power equalization when the virtual synchronous generator and the synchronous generator operate in parallel, it can keep the fast voltage regulation and frequency modulation ability when the virtual synchronous generator operates independently, and can realize smooth switching between independent and parallel operation modes.
A chlorzoxazone–folic acid combination improves cognitive affective decline in SCA2-58Q mice
Authors: Marinina Ksenia S. , Bezprozvanny Ilya B. , Egorova Polina A.
Published: August 2023

Spinocerebellar ataxia type 2 (SCA2) is a polyglutamine disorder caused by a pathological expansion of CAG repeats in ATXN2 gene. SCA2 is accompanied by cerebellar degeneration and progressive motor decline. Cerebellar Purkinje cells (PCs) seem to be primarily affected in this disorder. The majority of the ataxia research is focused on the motor decline observed in ataxic patients and animal models of the disease. However, recent evidence from patients and ataxic mice suggests that SCA2 can also share the symptoms of the cerebellar cognitive affective syndrome. We previously reported that SCA2-58Q PC-specific transgenic mice exhibit anxiolytic behavior, decline in spatial memory, and a depressive-like state. Here we studied the effect of the activation of the small conductance calcium-activated potassium channels (SK channels) by chlorzoxazone (CHZ) combined with the folic acid (FA) on the PC firing and also motor, cognitive and affective symptoms in SCA2-58Q mice. We realized that CHZ-FA combination improved motor and cognitive decline as well as ameliorated mood alterations in SCA2-58Q mice without affecting the firing rate of their cerebellar PCs. Our results support the idea of the combination therapy for both ataxia and non-motor symptoms in ataxic mice without affecting the firing frequency of PCs.
Neuronal correlates of eyeblinks are an expression of primary consciousness phenomena
Authors: Callara Alejandro Luis , Greco Alberto , Scilingo Enzo Pasquale , Bonfiglio Luca
Published: August 2023

The blinking rate far exceeds that required for moistening the cornea and changes depending on whether a person is resting or engaged in cognitive tasks. During ecological cognitive tasks (such as speaking, reading, and watching videos), blinks occur at breakpoints of attention suggesting a role in information segmentation, but the close relationship between cognition dynamics and blink timing still escapes a full understanding. The aim of the present study is to seek (1) if there is a temporal relationship between blink events and the consecutive steps of cognitive processing, and (2) if blink timing and the intensity of blink-related EEG responses are affected by task-relevance of stimuli. Our results show that, in a classical visual oddball task, (i) the occurrence of blinks is influenced by stimuli, irrespective of their relevance, (ii) blinks following relevant stimuli are only apparently delayed due to the need of finalizing a behavioural response, and (iii) stimulus relevance does not affect the intensity of the blink-related EEG response. This evidence reinforce the idea that blinks are not emitted until the last step of the processing sequence has been completed and suggests that blink-related EEG responses are generated by primary consciousness phenomena which are considered by their nature non-modulable (all-or-nothing) phenomena.
GlobalUsefulNativeTrees, a database documenting 14,014 tree species, supports synergies between biodiversity recovery and local livelihoods in landscape restoration
Authors: Kindt Roeland , Graudal Lars , Lillesø Jens-Peter B. , Pedercini Fabio , Smith Paul , Jamnadass Ramni
Published: August 2023

Tree planting has the potential to improve the livelihoods of millions of people as well as to support environmental services such as biodiversity conservation. Planting however needs to be executed wisely if benefits are to be achieved. We have developed the GlobalUsefulNativeTrees (GlobUNT) database to directly support the principles advocated by the ‘golden rules for reforestation’, including planting tree mixtures that maximize the benefits to local livelihoods and the diversity of native trees. Developed primarily by combining data from GlobalTreeSearch with the World Checklist of Useful Plant Species (WCUPS), GlobUNT includes 14,014 tree species that can be filtered for ten major use categories, across 242 countries and territories. The 14,014 species represent roughly a quarter of the tree species from GlobalTreeSearch and a third of the plant species from WCUPS. GlobUNT includes over 8000 species used as materials (9261 species; 68.4% of the total in WCUPS for that use category) or medicines (8283; 31.1%), over 2000 species with environmental uses (3317; 36.9%), used as human food (3310; 47.0%) or fuel (2162; 85.5%), over 1000 species used as gene sources (1552; 29.8%), animal food (1494; 33.7%), social uses (1396; 53.8%) or poisons (1109; 36.8%), and 712 species (68.4%) as insect food.
DNA-based assessment of root lesion nematode infections in cereal roots
Authors: Fatemi Ehsan , Melzer Siegbert , Jung Christian
Published: August 2023

Root lesion nematodes (RLN) of the genus Pratylenchus are causing significant damage in cereal production worldwide. Due to climate change and without efficient and environment-friendly treatments, the damages through RLNs are predicted to increase. Microscopic assessments of RLNs in the field and the greenhouses are time-consuming and laborious. As a result, cereal breeders have mostly ignored this pest. We present a method measuring RLN in infected cereal roots using a standardized PCR approach. Publicly available Pratylenchus neglectus primer combinations were evaluated. An optimal primer combination for RT-qPCR assay was identified to detect and quantify P. neglectus within infected cereal roots. Using the RT-qPCR detection assay, P. neglectus could be clearly distinguished from other plant parasitic nematodes. We could identify P. neglectus DNA in barley and wheat roots as low as 0.863 and 0.916 ng/µl of total DNA, respectively. A single P. neglectus individual was detected in water suspension and within barley and wheat roots. The RT-qPCR detection assay provides a robust and accurate alternative to microscopic nematode identification and quantification. It could be of interest for resistance breeding, where large populations must be screened to detect and quantify P. neglectus in farmer’s fields.
Active ingredients Isorhamnetin of Croci Srigma inhibit stomach adenocarcinomas progression by MAPK/mTOR signaling pathway
Authors: Shi Xue-feng , Yu Qi , Wang Kai-bo , Fu Yi-dong , Zhang Shun , Liao Zhen-yun , Li Yan , Cai Ting
Published: August 2023

Gastric cancer (GC) remains the third leading cause of cancer-related mortality in the world, and ninety-five percent of GC are stomach adenocarcinomas (STAD). The active ingredients of Croci Stigma, such as Isorhamnetin, Crocin, Crocetin and Kaempferol, all have antitumor activity. However, their chemical and pharmacological profiles remain to be elusive. In this study, network pharmacology was used to characterize the action mechanism of Croci Stigma. All compounds were obtained from the traditional Chinese medicine systems pharmacology (TCMSP) database, and active ingredients were selected by their oral bioavailability and drug-likeness index. The targets of Croci Stigma active ingredients were obtained from the traditional Chinese medicine integrated database (TCMID), whereas the related genes of STAD were obtained from DisGeNET platform. Cytoscape was used to undertake visual analyses of the Drug Ingredients–Gene Symbols–Disease (I–G–D) network, and 2 core genes including MAPK14, ERBB3 were obtained, which are the predicted targets of isorhamnetin (IH) and quercetin, respectively. Data analysis from TCGA platform showed that MAPK14 and ERBB3 all upregulated in STAD patients, but only the effect of MAPK14 expression on STAD patients’ survival was significant. Molecular docking showed that IH might affect the function of MAPK14 protein, and then the underlying action mechanisms of IH on STAD were experimentally validated using human gastric cancer cell line, HGC-27 cells. The results showed that IH can inhibit cell proliferation, migration, clonal formation, and arrest cell cycle, but promote the apoptosis of HGC-27 cells. qRT-PCR data demonstrated that IH downregulated the MAPK14 mRNA expression and EMT related genes. WB results showed that IH regulates MAPK/mTOR signaling pathway. These findings suggest that IH has the therapeutic potential for the treatment of STAD.
Genomic and phenotypic characterization of Acinetobacter colistiniresistens isolated from the feces of a healthy member of the community
Authors: Muzahid Nazmul Hasan , Md Zoqratt Muhammad Zarul Hanifah , Ten Kah Ern , Hussain Md Hamed , Su Tin Tin , Ayub Qasim , Tan Hock Siew , Rahman Sadequr
Published: August 2023

Acinetobacter species are widely known opportunistic pathogens causing severe community and healthcare-associated infections. One such emerging pathogen, Acinetobacter colistiniresistens, is known to exhibit intrinsic resistance to colistin. We investigated the molecular characteristics of A. colistiniresistens strain C-214, isolated from the fecal sample of a healthy community member, as part of a cohort study being conducted in Segamat, Malaysia. Comparison of the whole genome sequence of C-214 with other A. colistiniresistens sequences retrieved from the NCBI database showed 95% sequence identity or more with many of the genome sequences representing that species. Use of the Galleria mellonella killing assay showed that C-214 was pathogenic in this model infection system. The strain C-214 had a colistin and polymyxin B MIC of 32 and 16 mg/L, respectively. Besides, it was resistant to cefotaxime, amikacin, and tetracycline and showed moderate biofilm-producing ability. Different genes associated with virulence or resistance to major classes of antibiotics were detected. We observed mutations in lpxA/C/D in C-214 and other A. colistiniresistens strains as probable causes of colistin resistance, but the biological effects of these mutations require further investigation. This study provides genomic insights into A. colistiniresistens, a potentially pathogenic bacterium isolated from a community member and notes the public health threat it may pose.
Invasion success of a Lessepsian symbiont-bearing foraminifera linked to high dispersal ability, preadaptation and suppression of sexual reproduction
Authors: S. Raposo Débora , A. Zufall Rebecca , Caruso Antonio , Titelboim Danna , Abramovich Sigal , Hassenrück Christiane , Kucera Michal , Morard Raphaël
Published: August 2023

Among the most successful Lessepsian invaders is the symbiont-bearing benthic foraminifera Amphistegina lobifera. In its newly conquered habitat, this prolific calcifier and ecosystem engineer is exposed to environmental conditions that exceed the range of its native habitat. To disentangle which processes facilitated the invasion success of A. lobifera into the Mediterranean Sea we analyzed a ~ 1400 bp sequence fragment covering the SSU and ITS gene markers to compare the populations from its native regions and along the invasion gradient. The genetic variability was studied at four levels: intra-genomic, population, regional and geographical. We observed that the invasion is not associated with genetic differentiation, but the invasive populations show a distinct suppression of intra-genomic variability among the multiple copies of the rRNA gene. A reduced genetic diversity compared to the Indopacific is observed already in the Red Sea populations and their high dispersal potential into the Mediterranean appears consistent with a bridgehead effect resulting from the postglacial expansion from the Indian Ocean into the Red Sea. We conclude that the genetic structure of the invasive populations reflects two processes: high dispersal ability of the Red Sea source population pre-adapted to Mediterranean conditions and a likely suppression of sexual reproduction in the invader. This discovery provides a new perspective on the cost of invasion in marine protists: The success of the invasive A. lobifera in the Mediterranean Sea comes at the cost of abandonment of sexual reproduction.
Exploring the G-quadruplex binding and unwinding activity of the bacterial FeS helicase DinG
Authors: De Piante Elisa , D’Aria Federica , Napolitano Luisa M. R. , Amato Jussara , Pirrello Simone , Onesti Silvia , Giancola Concetta
Published: August 2023

Despite numerous reports on the interactions of G-quadruplexes (G4s) with helicases, systematic analysis addressing the selectivity and specificity of each helicase towards a variety of G4 topologies are scarce. Among the helicases able to unwind G4s are those containing an iron-sulphur (FeS) cluster, including both the bacterial DinG (found in E. coli and several pathogenic bacteria) and the medically important eukaryotic homologues (XPD, FancJ, DDX11 and RTEL1). We carried out a detailed study of the interactions between the E. coli DinG and a variety of G4s, by employing physicochemical and biochemical methodologies. A series of G4-rich sequences from different genomic locations (promoter and telomeric regions), able to form unimolecular G4 structures with diverse topologies, were analyzed (c-KIT1, KRAS, c-MYC, BCL2, Tel23, T30695, Zic1). DinG binds to most of the investigated G4s with little discrimination, while it exhibits a clear degree of unwinding specificity towards different G4 topologies. Whereas previous reports suggested that DinG was active only on bimolecular G4s, here we show that it is also able to bind to and resolve the more physiologically relevant unimolecular G4s. In addition, when the G4 structures were stabilized by ligands (Pyridostatin, PhenDC3, BRACO-19 or Netropsin), the DinG unwinding activity decreased and in most cases was abolished, with a pattern that is not simply explained by a change in binding affinity. Overall, these results have important implications for the biochemistry of helicases, strongly suggesting that when analysing the G4 unwinding property of an enzyme, it is necessary to investigate a variety of G4 substrates.
Gata3 is required in late proneurosensory development for proper sensory cell formation and organization
Authors: Blinkiewicz Paige V. , Long Makayla R. , Stoner Zachary A. , Ketchum Elizabeth M. , Sheltz-Kempf Sydney N. , Duncan Jeremy S.
Published: August 2023

It has previously been shown that the zinc-finger transcription factor Gata3 has dynamic expression within the inner ear throughout embryonic development and is essential for cochlear neurosensory development. However, the temporal window for which Gata3 is required for proper formation of the cochlear neurosensory epithelia remains unclear. To investigate the role of Gata3 in cochlear neurosensory development in the late prosensory stages, we used the Sox2-creERT2 mouse line to target and conditionally delete Gata3 at E11.5, a timepoint before cells have fully committed to a neurosensory fate. While the inner ears of Sox2-creERT2: Gata3 f/f mice appear normal with no gross structural defects, the sensory cells in the organ of Corti are partially lost and disorganized in an increasing severity from base to apex. Additionally, spiral ganglion neurons display aberrant peripheral projections, including increased distances between radial bundles and disorganization upon reaching the organ of Corti. Furthermore, heterozygous Sox2-creERT2: Gata3 f/+ mice show a reduced aberrant phenotype in comparison to the homozygous mutant, supporting the hypothesis that Gata3 is not only required for proper formation at the later proneurosensory stage, but also that a specific expression level of Gata3 is required. Therefore, this study provides evidence that Gata3 plays a time-sensitive and dose-dependent role in the development of sensory and neuronal cells in late proneurosensory stages.
A new formula to predict the size and insertion depth of cuffed nasotracheal tube in children receiving dental surgery: a retrospective study
Authors: Chou Chen-Hung , Tsai Chia-Ling , Lin Kai-Lieh , Wu Shao-Chun , Chiang Min-Hsien , Huang Hui-Wen , Hung Kuo-Chuan
Published: August 2023

This retrospective study aimed to develop a new formula for selecting the appropriate size and determining the depth of the cuffed nasotracheal intubation (NTI) for a cuffed endotracheal tube (cETT) in pediatric patients undergoing dental surgery. In addition, the clinical data on cETT (i.e., the size and depth of insertion) was compared with those calculated with age-based formulas to evaluate their correlation. A total number of 684 patients who received NTI were enrolled (healthy group, n = 607; special-need group, n = 77). The ETT size used in real-world scenarios was smaller (i.e., about 0.5 and 0.94 mm) than the age-based formula, while the ETT depth was greater (i.e., about 1.5 cm) than the age-based formula in both groups. In the healthy group, age, gender, and body weight were identified as predictors of ETT size and depth through multiple linear regression analysis, while only age and body weight were predictors in the special-needs group. New formulas were developed based on these findings, with ETT size = 3.98 + 0.052 × age + 0.048 × gender (male = 1, female = 0) + 0.023 × body weight (kg) and ETT depth = 15.1 + 0.43 × age + 0.300 × gender (male = 1, female = 0) + 0.007 × body weight (kg). The new formula could be useful for both healthy and special-need pediatric populations undergoing dental procedures.