bluuebunny/crossref_metadata_2025 huggingface dataset:
eDIG-CHANGES I: extended Hα emission from the extraplanar diffuse ionized gas (eDIG) around CHANG-ES galaxies
Authors: Lu Li-Yuan , Li Jiang-Tao , Vargas Carlos J , Beck Rainer , Bregman Joel N , Dettmar Ralf-Jürgen , English Jayanne , Fang Taotao , Heald George H , Li Hui , Qu Zhijie , Rand Richard J , Stein Michael , Wang Q Daniel , Wang Jing , Wiegert Theresa , Zheng Yun
Published: January 2023

The extraplanar diffuse ionized gas (eDIG) represents the cool/warm ionized gas reservoir around galaxies. We present spatial analysis of the Hα images of 22 nearby edge-on spiral galaxies taken with the Apache Point Observatory 3.5-m telescope (eDIG-CHANGES). We conduct an exponential fit to the vertical Hα intensity profiles of the galaxies, of which 16 can be decomposed into thin + thick disk components. The median value of the Hα scale height of the thick disk is $\langle h_{\rm H\alpha }\rangle =1.13\pm 0.14\rm ~kpc$. We further examine the dependence of hHα on the stellar mass, SFR, and SFR surface density (SFRSD) of the galaxies. We find a tight sublinear correlation between hHα and SFR, expressed in hHα ∝ SFRα, where α ≈ 0.29. Moreover, the offset of individual galaxies from the best-fit SFR-hHα relation, expressed in hHα/SFRα, shows significant anti-correlation with SFRSD. We further compare the vertical extension of the eDIG to multi-wavelength measurements of other CGM phases. We find the eDIG slightly more extended than the neutral gas. This indicates the existence of some extended ionizing sources, in addition to the leaking photons from the disk star formation regions. Most galaxies have an X-ray scale height smaller than Hα, suggesting the majority of the X-ray photons are actually from the thick disk instead of the extended CGM. hHα is comparable to the L-band radio continuum scale height. This indicates that the thermal and non-thermal electrons have similar spatial distributions, a natural result if both are transported outwards by a galactic wind. This further indicates the thermal gas, cosmic rays, and magnetic field may be close to energy equipartition.
Photometric variable stars in the young open cluster NGC 6823
Authors: Lata Sneh , Chen W P , Pandey J C , Dileep Athul , Ai Zhong-Han , Hojaev Alisher S , Panwar Neelam , Joshi Santosh , Mondal Soumen , Biswas Siddhartha , Bhatt B C
Published: January 2023

We present stellar variability towards the young open cluster NGC 6823. Time series V- and I-band CCD photometry led to identification and characterization of 88 variable stars, of which only 14 have been previously recognized. We ascertain the membership of each variable with optical UBVI and infrared photometry, and with Gaia EDR3 parallax and proper motion data. Seventy two variable stars are found to be cluster members, of which 25 are main sequence stars and 48 are pre-main-sequence stars. The probable cluster members collectively suggest an isochrone age of the cluster to be about 2 Myrs based on the GAIA photometry. With the colour and magnitude, as well as the shape of the light curve, we have classified the main sequence variables into β Cep, δ Scuti, slowly pulsating B type, and new class variables. Among the pre-main-sequence variables, eight are classical T Tauri variables, and four are Herbig Ae/Be objects, whereas the remaining belong to the weak-lined T Tauri population. The variable nature of 32 stars is validated with TESS light curves. Our work provides refined classification of variability of pre-main-sequence and main-sequence cluster members of the active star-forming complex, Sharpless 86. Despite no strong evidence of the disc-locking mechanism in the present sample of TTSs, one TTS with larger Δ(I − K) is found to be a slow rotator.
MAXI J1820+070 X-ray spectral-timing reveals the nature of the accretion flow in black hole binaries
Authors: Kawamura Tenyo , Done Chris , Axelsson Magnus , Takahashi Tadayuki
Published: January 2023

Black hole X-ray binaries display significant stochastic variability on short time-scales (0.01–100 s), with a complex pattern of lags in correlated variability seen in different energy bands. This behaviour is generally interpreted in a model where slow fluctuations stirred up at large radii propagate down through the accretion flow, modulating faster fluctuations generated at smaller radii. Coupling this scenario with radially stratified emission opens the way to measure the propagation time-scale from data, allowing direct tests of the accretion flow structure. We previously developed a model based on this picture and showed that it could fit the Neutron star Interior Composition Explorer (NICER; 0.5–10 keV) data from the brightest recent black hole transient, MAXI J1820+070. However, here we show it fails when extrapolated to higher energy variability data from the Insight-Hard X-ray Modulation Telescope(HXMT). We extend our model so that the spectrum emitted at each radius changes shape in response to fluctuations (pivoting) rather than just changing normalization. This gives the strong suppression of fractional variability as a function of energy seen in the data. The derived propagation time-scale is slower than predicted by a magnetically arrested disc (MAD), despite this system showing a strong jet. Our new model jointly fits the spectrum and variability up to 50 keV, though still cannot match all the data above this. Nonetheless, the good fit from 3 to 40 keV means the quasi-periodic oscillation (QPO) can most easily be explained as an extrinsic modulation of the flow, such as produced in the Lense–Thirring precession, rather than arising in an additional spectral-timing component such as the jet.
MaLAdapt Reveals Novel Targets of Adaptive Introgression From Neanderthals and Denisovans in Worldwide Human Populations
Authors: Zhang Xinjun , Kim Bernard , Singh Armaan , Sankararaman Sriram , Durvasula Arun , Lohmueller Kirk E
Published: January 2023

Adaptive introgression (AI) facilitates local adaptation in a wide range of species. Many state-of-the-art methods detect AI with ad-hoc approaches that identify summary statistic outliers or intersect scans for positive selection with scans for introgressed genomic regions. Although widely used, approaches intersecting outliers are vulnerable to a high false-negative rate as the power of different methods varies, especially for complex introgression events. Moreover, population genetic processes unrelated to AI, such as background selection or heterosis, may create similar genomic signals to AI, compromising the reliability of methods that rely on neutral null distributions. In recent years, machine learning (ML) methods have been increasingly applied to population genetic questions. Here, we present a ML-based method called MaLAdapt for identifying AI loci from genome-wide sequencing data. Using an Extra-Trees Classifier algorithm, our method combines information from a large number of biologically meaningful summary statistics to capture a powerful composite signature of AI across the genome. In contrast to existing methods, MaLAdapt is especially well-powered to detect AI with mild beneficial effects, including selection on standing archaic variation, and is robust to non-AI selective sweeps, heterosis from deleterious mutations, and demographic misspecification. Furthermore, MaLAdapt outperforms existing methods for detecting AI based on the analysis of simulated data and the validation of empirical signals through visual inspection of haplotype patterns. We apply MaLAdapt to the 1000 Genomes Project human genomic data and discover novel AI candidate regions in non-African populations, including genes that are enriched in functionally important biological pathways regulating metabolism and immune responses.
Development of ANCA-associated vasculitis followed by SARS-CoV-2 vaccination in a patient with HLA-DRB1*09:01 allele
Authors: Kawamura Takuro , Nakazawa Daigo , Nishio Saori , Isozaki Taiki , Komatsumoto Maki , Atsumi Tatsuya
Published: January 2023

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), presents with severe pneumonia and fatal systemic complications. Currently, SARS-CoV-2 vaccines are effective in reducing the risk of new onset and getting worse of the disease. However, autoimmune diseases such as antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) have been reported to develop after COVID-19 vaccine administration. A 71-year-old woman presented with fever, malaise, urinary abnormalities, and renal dysfunction after receiving the COVID-19 vaccine (Pfizer-BioNTech). We clinically diagnosed AAV with her manifestations and serological test (myeloperoxidase-ANCA-positive). Her clinical findings were improved after immunosuppressive therapy. We examined her genetic susceptibility to AAV, and we found that her allele was HLA-DRB1*09:01, which is a risk allele of myeloperoxidase-AAV. Mechanistically, SARS-CoV-2 vaccines would activate immunity, including neutrophils, and trigger AAV onset in this patient with a genetic risk to develop AAV. The pathophysiology of this case would share with that of autoimmune/inflammatory syndrome induced by adjuvants in the absence of external adjuvants.
The putative metal-binding proteome of the Coronaviridae family
Authors: Dixit Himisha , Upadhyay Vipin , Kulharia Mahesh , Verma Shailender Kumar
Published: January 2023

Metalloproteins are well-known for playing various physicochemical processes in all life forms, including viruses. Some life-threatening viruses (such as some members of the Coronaviridae family of viruses) are emerged and remerged frequently and are rapidly transmitted throughout the globe. This study aims to identify and characterize the metal-binding proteins (MBPs) of the Coronaviridae family of viruses and further provides insight into the MBP’s role in sustaining and propagating viruses inside a host cell and in the outer environment. In this study, the available proteome of the Coronaviridae family was exploited. Identified potential MBPs were analyzed for their functional domains, structural aspects, and subcellular localization. We also demonstrate phylogenetic aspects of all predicted MBPs among other Coronaviridae family members to understand the evolutionary trend among their respective hosts. A total of 256 proteins from 51 different species of coronaviruses are predicted as MBPs. These MBPs perform various key roles in the replication and survival of viruses within the host cell. Cysteine, aspartic acid, threonine, and glutamine are key amino acid residues interacting with respective metal ions. Our observations also indicate that the metalloproteins of this family of viruses circulated and evolved in different hosts, which supports the zoonotic nature of coronaviruses. The comprehensive information on MBPs of the Coronaviridae family may be further helpful in designing novel therapeutic metalloprotein targets. Moreover, the study of viral MBPs can also help to understand the roles of MBPs in virus pathogenesis and virus–host interactions.
CRISPR-Cas9 recognition of enzymatically synthesized base-modified nucleic acids
Authors: Yang Hui , Eremeeva Elena , Abramov Mikhail , Jacquemyn Maarten , Groaz Elisabetta , Daelemans Dirk , Herdewijn Piet
Published: January 2023

An enzymatic method has been successfully established enabling the generation of partially base-modified RNA (previously named RZA) constructs, in which all G residues were replaced by isomorphic fluorescent thienoguanosine (thG) analogs, as well as fully modified RZA featuring thG, 5-bromocytosine, 7-deazaadenine and 5-chlorouracil. The transcriptional efficiency of emissive fully modified RZA was found to benefit from the use of various T7 RNA polymerase variants. Moreover, dthG could be incorporated into PCR products by Taq DNA polymerase together with the other three base-modified nucleotides. Notably, the obtained RNA products containing thG as well as thG together with 5-bromocytosine could function as effectively as natural sgRNAs in an in vitro CRISPR-Cas9 cleavage assay. N1-Methylpseudouridine was also demonstrated to be a faithful non-canonical substitute of uridine to direct Cas9 nuclease cleavage when incorporated in sgRNA. The Cas9 inactivation by 7-deazapurines indicated the importance of the 7-nitrogen atom of purines in both sgRNA and PAM site for achieving efficient Cas9 cleavage. Additional aspects of this study are discussed in relation to the significance of sgRNA–protein and PAM–-protein interactions that were not highlighted by the Cas9–sgRNA–DNA complex crystal structure. These findings could expand the impact and therapeutic value of CRISPR-Cas9 and other RNA-based technologies.
The 2023 Nucleic Acids Research Database Issue and the online molecular biology database collection
Authors: Rigden Daniel J , Fernández Xosé M
Published: January 2023

The 2023 Nucleic Acids Research Database Issue contains 178 papers ranging across biology and related fields. There are 90 papers reporting on new databases and 82 updates from resources previously published in the Issue. Six more papers are updates from databases most recently published elsewhere. Major nucleic acid databases reporting updates include Genbank, ENA, ChIPBase, JASPAR, mirDIP and the Issue's first Breakthrough Article, NACDDB for Circular Dichroism data. Updates from BMRB and RCSB cover experimental protein structural data while AlphaFold 2 computational structure predictions feature widely. STRING and REBASE are stand-out updates in the signalling and enzymes section. Immunology-related databases include CEDAR, the second Breakthrough Article, for cancer epitopes and receptors alongside returning IPD-IMGT/HLA and the new PGG.MHC. Genomics-related resources include Ensembl, GWAS Central and UCSC Genome Browser. Major returning databases for drugs and their targets include Open Targets, DrugCentral, CTD and Pubchem. The EMPIAR image archive appears in the Issue for the first time. The entire database Issue is freely available online on the Nucleic Acids Research website (https://academic.oup.com/nar). The NAR online Molecular Biology Database Collection has been updated, revisiting 463 entries, adding 92 new resources and eliminating 96 discontinued URLs so bringing the current total to 1764 databases. It is available at http://www.oxfordjournals.org/nar/database/c/.
The DEAD-box protein Dbp6 is an ATPase and RNA annealase interacting with the peptidyl transferase center (PTC) of the ribosome
Authors: Khreiss Ali , Capeyrou Régine , Lebaron Simon , Albert Benjamin , Bohnsack Katherine E , Bohnsack Markus T , Henry Yves , Henras Anthony K , Humbert Odile
Published: January 2023

Ribosomes are ribozymes, hence correct folding of the rRNAs during ribosome biogenesis is crucial to ensure catalytic activity. RNA helicases, which can modulate RNA–RNA and RNA/protein interactions, are proposed to participate in rRNA tridimensional folding. Here, we analyze the biochemical properties of Dbp6, a DEAD-box RNA helicase required for the conversion of the initial 90S pre-ribosomal particle into the first pre-60S particle. We demonstrate that in vitro, Dbp6 shows ATPase as well as annealing and clamping activities negatively regulated by ATP. Mutations in Dbp6 core motifs involved in ATP binding and ATP hydrolysis are lethal and impair Dbp6 ATPase activity but increase its RNA binding and RNA annealing activities. These data suggest that correct regulation of these activities is important for Dbp6 function in vivo. Using in vivo cross-linking (CRAC) experiments, we show that Dbp6 interacts with 25S rRNA sequences located in the 5′ domain I and in the peptidyl transferase center (PTC), and also crosslinks to snoRNAs hybridizing to the immature PTC. We propose that the ATPase and RNA clamping/annealing activities of Dbp6 modulate interactions of snoRNAs with the immature PTC and/or contribute directly to the folding of this region.
Dissecting Trypanosoma brucei RRP44 function in the maturation of segmented ribosomal RNA using a regulated genetic complementation system
Authors: Guerra-Slompo Eloise Pavão , Cesaro Giovanna , Guimarães Beatriz Gomes , Zanchin Nilson Ivo Tonin
Published: January 2023

Trypanosoma brucei belongs to a group of protozoans presenting fragmented large subunit rRNA. Its LSU rRNA equivalent to the 25S/28S rRNA of other eukaryotes is split into six fragments, requiring additional processing for removal of the extra spacer sequences. We have used a genetic complementation strategy to further investigate the T. brucei RRP44 nuclease in pre-rRNA maturation. TbRRP44 contains both a PIN and a RNB domain whose homologues are found in association with the exosome complex. We found that the exonucleolytic activity of the RNB domain as well as the physical presence of the PIN domain are essential for TbRRP44 function, while a catalytic site mutation in the PIN domain has no detectable effect on cell growth. A new endonucleolytic cleavage site in ITS1 was identified. In addition to the 5.8S rRNA 3′-end maturation, TbRRP44 is required for degradation of the excised 5′-ETS and for removal of part of ITS1 during maturation of the 18S rRNA 3′-end. TbRRP44 deficiency leads to accumulation of many LSU intermediate precursors, most of them not detected in control cells. TbRRP44 is also required for U3 snoRNA and spliced leader processing, indicating that TbRRP44 may have a wide role in RNA processing in T. brucei.
The ESKAPE mobilome contributes to the spread of antimicrobial resistance and CRISPR-mediated conflict between mobile genetic elements
Authors: Botelho João , Cazares Adrian , Schulenburg Hinrich
Published: January 2023

Mobile genetic elements (MGEs) mediate the shuffling of genes among organisms. They contribute to the spread of virulence and antibiotic resistance (AMR) genes in human pathogens, such as the particularly problematic group of ESKAPE pathogens. Here, we performed the first systematic analysis of MGEs, including plasmids, prophages, and integrative and conjugative/mobilizable elements (ICEs/IMEs), across all ESKAPE pathogens. We found that different MGE types are asymmetrically distributed across these pathogens, and that most horizontal gene transfer (HGT) events are restricted by phylum or genus. We show that the MGEs proteome is involved in diverse functional processes and distinguish widespread proteins within the ESKAPE context. Moreover, anti-CRISPRs and AMR genes are overrepresented in the ESKAPE mobilome. Our results also underscore species-specific trends shaping the number of MGEs, AMR, and virulence genes across pairs of conspecific ESKAPE genomes with and without CRISPR-Cas systems. Finally, we observed that CRISPR spacers found on prophages, ICEs/IMEs, and plasmids have different targeting biases: while plasmid and prophage CRISPRs almost exclusively target other plasmids and prophages, respectively, ICEs/IMEs CRISPRs preferentially target prophages. Overall, our study highlights the general importance of the ESKAPE mobilome in contributing to the spread of AMR and mediating conflict among MGEs.
Mycobacterial helicase Lhr abets resistance to DNA crosslinking agents mitomycin C and cisplatin
Authors: Warren Garrett M , Ejaz Anam , Fay Allison , Glickman Michael S , Shuman Stewart
Published: January 2023

Mycobacterium smegmatis Lhr exemplifies a novel clade of helicases composed of an N-terminal ATPase/helicase domain (Lhr-Core) and a large C-terminal domain (Lhr-CTD) that nucleates a unique homo-tetrameric quaternary structure. Expression of Lhr, and its operonic neighbor Nei2, is induced in mycobacteria exposed to mitomycin C (MMC). Here we report that lhr deletion sensitizes M. smegmatis to killing by DNA crosslinkers MMC and cisplatin but not to killing by monoadduct-forming alkylating agent methyl methanesulfonate or UV irradiation. Testing complementation of MMC and cisplatin sensitivity by expression of Lhr mutants in Δlhr cells established that: (i) Lhr-CTD is essential for DNA repair activity, such that Lhr-Core does not suffice; (ii) ATPase-defective mutant D170A/E171A fails to complement; (iii) ATPase-active, helicase-defective mutant W597A fails to complement and (iv) alanine mutations at the CTD–CTD interface that interdict homo-tetramer formation result in failure to complement. Our results instate Lhr's ATP-driven motor as an agent of inter-strand crosslink repair in vivo, contingent on Lhr's tetrameric quaternary structure. We characterize M. smegmatis Nei2 as a monomeric enzyme with AP β-lyase activity on single-stranded DNA. Counter to previous reports, we find Nei2 is inactive as a lyase at a THF abasic site and has feeble uracil glycosylase activity.
Cellular APOBEC3A deaminase drives mutations in the SARS-CoV-2 genome
Authors: Nakata Yoshihiro , Ode Hirotaka , Kubota Mai , Kasahara Takaaki , Matsuoka Kazuhiro , Sugimoto Atsuko , Imahashi Mayumi , Yokomaku Yoshiyuki , Iwatani Yasumasa
Published: January 2023

The number of genetic variations in the SARS-CoV-2 genome has been increasing primarily due to continuous viral mutations. Here, we report that the human APOBEC3A (A3A) cytidine deaminase plays a critical role in the induction of C-to-U substitutions in the SARS-CoV-2 genome. Bioinformatic analysis of the chronological genetic changes in a sequence database indicated that the largest UC-to-UU mutation signature, consistent with APOBEC-recognized nucleotide motifs, was predominant in single-stranded RNA regions of the viral genome. In SARS-CoV-2-infected cells, exogenous expression of A3A but not expression of other APOBEC proteins induced UC-to-UU mutations in viral RNA (vRNA). Additionally, the mutated C bases were often located at the tips in bulge or loop regions in the vRNA secondary structure. Interestingly, A3A mRNA expression was drastically increased by interferons (IFNs) and tumour necrosis factor-α (TNF-α) in epithelial cells derived from the respiratory system, a site of efficient SARS-CoV-2 replication. Moreover, the UC-to-UU mutation rate was increased in SARS-CoV-2 produced from lung epithelial cells treated with IFN-ß and TNF-α, but not from CRISPR/Cas9-based A3A knockout cells. Collectively, these findings demonstrate that A3A is a primary host factor that drives mutations in the SARS-CoV-2 RNA genome via RNA editing.
The functions of consciousness in visual processing
Authors: Ludwig Dylan
Published: January 2023

Conscious experiences form a relatively diverse class of psychological phenomena, supported by a range of distinct neurobiological mechanisms. This diversity suggests that consciousness occupies a variety of different functional roles across different task domains, individuals, and species; a position I call functional pluralism. In this paper, I begin to tease out some of the functional contributions that consciousness makes to (human) visual processing. Consolidating research from across the cognitive sciences, I discuss semantic and spatiotemporal processing as specific points of comparison between the functional capabilities of the visual system in the presence and absence of conscious awareness. I argue that consciousness contributes a cluster of functions to visual processing; facilitating, among other things, (i) increased capacities for semantically processing informationally complex visual stimuli, (ii) increased spatiotemporal precision, and (iii) increased capacities for representational integration over large spatiotemporal intervals. This sort of analysis should ultimately yield a plurality of functional markers that can be used to guide future research in the philosophy and science of consciousness, some of which are not captured by popular theoretical frameworks like global workspace theory and information integration theory.
Trends in kidney transplantation rate across Europe: study from the ERA Registry
Authors: Boenink Rianne , Kramer Anneke , Tuinhout Rosalie E , Savoye Emilie , Åsberg Anders , Idrizi Alma , Kerschbaum Julia , Ziedina Ieva , Ziginskiene Edita , Farrugia Emanuel , Garneata Liliana , Zakharova Elena V , Bell Samira , Arnol Miha , Segelmark Mårten , Ioannou Kyriakos , Hommel Kristine , Rosenberg-Ots Mai , Vazelov Evgueniy , Helve Jaakko , Mihály Sándor , Pálsson Runólfur , Nordio Maurizio , Gjorgjievski Nikola , de Vries Aiko P J , Seyahi Nurhan , Magadi Winnie A , Resić Halima , Kalachyk Aleh , Rahmel Axel O , Galvão Ana A , Naumovic Radomir , Lundgren Torbjörn , Arici Mustafa , de Meester Johan M , Ortiz Alberto , Jager Kitty J , Stel Vianda S
Published: January 2023

Background

The aim of this study was to identify trends in total, deceased donor (DD) and living donor (LD) kidney transplantation (KT) rates in European countries.

Methods

The European Renal Association (ERA) Registry and the Global Observatory on Donation and Transplantation (GODT) databases were used to obtain the number of KTs in individual European countries between 2010 and 2018. General population counts were obtained from Eurostat or the national bureaus of statistics. The KT rate per million population (p.m.p.) and the average annual percentage change (APC) were calculated.

Results

The total KT rate in the 40 participating countries increased with 1.9% annually  [95%  confidence  interval  (CI) 1.5, 2.2] from 29.6 p.m.p. in 2010 to 34.7 p.m.p. in 2018, reflecting an increase of 3.4 p.m.p. in the DD-KT rate (from 21.6 p.m.p. to 25.0 p.m.p.; APC 1.9%; 95% CI 1.3, 2.4) and of 1.5 p.m.p. in the LD-KT rate (from 8.1 p.m.p. to 9.6 p.m.p.; APC 1.6%; 95% CI 1.0, 2.3). The trends in KT rate varied widely across European countries. An East–West gradient was observed for DD-KT rate, with Western European countries performing more KTs. In addition, most countries performed fewer LD-KTs. In 2018, Spain had the highest DD-KT rate (64.6 p.m.p.) and Turkey the highest LD-KT rate (37.0 p.m.p.).

Conclusions

The total KT rate increased due to a rise in the KT rate from DDs and to a lesser extent from LDs, with large differences between individual European countries.
Objective response rate targets for recurrent glioblastoma clinical trials based on the historic association between objective response rate and median overall survival
Authors: Ellingson Benjamin M , Wen Patrick Y , Chang Susan M , van den Bent Martin , Vogelbaum Michael A , Li Gang , Li Shanpeng , Kim Jiyoon , Youssef Gilbert , Wick Wolfgang , Lassman Andrew B , Gilbert Mark R , de Groot John F , Weller Michael , Galanis Evanthia , Cloughesy Timothy F
Published: January 2023

Durable objective response rate (ORR) remains a meaningful endpoint in recurrent cancer; however, the target ORR for single-arm recurrent glioblastoma trials has not been based on historic information or tied to patient outcomes. The current study reviewed 68 treatment arms comprising 4793 patients in past trials in recurrent glioblastoma in order to judiciously define target ORRs for use in recurrent glioblastoma trials. ORR was estimated at 6.1% [95% CI 4.23; 8.76%] for cytotoxic chemothera + pies (ORR = 7.59% for lomustine, 7.57% for temozolomide, 0.64% for irinotecan, and 5.32% for other agents), 3.37% for biologic agents, 7.97% for (select) immunotherapies, and 26.8% for anti-angiogenic agents. ORRs were significantly correlated with median overall survival (mOS) across chemotherapy (R2= 0.4078, P < .0001), biologics (R2= 0.4003, P = .0003), and immunotherapy trials (R2= 0.8994, P < .0001), but not anti-angiogenic agents (R2= 0, P = .8937). Pooling data from chemotherapy, biologics, and immunotherapy trials, a meta-analysis indicated a strong correlation between ORR and mOS (R2= 0.3900, P < .0001; mOS [weeks] = 1.4xORR + 24.8). Assuming an ineffective cytotoxic (control) therapy has ORR = 7.6%, the average ORR for lomustine and temozolomide trials, a sample size of ≥40 patients with target ORR>25% is needed to demonstrate statistical significance compared to control with a high level of confidence (P < .01) and adequate power (>80%). Given this historic data and potential biases in patient selection, we recommend that well-controlled, single-arm phase II studies in recurrent glioblastoma should have a target ORR >25% (which translates to a median OS of approximately 15 months) and a sample size of ≥40 patients, in order to convincingly demonstrate antitumor activity. Crucially, this response needs to have sufficient durability, which was not addressed in the current study.
Histological and molecular classifications of pediatric glioma with time-dependent diffusion MRI-based microstructural mapping
Authors: Zhang Hongxi , Liu Kuiyuan , Ba Ruicheng , Zhang Zelin , Zhang Yi , Chen Ye , Gu Weizhong , Shen Zhipeng , Shu Qiang , Fu Junfen , Wu Dan
Published: January 2023

Background

Gliomas are the most common type of central nervous system tumors in children, and the combination of histological and molecular classification is essential for prognosis and treatment. Here, we proposed a newly developed microstructural mapping technique based on diffusion-time-dependent diffusion MRI td-dMRI theory to quantify tumor cell properties and tested these microstructural markers in identifying histological grade and molecular alteration of H3K27.

Methods

This prospective study included 69 pediatric glioma patients aged 6.14 ± 3.25 years old, who underwent td-dMRI with pulsed and oscillating gradient diffusion sequences on a 3T scanner. dMRI data acquired at varying tds were fitted into a 2-compartment microstructural model to obtain intracellular fraction (fin), cell diameter, cellularity, etc. Apparent diffusivity coefficient (ADC) and T1 and T2 relaxation times were also obtained. H&E stained histology was used to validate the estimated microstructural properties.

Results

For histological classification of low- and high-grade pediatric gliomas, the cellularity index achieved the highest area under the receiver-operating-curve (AUC) of 0.911 among all markers, while ADC, T1, and T2 showed AUCs of 0.906, 0.885, and 0.886. For molecular classification of H3K27-altered glioma in 39 midline glioma patients, cell diameter showed the highest discriminant power with an AUC of 0.918, and the combination of cell diameter and extracellular diffusivity further improved AUC to 0.929. The td-dMRI estimated fin correlated well with the histological ground truth with r = 0.7.

Conclusions

The td-dMRI-based microstructural properties outperformed routine MRI measurements in diagnosing pediatric gliomas, and the different microstructural features showed complementary strength in histological and molecular classifications.
Novel genetically engineered H3.3G34R model reveals cooperation with ATRX loss in upregulation ofHoxacluster genes and promotion of neuronal lineage
Authors: Abdallah Aalaa S , Cardona Herminio J , Gadd Samantha L , Brat Daniel J , Powla Plamena P , Alruwalli Waleed S , Shen Chen , Picketts David J , Li Xiao-Nan , Becher Oren J
Published: January 2023

Background

Pediatric high-grade gliomas (pHGGs) are aggressive pediatric CNS tumors and an important subset are characterized by mutations in H3F3A, the gene that encodes Histone H3.3 (H3.3). Substitution of Glycine at position 34 of H3.3 with either Arginine or Valine (H3.3G34R/V), was recently described and characterized in a large cohort of pHGG samples as occurring in 5–20% of pHGGs. Attempts to study the mechanism of H3.3G34R have proven difficult due to the lack of knowledge regarding the cell-of-origin and the requirement for co-occurring mutations for model development. We sought to develop a biologically relevant animal model of pHGG to probe the downstream effects of the H3.3G34R mutation in the context of vital co-occurring mutations.

Methods

We developed a genetically engineered mouse model (GEMM) that incorporates PDGF-A activation, TP53 loss and the H3.3G34R mutation both in the presence and loss of Alpha thalassemia/mental retardation syndrome X-linked (ATRX), which is commonly mutated in H3.3G34 mutant pHGGs.

Results

We demonstrated that ATRX loss significantly increases tumor latency in the absence of H3.3G34R and inhibits ependymal differentiation in the presence of H3.3G34R. Transcriptomic analysis revealed that ATRX loss in the context of H3.3G34R upregulates Hoxa cluster genes. We also found that the H3.3G34R overexpression leads to enrichment of neuronal markers but only in the context of ATRX loss.

Conclusions

This study proposes a mechanism in which ATRX loss is the major contributor to many key transcriptomic changes in H3.3G34R pHGGs.

Accession number

GSE197988.
Review of progress and challenges of key mechanical issues in high-field superconducting magnets
Authors: Zhou You-He , Park Dongkeun , Iwasa Yukikazu
Published: January 2023

The development of modern science and technology requires high magnetic fields exceeding 25T. Second-generation high-temperature superconducting wires, i.e. REBCO (REBa2Cu3O7-x, RE refers to Y, Gd, Dy, Eu and other rare-earth elements) coated conductors (CCs), have become the first choice for high-field magnet construction because of their high irreversible magnetic field. The mechanical stresses caused by manufacturing, thermal mismatch and Lorenz forces closely influence electromagnetic performance during operation for REBCO CCs. In addition, the recently studied screen currents have effects on the mechanical characteristics of high-field REBCO magnets. In this review, the experimental and main theoretical works on critical current degradation, delamination and fatigue, and shear investigations on REBCO CCs, are reviewed at first. Then, research progress on the screening-current effect in the development of high-field superconducting magnets is introduced. Finally, the key mechanical problems facing the future development of high-field magnets based on REBCO CCs are prospected.
The Role of Emotion Differentiation in the Association Between Momentary Affect and Tobacco/Nicotine Craving in Young Adults
Authors: Walters Kyle J , Gray Kevin M , Gex Kathryn S , McClure Erin A
Published: January 2023

Introduction

Tobacco/nicotine use is commonly initiated during adolescence or young adulthood, which increases the likelihood of continued use into adulthood and related adverse health outcomes. Despite interest in cessation, achieving and maintaining abstinence is difficult among this population. Cravings are often a barrier to abstinence, which have been associated with intensity of affect at the moment level. Emotion differentiation involves the ability to distinguish between discrete emotion states, and previous work suggests it may moderate the effect of momentary affect on craving, which has never been explored among young adults who are smoking or vaping nicotine.

Aims and Methods

In a sample of young adults (N = 37, observations = 2020, ages 18–25, 51% female, and 78% white) interested in quitting smoking or vaping, we used real-time, naturalistic data capture via mobile phones to examine the interaction of momentary affect and trait emotion differentiation on nicotine craving. Participants were prompted with four surveys per day for 35 days and asked to make a 48-h quit attempt on day 7.

Results

Multilevel models showed moments of higher-than-average momentary negative affect (NA; b = 0.39, p < .001), and positive affect (PA; b = 0.26, p = .001) were associated with greater levels of craving. NA emotion differentiation significantly moderated the associations between PA and craving (b = −0.63, p = .031) and NA and craving (b = −0.67, p = .003).

Conclusions

Findings from this exploratory analysis suggest that for young adults engaging in a nicotine quit attempt, greater ability to differentiate NA weakens the momentary association between intense affect and craving.

Implications

Results of this study show that the ability to differentiate between discrete emotional experiences may protect young adults against nicotine craving during moments of intense affective experience. These preliminary findings suggest that emotion differentiation, a modifiable construct, could be an important treatment target for individuals engaged in treatment for nicotine dependence.
Fungal Nomenclature: Managing Change is the Name of the Game
Authors: Kidd Sarah E , Abdolrasouli Alireza , Hagen Ferry
Published: January 2023

Fungal species have undergone and continue to undergo significant nomenclatural change, primarily due to the abandonment of dual species nomenclature in 2013 and the widespread application of molecular technologies in taxonomy allowing correction of past classification errors. These have effected numerous name changes concerning medically important species, but by far the group causing most concern are the Candida yeasts. Among common species, Candida krusei, Candida glabrata, Candida guilliermondii, Candida lusitaniae, and Candida rugosa have been changed to Pichia kudriavzevii, Nakaseomyces glabrata, Meyerozyma guilliermondii, Clavispora lusitaniae, and Diutina rugosa, respectively. There are currently no guidelines for microbiology laboratories on implementing changes, and there is ongoing concern that clinicians will dismiss or misinterpret laboratory reports using unfamiliar species names. Here, we have outlined the rationale for name changes across the major groups of clinically important fungi and have provided practical recommendations for managing change.
In Outpatients Receiving Parenteral Vancomycin, Dosing Adjustments Produced by Area Under the Curve-Based and Trough-Based Monitoring Differ Only at the Extremes of the Therapeutic Trough Range
Authors: Shi Yufei , Alexander Bryan T , Avedissian Sean , Bergman Scott J , Cortés-Penfield Nicolás
Published: January 2023

Area under the curve (AUC)-based vancomycin dosing reduces nephrotoxicity but is burdensome. Reviewing 115 adults receiving ≥2 weeks of outpatient vancomycin, we found AUC-based and trough-based dose adjustments discordant only for troughs <12 or >16 mg/L. Selective versus universal outpatient AUC calculation would likely offer similar benefit with reduced workload.
Efficacy of a Primary Care-Based Mobile Application to Increase Hepatitis C Screening Among Asian Americans: A Secondary Analysis of a Randomized Clinical Trial
Authors: Khalili Mandana , Kim Nicole J , Tsoh Janice Y , Walsh Judith M E , Elizabeth Goldman L , Park Helen , Lau Ivy , Wong Ching , Gildengorin Ginny , Nguyen Tung T
Published: January 2023

Background

Hepatitis C virus (HCV) screening remains suboptimal. We assessed the efficacy of a mobile application and provider alert in enhancing HCV screening among Asian Americans.

Methods

A secondary analysis of a cluster-randomized clinical trial was performed during the birth cohort screening era to assess the efficacy of a Hepatitis App (intervention), a multilingual mobile application delivering interactive video education on viral hepatitis and creating a Provider Alert printout, at primary care clinics within 2 healthcare systems in San Francisco from 2015 to 2017. A comparison group received usual care and a similar intervention on nutrition and physical activity. The outcome was electronic health record (EHR) documentation of HCV screening along with patient-provider communication about testing and test ordering.

Results

Four hundred fifty-two participants (mean age 57 years, 36% male, 80% foreign-born) were randomized by provider clusters to the intervention (n = 270) or comparison groups (n = 182). At 3-month follow up, the intervention group was more likely than the comparison group to be aware of HCV (75% vs 59%, P = .006), to discuss HCV testing with their providers (63% vs 13%, P < .001), to have HCV testing ordered (39% vs 10%, P < .001), and to have EHR-verified HCV testing (30% vs 6%, P< .001). Within the intervention group, being born between 1945 and 1965 (odds ratio, 3.15; 95% confidence interval, 1.35–7.32) was associated with increased HCV testing.

Conclusions

The Hepatitis App delivered in primary care settings was effective in increasing HCV screening in a socioeconomically diverse Asian American cohort. This highlights the importance of mobile technology as a patient-centered strategy to address gaps in HCV care.
Treatment Success Following Standard Antibiotic Treatment for Bacterial Vaginosis Is Not Associated With Pretreatment Genital Immune or Microbial Parameters
Authors: Armstrong Eric , Hemmerling Anke , Joag Vineet , Huibner Sanja , Kulikova Maria , Crawford Emily , Castañeda Gloria R , Anzala Omu , Obila Onyango , Shahabi Kamnoosh , Ravel Jacques , Coburn Bryan , Cohen Craig R , Kaul Rupert
Published: January 2023

Background

Bacterial vaginosis (BV) is a proinflammatory genital condition associated with adverse reproductive health outcomes, including increased HIV incidence. However, BV recurrence rates are high after standard antibiotic treatment. While the composition of the vaginal microbiota before BV treatment may be linked to BV recurrence, it is unclear whether the preceding genital immune milieu is predictive of treatment success.

Methods

Here we assessed whether baseline vaginal soluble immune factors or the composition of the vaginal microbiota predicted treatment success 1 month after metronidazole treatment in 2 separate cohorts of women with BV, 1 in the United States and 1 in Kenya; samples within 48 hours of BV treatment were also available for the US cohort.

Results

Neither soluble immune factors nor the composition of the vaginal microbiota before BV treatment was associated with treatment response in either cohort. In the US cohort, although the absolute abundances of key vaginal bacterial taxa pretreatment were not associated with treatment response, participants with sustained BV clearance had a more pronounced reduction in the absolute abundance of Gardnerella vaginalis immediately after treatment.

Conclusions

Pretreatment immune and microbial parameters were not predictive of BV treatment success in these clinical cohorts.
Infrastructure investment and urban health: Why breaking the cycle of crises is so difficult
Authors: Konvitz Josef W
Published: January 2023

Infrastructure and health, the theme of this journal, are responsible for a major share of GDP. However, GDP alone does not define well-being. Disaggregating the components of GDP, changes over time and variations within countries and social groups, the OECD’s 2013 Better Living Initiative focused on jobs, earning, housing and work–life balance as well as educational attainment, health status and subjective well-being. These indicators took on greater importance as evidence of growing disparities accumulated in the 2010s (OECD, 2013). Under Pressure: The Squeezed Middle Class was not the title of a popular work for the general public, but of a 2019 OECD report for policy- makers. Too often we take the positive, mutual reinforcement of policies and programmes that contribute to well-being for granted. Sectoral silos, which favoured the expansion of public services earlier in the 20th century, now interfere with their delivery [26, 28]. Better policy linkages across sectors remains the holy grail of sound, evidence-based decision-making. It remains aspirational, just out of reach.
A Critical Review of Zebrafish Neurological Disease Models−1. The Premise: Neuroanatomical, Cellular and Genetic Homology and Experimental Tractability
Authors: Burgess Harold A , Burton Edward A
Published: January 2023

The last decade has seen a dramatic rise in the number of genes linked to neurological disorders, necessitating new models to explore underlying mechanisms and to test potential therapies. Over a similar period, many laboratories adopted zebrafish as a tractable model for studying brain development, defining neural circuits and performing chemical screens. Here we discuss strengths and limitations of using the zebrafish system to model neurological disorders. The underlying premise for many disease models is the high degree of homology between human and zebrafish genes, coupled with the conserved vertebrate Bauplan and repertoire of neurochemical signaling molecules. Yet, we caution that important evolutionary divergences often limit the extent to which human symptoms can be modeled meaningfully in zebrafish. We outline advances in genetic technologies that allow human mutations to be reproduced faithfully in zebrafish. Together with methods that visualize the development and function of neuronal pathways at the single cell level, there is now an unprecedented opportunity to understand how disease-associated genetic changes disrupt neural circuits, a level of analysis that is ideally suited to uncovering pathogenic changes in human brain disorders.
Endogenous antibody responses in REGN-COV2-treated SARS-CoV-2-infected individuals
Authors: Kurshan Ashwini , Snell Luke B , Prior Lucie , Tam Jerry C H , Graham Carl , Thangarajah Rajeni , Edgeworth Jonathan D , Nebbia Gaia , Doores Katie J
Published: January 2023

Neutralizing monoclonal antibodies (mAbs) targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike glycoprotein have been developed for the treatment of COVID-19. Whilst antibody therapy has been shown to reduce the risk of COVID-19-associated hospitalization and death, there is limited understanding of the endogenous immunity to SARS-CoV-2 generated in mAb-treated patients and therefore ongoing susceptibility to future infections. Here we measure the endogenous antibody response in SARS-CoV-2-infected individuals treated with REGN-COV2 (Ronapreve). We show that in the majority of unvaccinated, delta-infected REGN-COV2-treated individuals, an endogenous antibody response is generated, but, like untreated, delta-infected individuals, there was a limited neutralization breadth. However, some vaccinated individuals who were seronegative at SARS-CoV-2 infection baseline and some unvaccinated individuals failed to produce an endogenous immune response following infection and REGN-COV2 treatment demonstrating the importance of mAb therapy in some patient populations.
Priority topics for child and family health research in community-based paediatric health care according to caregivers and health care professionals
Authors: Eaton Andrea , Dyson Michele P , Gokiert Rebecca , Rajani Hasu , O’Neill Marcus , Ladha Tehseen , Zhang Mona , Birken Catherine S , Maguire Jonathon L , Ball Geoff D C
Published: January 2023

Background

Patient-oriented research (POR) aligns research with stakeholders’ priorities to improve health services and outcomes. Community-based health care settings offer an opportunity to engage stakeholders to determine the most important research topics to them. Our objectives were to identify unanswered questions that stakeholders had regarding any aspect of child and family health and prioritize their ‘top 10’ questions.

Methods

We followed the James Lind Alliance (JLA) priority setting methodology in partnership with stakeholders from the Northeast Community Health Centre (NECHC; Edmonton, Canada). We partnered with stakeholders (five caregivers, five health care professionals [HCPs]) to create a steering committee. Stakeholders were surveyed in two rounds (n = 125 per survey) to gather and rank-order unanswered questions regarding child and family health. A final priority setting workshop was held to finalize the ‘top 10’ list.

Results

Our initial survey generated 1,265 submissions from 100 caregivers and 25 HCPs. Out of scope submissions were removed and similar questions were combined to create a master list of questions (n = 389). Only unanswered questions advanced (n = 108) and were rank-ordered through a second survey by 100 caregivers and 25 HCPs. Stakeholders (n = 12) gathered for the final workshop to discuss and finalize the ‘top 10’ list. Priority questions included a range of topics, including mental health, screen time, COVID-19, and behaviour.

Conclusion

Our stakeholders prioritized diverse questions within our ‘top 10’ list; questions regarding mental health were the most common. Future patient-oriented research at this site will be guided by priorities that were most important to caregivers and HCPs.