bluuebunny/crossref_metadata_2025 huggingface dataset:
Innate and Cellular Immune Response to the Ebola Vaccine Ad26.ZEBOV, MVA-BN-Filo: An Ancillary Study of the EBL2001 Phase 2 Trial
Authors: Lacabaratz Christine , Durand Mélany , Wiedemann Aurélie , Foucat Emile , Surénaud Mathieu , Krief Corinne , Guillaumat Lydia , Robinson Cynthia , Luhn Kerstin , Bockstal Viki , Thiébaut Rodolphe , Richert Laura , Lévy Yves
Published: July 2024

Background

The EBL2001 phase 2 trial tested the 2-dose Ad26.ZEBOV, MVA-BN-Filo Ebola vaccine in Europe. Safety and humoral immunogenicity assessments led to European Union market authorization in 2020. Complementary analyses of immune responses are warranted to better characterize vaccine effects.

Methods

We conducted an ancillary study to analyze changes in the serum and cellular responses. Serum biomarkers of activation/inflammation were evaluated using a Luminex assay. Vaccine-elicited T-cell responses and functions were evaluated by assessing their phenotype, cytokine production, proliferation, and cytotoxic potential. Integrated data analysis was performed through correlation and principal component analysis of serum biomarkers and cellular immune responses.

Results

Forty-eight volunteers were included. The Ad26.ZEBOV, MVA-BN-Filo vaccine elicited (1) serum increase of inflammatory/activation markers mainly at 1 day after the Ad26.ZEBOV vaccine; and (2) durable EBOV-specific T-cell proliferation and CD8+ T cells exhibiting a cytotoxic phenotype after Ad26.ZEBOV prime, after MVA-BN-Filo boost, and 6 months postvaccination. Integrated analysis revealed correlations between (1) EBOV-specific CD8+ T-cell proliferation and cytotoxic phenotype; and (2) high EBOV-specific CD8+ T-cell cytotoxic phenotype and low inflammatory marker IL-8 at day 1 postvaccination.

Discussion

This study provides unique insights into the in vivo contribution of proliferation/cytotoxic CD8+ T cells and inflammation to the Ad26.ZEBOV, MVA-BN-Filo vaccine-induced potency.

Clinical Trials Registration. NCT02416453.
Phylogenetic reconciliation: making the most of genomes to understand microbial ecology and evolution
Authors: Williams Tom A , Davin Adrian A , Szánthó Lénárd L , Stamatakis Alexandros , Wahl Noah A , Woodcroft Ben J , Soo Rochelle M , Eme Laura , Sheridan Paul O , Gubry-Rangin Cecile , Spang Anja , Hugenholtz Philip , Szöllősi Gergely J
Published: July 2024

In recent years, phylogenetic reconciliation has emerged as a promising approach for studying microbial ecology and evolution. The core idea is to model how gene trees evolve along a species tree and to explain differences between them via evolutionary events including gene duplications, transfers, and losses. Here, we describe how phylogenetic reconciliation provides a natural framework for studying genome evolution and highlight recent applications including ancestral gene content inference, the rooting of species trees, and the insights into metabolic evolution and ecological transitions they yield. Reconciliation analyses have elucidated the evolution of diverse microbial lineages, from Chlamydiae to Asgard archaea, shedding light on ecological adaptation, host–microbe interactions, and symbiotic relationships. However, there are many opportunities for broader application of the approach in microbiology. Continuing improvements to make reconciliation models more realistic and scalable, and integration of ecological metadata such as habitat, pH, temperature, and oxygen use offer enormous potential for understanding the rich tapestry of microbial life.
Calorie restriction in mice impairs cortical but not trabecular peak bone mass by suppressing bone remodeling
Authors: Liu Linyi , Le Phuong T , Stohn J Patrizia , Liu Hanghang , Ying Wangyang , Baron Roland , Rosen Clifford J
Published: July 2024

Calorie restriction (CR) can lead to weight loss and decreased substrate availability for bone cells. Ultimately, this can lead to impaired peak bone acquisition in children and adolescence and bone loss in adults. But the mechanisms that drive diet-induced bone loss in humans are not well characterized. To explore those in greater detail, we examined the impact of 30% CR for 4 and 8 wk in both male and female 8-wk-old C57BL/6 J mice. Body composition, areal bone mineral density (aBMD), skeletal microarchitecture by micro-CT, histomorphometric parameters, and in vitro trajectories of osteoblast and adipocyte differentiation were examined. After 8 wk, CR mice lost weight and exhibited lower femoral and whole-body aBMD vs ad libitum (AL) mice. By micro-CT, CR mice had lower cortical bone area fraction vs AL mice, but males had preserved trabecular bone parameters and females showed increased bone volume fraction compared to AL mice. Histomorphometric analysis revealed that CR mice had a profound suppression in trabecular as well as endocortical and periosteal bone formation in addition to reduced bone resorption compared to AL mice. Bone marrow adipose tissue was significantly increased in CR mice. In vitro, the pace of adipogenesis in bone marrow stem cells was greatly accelerated with higher markers of adipocyte differentiation and more oil red O staining, whereas osteogenic differentiation was reduced. qRT-PCR and western blotting suggested that the expression of Wnt16 and the canonical β-catenin pathway was compromised during CR. In sum, CR causes impaired peak cortical bone mass due to a profound suppression in bone remodeling. The increase in marrow adipocytes in vitro and in vivo is related to both progenitor recruitment and adipogenesis in the face of nutrient insufficiency. Long-term CR may lead to lower bone mass principally in the cortical envelope, possibly due to impaired Wnt signaling.
The contribution of academic inventors to regional technological diversification: the Italian evidence
Authors: Quatraro Francesco , Scandura Alessandra
Published: July 2024

This article investigates the interplay between scientific and technological capabilities in regional technological diversification dynamics by looking at the contributions of academic inventors. Combining the evolutionary economic approach and the theories on regional innovation capabilities on the one hand, and the distinctive features of academic inventors and university–industry patenting on the other, we hypothesize that the participation of university-based inventors to local patenting activity positively influences the chance of regional technological diversification and mitigates the path dependency engendered by the constraining role of the technological relatedness. In addition, we hypothesize that academic inventors tend to push regional technological trajectories towards their portfolio of specializations, hence allowing a process of technological convergence. The empirical results highlight the key role of academic institutions in the development of new regional technological trajectories while contributing to the academic and policy debate on regional diversification strategies.
Older adults with cancer and common comorbidities—challenges and opportunities in improving their cancer treatment outcomes
Authors: Chen Weiwei , Altshuler Rachel D , Daschner Phil , Salvador Morales Carolina , St. Germain Diane C , Guida Jennifer , Prasanna Pataje G S , Buchsbaum Jeffrey C
Published: July 2024

The older American population is rapidly increasing, and millions of older adults will be cancer survivors with comorbidities. This population faces specific challenges regarding treatment and has unique clinical needs. Recognizing this need, the National Cancer Institute, in collaboration with the National Institute on Aging, hosted a webinar series, entitled Cancer, Aging, and Comorbidities. This commentary provides a reflection of 5 thematic areas covered by the webinar series, which was focused on improving cancer treatment for older adults with cancer and comorbidities: 1) the impact of comorbidities on treatment tolerability and patient outcomes; 2) the impact of comorbidities on cancer clinical trial design; 3) the development of wearable devices in measuring comorbidities in cancer treatment; 4) the effects of nutrition and the microbiome on cancer therapy; and 5) the role of senescence and senotherapy in age-related diseases. Advances have been made in these areas, however, many gaps and challenges exist and are discussed in this commentary. To improve cancer survivorship in older populations with comorbidities, aging and comorbidities must be jointly considered and incorporated across the spectrum of cancer research. This includes more basic research of the mechanisms linking comorbidities and cancer development and treatment response, building critical resources and infrastructure (eg, preclinical models and patient samples), conducting clinical trials focused on the older population, integrating geriatric assessment into cancer treatment, and incorporating novel technologies, such as wearable devices, into clinical trials and cancer care.
Results of the RVA Breathes randomized controlled trial
Authors: Everhart Robin S , Lohr Katherine D , Holder Rachel L , Morton Sarah C M , Miller Ashley , Corona Rosalie , Mazzeo Suzanne E , Thacker II Leroy R , Schechter Michael S
Published: July 2024

Objective

This study tested a randomized controlled trial of RVA Breathes, a community asthma program, in reducing asthma-related healthcare utilization among children living in an area with a high poverty rate.

Methods

Participants included 250 caregivers (78% African American/Black; 73.3% household income<$25,000/year) and their children with asthma (5–11 years). Inclusion criteria included an asthma-related emergency department (ED) visit, hospitalization, unscheduled doctor’s visit, or systemic steroids in the past 2 years. Families were randomized to a full active intervention (asthma education with community health workers [CHWs], home remediation with home assessors, and a school nurse component; n = 118), partial active intervention (asthma education and home remediation; n = 69), or a control group (n = 63) for 9 months. Measures on healthcare utilization and asthma-related factors were collected. Follow-up assessments occurred across a 9-month period.

Results

Although we did not find any significant effects, there was a trend toward significance for a group by time effect with objective healthcare utilization as the outcome (F4,365 = 2.28, p = .061). The full intervention group experienced a significant decrease from baseline to 9-month follow-up compared with the other groups (p < .001). Only the full intervention group experienced a significant increase in reported asthma action plans across time (no significant group effect).

Conclusions

In the context of the unprecedented COVID-19 pandemic, which led to a substantial global decrease in healthcare utilization, the study’s main hypotheses were not supported. Nevertheless, findings support the benefit of community asthma programs that integrate care across multiple settings and connect families with CHWs.
Data-integration with pseudoweights and survey-calibration: application to developing US-representative lung cancer risk models for use in screening
Authors: Wang Lingxiao , Li Yan , Graubard Barry I , Katki Hormuzd A
Published: July 2024

Accurate cancer risk estimation is crucial to clinical decision-making, such as identifying high-risk people for screening. However, most existing cancer risk models incorporate data from epidemiologic studies, which usually cannot represent the target population. While population-based health surveys are ideal for making inference to the target population, they typically do not collect time-to-cancer incidence data. Instead, time-to-cancer specific mortality is often readily available on surveys via linkage to vital statistics. We develop calibrated pseudoweighting methods that integrate individual-level data from a cohort and a survey, and summary statistics of cancer incidence from national cancer registries. By leveraging individual-level cancer mortality data in the survey, the proposed methods impute time-to-cancer incidence for survey sample individuals and use survey calibration with auxiliary variables of influence functions generated from Cox regression to improve robustness and efficiency of the inverse-propensity pseudoweighting method in estimating pure risks. We develop a lung cancer incidence pure risk model from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial using our proposed methods by integrating data from the National Health Interview Survey and cancer registries.
New insights into plasmodesmata: complex ‘protoplasmic connecting threads’
Authors: Zanini Andrea A , Burch-Smith Tessa M
Published: July 2024

Intercellular communication in plants, as in other multicellular organisms, allows cells in tissues to coordinate their responses for development and in response to environmental stimuli. Much of this communication is facilitated by plasmodesmata (PD), consisting of membranes and cytoplasm, that connect adjacent cells to each other. PD have long been viewed as passive conduits for the movement of a variety of metabolites and molecular cargoes, but this perception has been changing over the last two decades or so. Research from the last few years has revealed the importance of PD as signaling hubs and as crucial players in hormone signaling. The adoption of advanced biochemical approaches, molecular tools, and high-resolution imaging modalities has led to several recent breakthroughs in our understanding of the roles of PD, revealing the structural and regulatory complexity of these ‘protoplasmic connecting threads’. We highlight several of these findings that we think well illustrate the current understanding of PD as functioning at the nexus of plant physiology, development, and acclimation to the environment.
Simulations of pulsed overpressure jets: formation of bellows and ripples in galactic environments
Authors: Richards Carl , Smith Michael D
Published: July 2024

Jets from active nuclei may supply the heating which moderates cooling and accretion from the circum-galactic medium. While steady overpressured jets can drive a circulatory flow, lateral energy transfer rarely exceeds 3 per cent of jet power, after the initial bow shock has advanced. Here, we explore if pulses in high-pressure jets are capable of sufficient lateral energy transfer into the surrounding environment. We answer this by performing a systematic survey of numerical simulations in an axisymmetric hydrodynamic mode. Velocity pulses along low Mach jets are studied at various overpressures. We consider combinations of jet velocity pulse amplitude and frequency. We find three flow types corresponding to slow, intermediate, and fast pulsations. Rapid pulsations in light jets generate a series of travelling shocks in the jet. They also create ripples which propagate into the ambient medium while a slow convection flow brings in ambient gas which is expelled along the jet direction. Long period pulses produce slowly evolving patterns which have little external effect, while screeching persists as in non-pulsed jets. In addition, rapid pulses in jets denser than the ambient medium generate a novel breathing cavity analogous to a lung. Intermediate period pulses generate a series of bows via a bellows action which transfer energy into the ambient gas, reaching power efficiencies of over 30 per cent when the jet overpressure is sufficiently large. This may adequately inhibit galaxy gas accretion. In addition, such pulses enhance the axial out-flow of jet material, potentially polluting the circum-galactic gas with metal-enriched interstellar gas.
Nearest neighbour analysis as a new probe for fuzzy dark matter
Authors: Kousha Hamed Manouchehri , Ansarifard Mohammad , Abolhasani Aliakbar
Published: July 2024

Fuzzy dark matter (FDM) is a promising candidate for dark matter (DM), characterized by its ultra-light mass, which gives rise to wave effects at astrophysical scales. These effects offer potential solutions to the small-scale issues encountered within the standard cold dark matter (CDM) paradigm. In this paper, we investigate the large-scale structure of the cosmic web using FDM simulations, comparing them to CDM-only simulations and a simulation incorporating baryonic effects. Our study employs the nearest neighbour (NN) analysis as a new statistical tool for examining the structure and statistics of the cosmic web in an FDM universe. This analysis could capture the information absent in the two-point correlation functions. In particular, we analyse data related to the spherical contact, nearest neighbour distances (NND), and the angle between the first and second nearest neighbours of haloes (NNA). Specifically, we utilize probability distribution functions, statistical moments, and fitting parameters, as well as G(x), F(x), and J(x) functions to analyse the above data. Remarkably, the results from the FDM simulations differ significantly from the others across these analyses, while no noticeable distinction is observed between the baryonic and CDM-only simulations. Moreover, the lower FDM mass leads to more significant deviations from the CDM simulations. These compelling results highlight the efficiency of the NN analysis – mainly through the use of the J(x) function, $s_3$, $l_{3}$, and $a_4$ parameters – as a prominent new tool for investigating FDM on large scales and making observational predictions.
Hybrid GRMHD and force-free simulations of black hole accretion
Authors: Chael Andrew
Published: July 2024

We present a new approach for stably evolving general relativistic magnetohydrodynamic (GRMHD) simulations in regions where the magnetization $\sigma =b^2/\rho c^2$ becomes large. GRMHD codes typically struggle to evolve plasma above $\sigma \approx 100$ in simulations of black hole accretion. To ensure stability, GRMHD codes will inject mass density artificially to the simulation as necessary to keep the magnetization below a ceiling value $\sigma _{\rm max}$. We propose an alternative approach where the simulation transitions to solving the equations of general relativistic force-free electrodynamics (GRFFE) above a magnetization $\sigma _{\rm trans}$. We augment the GRFFE equations in the highly magnetized region with approximate equations to evolve the decoupled field-parallel velocity and plasma energy density. Our hybrid scheme is explicit and easily added to the framework of standard-volume GRMHD codes. We present a variety of tests of our method, implemented in the GRMHD code koral, and we show results from a 3D hybrid GRMHD + GRFFE simulation of a magnetically arrested disc (MAD) around a spinning black hole. Our hybrid MAD simulation closely matches the average properties of a standard GRMHD MAD simulation with the same initial conditions in low magnetization regions, but it achieves a magnetization $\sigma \approx 10^6$ in the evacuated jet funnel. We present simulated horizon-scale images of both simulations at 230 GHz with the black hole mass and accretion rate matched to M87*. Images from the hybrid simulation are less affected by the choice of magnetization cut-off $\sigma _{\rm cut}$ imposed in radiative transfer than images from the standard GRMHD simulation.
The NIRVANDELS survey: the stellar and gas-phase mass-metallicity relations of star-forming galaxies at z = 3.5
Authors: Stanton T M , Cullen F , McLure R J , Shapley A E , Arellano-Córdova K Z , Begley R , Amorín R , Barrufet L , Calabrò A , Carnall A C , Cirasuolo M , Dunlop J S , Donnan C T , Hamadouche M L , Liu F Y , McLeod D J , Pentericci L , Pozzetti L , Sanders R L , Scholte D , Topping M W
Published: July 2024

We present determinations of the gas-phase and stellar metallicities of a sample of 65 star-forming galaxies at $z \simeq 3.5$ using rest-frame far-ultraviolet (FUV) spectroscopy from the VANDELS survey in combination with follow-up rest-frame optical spectroscopy from VLT/KMOS and Keck/MOSFIRE. We infer gas-phase oxygen abundances ($Z_{\mathrm{g}}$; tracing O/H) via strong optical nebular lines and stellar iron abundances ($Z_{\star }$; tracing Fe/H) from full spectral fitting to the FUV continuum. Our sample spans the stellar mass range $8.5 \lt \mathrm{log}(M_{\star }/\mathrm{M}_{\odot }) \lt 10.5$ and shows clear evidence for both a stellar and gas-phase mass-metallicity relation (MZR). We find that our O and Fe abundance estimates both exhibit a similar mass-dependence, such that $\mathrm{Fe/H}\propto M_{\star }^{0.30\pm 0.11}$ and $\mathrm{O/H}\propto M_{\star }^{0.32\pm 0.09}$. At fixed $M_{\star }$ we find that, relative to their solar values, O abundances are systematically larger than Fe abundances (i.e. α-enhancement). We estimate an average enhancement of $\mathrm{(O/Fe)} = 2.65 \pm 0.16 \times \mathrm{(O/Fe)_\odot }$ which appears to be independent of $M_{\star }$. We employ analytic chemical evolution models to place a constraint on the strength of galactic-level outflows via the mass-outflow factor ($\eta$). We show that outflow efficiencies that scale as $\eta \propto M_{\star }^{-0.32}$ can simultaneously explain the functional form of of the stellar and gas-phase MZR, as well as the degree of α-enhancement at fixed Fe/H. Our results add further evidence to support a picture in which α-enhanced abundance ratios are ubiquitous in high-redshift star-forming galaxies, as expected for young systems whose interstellar medium is primarily enriched by core-collapse supernovae.
Neutral hydrogen lensing simulations in the hubble frontier fields
Authors: Blecher Tariq , Deane Roger , Obreschkow Danail , Heywood Ian
Published: July 2024

Cold gas evolution ties the formation of dark matter haloes to the star formation history of the universe. A primary component of cold gas, neutral atomic hydrogen (HI), can be traced by its 21-cm emission line. However, the faintness of this emission typically limits individual detections to low redshifts ($z\lesssim 0.2$). To address this limitation, we investigate the potential of targeting gravitationally lensed systems. Building on our prior galaxy–galaxy simulations, we have developed a ray-tracing code to simulate lensed HI images for known galaxies situated behind the massive hubble frontier field galaxy clusters. Our findings reveal the existence of high HI mass, high HI magnification systems in these cluster-lensing scenarios. Through simulations of hundreds of sources, we have identified compelling targets within the redshift range $z\approx 0.7 - 1.5$. The most promising candidate from our simulations is the Great Arc at z = 0.725 in Abell 370, which should be detectable by MeerKAT in approximately 50 h. Importantly, the derived HI mass is predicted to be relatively insensitive to systematic uncertainties in the lensing model, and should be constrained within a factor of ${\sim }2.5$ for a 95 per cent confidence interval.
Ancestral Origins and Admixture History of Kazakhs
Authors: Lei Chang , Liu Jiaojiao , Zhang Rui , Pan Yuwen , Lu Yan , Gao Yang , Ma Xixian , Yang Yajun , Guan Yaqun , Mamatyusupu Dolikun , Xu Shuhua
Published: July 2024

Kazakh people, like many other populations that settled in Central Asia, demonstrate an array of mixed anthropological features of East Eurasian (EEA) and West Eurasian (WEA) populations, indicating a possible scenario of biological admixture between already differentiated EEA and WEA populations. However, their complex biological origin, genomic makeup, and genetic interaction with surrounding populations are not well understood. To decipher their genetic structure and population history, we conducted, to our knowledge, the first whole-genome sequencing study of Kazakhs residing in Xinjiang (KZK). We demonstrated that KZK derived their ancestries from 4 ancestral source populations: East Asian (∼39.7%), West Asian (∼28.6%), Siberian (∼23.6%), and South Asian (∼8.1%). The recognizable interactions of EEA and WEA ancestries in Kazakhs were dated back to the 15th century BCE. Kazakhs were genetically distinctive from the Uyghurs in terms of their overall genomic makeup, although the 2 populations were closely related in genetics, and both showed a substantial admixture of western and eastern peoples. Notably, we identified a considerable sex-biased admixture, with an excess of western males and eastern females contributing to the KZK gene pool. We further identified a set of genes that showed remarkable differentiation in KZK from the surrounding populations, including those associated with skin color (SLC24A5, OCA2), essential hypertension (HLA-DQB1), hypertension (MTHFR, SLC35F3), and neuron development (CNTNAP2). These results advance our understanding of the complex history of contacts between Western and Eastern Eurasians, especially those living or along the old Silk Road.
Narrative and Tonal Structure in Herrmann’s Score for Vertigo
Authors: Şehİraltı Oğuz
Published: July 2024

This article examines the relationship between tonal and narrative structures in Alfred Hitchcock’s 1958 film Vertigo. I argue that this relationship is reciprocal and that Bernard Herrmann’s score for the film affects the perception of the plot despite the generally accepted conventions of understanding film music as subordinate to overall cinematic structure. Using methodologies ranging from Schenkerian theory to analytical approaches to popular music, I suggest that the tonal structure unfolds in two broad episodes that segment the film and help us interpret it from the protagonist’s psychological perspective through the alignment of strong cadential points with important kernel events in the plot.
Hermeneutic Limits; or, When Not to Theorize: Notes for Interpreting Our Phoenix by Trans Indigenous Mexican-American Composer Mari Esabel Valverde
Authors: Lee Gavin S K
Published: July 2024

Trans composers, like other people marginalized by race, gender, or sexuality, are often caught in the trap of identity constructs, which both envoice minorities and also pigeonhole their possible range of musical expression. In this essay on US-based transgender Indigenous Mexican choral composer Mari Esabel Valverde, I let my consideration of “trans music theory” be guided by her view that writers have sensationalized trans identity, and that while she celebrates trans lives in her choral work Our Phoenix (2016), she is not attempting to create music that “sounds” transgender. With Valverde in mind, I construct an intersectional interpretive framework that calls for various kind of limits (the limits of queering, of authorial subjectivity, and of the notion of “unconscious” expression of identity) and proposes essential conditions (the centrality of the voices, bodies, and musical structures of trans composers) that create an ethical environment for a compassionate trans music theory to emerge.
Loss of Lamin A leads to the nuclear translocation of AGO2 and compromised RNA interference
Authors: Lobo Vivian , Nowak Iwona , Fernandez Carola , Correa Muler Ana Iris , Westholm Jakub O , Huang Hsiang-Chi , Fabrik Ivo , Huynh Hang T , Shcherbinina Evgeniia , Poyraz Melis , Härtlova Anetta , Benhalevy Daniel , Angeletti Davide , Sarshad Aishe A
Published: July 2024

In mammals, RNA interference (RNAi) was historically studied as a cytoplasmic event; however, in the last decade, a growing number of reports convincingly show the nuclear localization of the Argonaute (AGO) proteins. Nevertheless, the extent of nuclear RNAi and its implication in biological mechanisms remain to be elucidated. We found that reduced Lamin A levels significantly induce nuclear influx of AGO2 in SHSY5Y neuroblastoma and A375 melanoma cancer cell lines, which normally have no nuclear AGO2. Lamin A KO manifested a more pronounced effect in SHSY5Y cells compared to A375 cells, evident by changes in cell morphology, increased cell proliferation, and oncogenic miRNA expression. Moreover, AGO fPAR-CLIP in Lamin A KO SHSY5Y cells revealed significantly reduced RNAi activity. Further exploration of the nuclear AGO interactome by mass spectrometry identified FAM120A, an RNA-binding protein and known interactor of AGO2. Subsequent FAM120A fPAR-CLIP, revealed that FAM120A co-binds AGO targets and that this competition reduces the RNAi activity. Therefore, loss of Lamin A triggers nuclear AGO2 translocation, FAM120A mediated RNAi impairment, and upregulation of oncogenic miRNAs, facilitating cancer cell proliferation.
Cas9 interaction with the tracrRNA nexus modulates the repression of type II-A CRISPR-cas genes
Authors: Kim Hyejin , Marraffini Luciano A
Published: July 2024

Immune responses need to be regulated to prevent autoimmunity. CRISPR-Cas systems provide adaptive immunity in prokaryotes through the acquisition of short DNA sequences from invading viruses (bacteriophages), known as spacers. Spacers are inserted into the CRISPR locus and serve as templates for the transcription of guides used by RNA-guided nucleases to recognize complementary nucleic acids of the invaders and start the CRISPR immune response. In type II-A CRISPR systems, Cas9 uses the guide RNA to cleave target DNA sequences in the genome of infecting phages, and the tracrRNA to bind the promoter of cas genes and repress their transcription. We previously isolated a Cas9 mutant carrying the I473F substitution that increased the frequency of spacer acquisition by 2–3 orders of magnitude, leading to a fitness cost due to higher levels of autoimmunity. Here, we investigated the molecular basis underlying these findings. We found that the I473F mutation decreases the association of Cas9 to tracrRNA, limiting its repressor function, leading to high levels of expression of cas genes, which in turn increase the strength of the type II-A CRISPR-Cas immune response. We obtained similar results for a related type II-A system, and therefore our findings highlight the importance of the interaction between Cas9 and its tracrRNA cofactor in tuning the immune response to balanced levels that enable phage defense but avoid autoimmunity.
Conformational dynamics of CasX (Cas12e) in mediating DNA cleavage revealed by single-molecule FRET
Authors: Xing Wenjing , Li Danyuan , Wang Wenjuan , Liu Jun-Jie Gogo , Chen Chunlai
Published: July 2024

CasX (also known as Cas12e), a Class 2 CRISPR-Cas system, shows promise in genome editing due to its smaller size compared to the widely used Cas9 and Cas12a. Although the structures of CasX–sgRNA–DNA ternary complexes have been resolved and uncover a distinctive NTSB domain, the dynamic behaviors of CasX are not well characterized. In this study, we employed single-molecule and biochemical assays to investigate the conformational dynamics of two CasX homologs, DpbCasX and PlmCasX, from DNA binding to target cleavage and fragment release. Our results indicate that CasX cleaves the non-target strand and the target strand sequentially with relative irreversible dynamics. The two CasX homologs exhibited different cleavage patterns and specificities. The dynamic characterization of CasX also reveals a PAM-proximal seed region, providing guidance for CasX-based effector design. Further studies elucidate the mechanistic basis for why modification of sgRNA and the NTSB domain can affect its activity. Interestingly, CasX has less effective target search efficiency than Cas9 and Cas12a, potentially accounting for its lower genome editing efficiency. This observation opens a new avenue for future protein engineering.
High resolution landscape of ribosomal RNA processing and surveillance
Authors: An Weidong , Yan Yunxiao , Ye Keqiong
Published: July 2024

Ribosomal RNAs are processed in a complex pathway. We profiled rRNA processing intermediates in yeast at single-molecule and single-nucleotide levels with circularization, targeted amplification and deep sequencing (CircTA-seq), gaining significant mechanistic insights into rRNA processing and surveillance. The long form of the 5′ end of 5.8S rRNA is converted to the short form and represents an intermediate of a unified processing pathway. The initial 3′ end processing of 5.8S rRNA involves trimming by Rex1 and Rex2 and Trf4-mediated polyadenylation. The 3′ end of 25S rRNA is formed by sequential digestion by four Rex proteins. Intermediates with an extended A1 site are generated during 5′ degradation of aberrant 18S rRNA precursors. We determined precise polyadenylation profiles for pre-rRNAs and show that the degradation efficiency of polyadenylated 20S pre-rRNA critically depends on poly(A) lengths and degradation intermediates released from the exosome are often extensively re-polyadenylated.
Electron-injection-engineering induced dual-phase MoO2.8F0.2/MoO2.4F0.6 heterostructure for magnesium storage
Authors: Wang Weixiao , Xiong Fangyu , Zhu Shaohua , Yan Mengyu , Liao Xiaobin , Yu Kesong , Cui Lianmeng , Chen Jinghui , Wang Junjun , Lan Ruoqi , Xie Jun , An Qinyou , Mai Liqiang
Published: July 2024

Rechargeable magnesium batteries (RMBs) have received increased attention due to their high volumetric capacity and safety. Nevertheless, the sluggish diffusion kinetics of highly polarized Mg2+ in host lattices severely hinders the development of RMBs. Herein, we report an electron injection strategy for modulating the Mo 4d-orbital splitting manner and first fabricate a dual-phase MoO2.8F0.2/MoO2.4F0.6 heterostructure to accelerate Mg2+ diffusion. The electron injection strategy triggers weak Jahn–Teller distortion in MoO6 octahedra and reorganization of the Mo 4d-orbital, leading to a partial phase transition from orthorhombic phase MoO2.8F0.2 to cubic phase MoO2.4F0.6. As a result, the designed heterostructure generates a built-in electric field, simultaneously improving its electronic conductivity and ionic diffusivity by at least one order of magnitude compared to MoO2.8F0.2 and MoO2.4F0.6. Importantly, the assembled MoO2.8F0.2/MoO2.4F0.6//Mg full cell exhibits a remarkable reversible capacity of 172.5 mAh g−1 at 0.1 A g−1, pushing forward the orbital-scale manipulation for high-performance RMBs.
Mantle plume trail beneath the ca. 1.1 Ga North American Midcontinent Rift revealed by magnetotelluric data
Authors: Lin Wule , Schultz Adam , Yang Bo , Harris Lyal B , Hu Xiangyun
Published: July 2024

Whilst the 1.1 Ga North American Midcontinent Rift (MCR) system is formed in association with the Keweenaw mantle plume, the absence of a northern third rift arm or aulacogen (a general characteristic of mantle plumes) has previously not been well understood. To help clarify this unusual plume–rift relationship and to better establish the region affected by the Keweenaw mantle plume, we present the first electrical resistivity model of the MCR derived from 3D inversion of EarthScope USArray and Lithoprobe magnetotelluric (MT) data, extending northwards into the Archean Superior Province. Our model shows a prominent highly conductive anomaly trending NW-SE at the base of Western Superior's cratonic lithospheric mantle, cross-cutting and extending for over 300 km on both sides of the western rift branch. We propose that this anomaly reflects the ancient signature of a plume trail, resulting from metasomatism and/or partial melting of the sulfide-rich basal lithospheric mantle during impingement of the Keweenaw mantle plume.
Switching to E-cigarettes as Harm Reduction Among Individuals With Chronic Disease Who Currently Smoke: Results of a Pilot Randomized Controlled Trial
Authors: Vojjala Mahathi , Stevens Elizabeth R , Nicholson Andrew , Morgan Tucker , Kaneria Aayush , Xiang Grace , Wilker Olivia , Wisniewski Rachel , Melnic Irina , El Shahawy Omar , Berger Kenneth I , Sherman Scott E
Published: July 2024

Introduction

E-cigarettes (ECs) may be an effective harm reduction strategy for individuals with conditions like chronic obstructive pulmonary disease (COPD), asthma, coronary artery disease (CAD), and peripheral arterial disease who smoke combustible cigarettes (CCs). Our aim was to examine how individuals with chronic conditions transition from CCs to ECs and its impact on health outcomes.

Aims and Methods

In a pilot randomized controlled trial (RCT), patients with COPD, asthma, and CAD/PAD who currently smoke CCs and have not used nicotine replacement therapy (NRT) or ECs in the past 14 days were randomized to receive ECs or combination NRT with behavioral counseling. Disease symptoms, acceptability/satisfaction (TSQM-9) and feasibility, and cigarettes per day (CPD), and/or EC use were collected at baseline, 3-, and 6 months. Descriptive statistics and a linear regression were conducted to explore changes in CPD and chronic condition-specific assessments (CAT, SAQ-7, and ACT) that assess COPD, asthma, and CAD/PAD symptom change.

Results

At 3 months, the EC group (n = 63, mean CPD = 9 ± 11) reduced their CPD by 54% versus 60% in the NRT group (n = 58, mean CPD = 7 ± 6), p = .56. At 6 months, 17.5% had switched completely to ECs while 23% quit smoking in the NRT arm. CAT scores showed a significant 6-point reduction in the EC arm (p = .03). Participants scored an average of 69 ± 27 for EC effectiveness, 87 ± 23 for convenience, and 75 ± 27 for overall satisfaction.

Conclusions

This pilot study suggests that ECs may be a safer alternative for chronic condition patients using CCs and warrants further research on expected smoking cessation/reduction among individuals who use ECs.

Implications

The findings from this pilot RCT hold significant implications for chronic conditions such as COPD, asthma, CAD, and peripheral arterial disease who smoke CCs. The observed reduction in CPD and improvement in respiratory symptoms suggest that switching to ECs appears feasible and acceptable among those with chronic diseases. These results suggest that ECs may offer an alternative for individuals struggling to quit CC smoking through existing pharmacotherapies. This study supports further exploration of switching to ECs as a harm reduction strategy among CC users who have been unsuccessful at quitting by other means.
PHOSPHATASE 2A dephosphorylates PHYTOCHROME-INTERACTING FACTOR3 to modulate photomorphogenesis in Arabidopsis
Authors: Cai Xingbo , Lee Sanghwa , Gómez Jaime Andrea Paola , Tang Wenqiang , Sun Yu , Huq Enamul
Published: July 2024

The phytochrome (phy) family of sensory photoreceptors modulates developmental programs in response to ambient light. Phys also control gene expression in part by directly interacting with the bHLH class of transcription factors, PHYTOCHROME-INTERACTING FACTORS (PIFs), and inducing their rapid phosphorylation and degradation. Several kinases have been shown to phosphorylate PIFs and promote their degradation. However, the phosphatases that dephosphorylate PIFs are less understood. In this study, we describe 4 regulatory subunits of the Arabidopsis (Arabidopsis thaliana) protein PHOSPHATASE 2A (PP2A) family (B′α, B′β, B″α, and B″β) that interact with PIF3 in yeast 2-hybrid, in vitro and in vivo assays. The pp2ab″αβ and b″αβ/b′αβ mutants display short hypocotyls, while the overexpression of the B subunits induces longer hypocotyls compared with the wild type (WT) under red light. The light-induced degradation of PIF3 is faster in the b″αβ/b′αβ quadruple mutant compared with that in the WT. Consistently, immunoprecipitated PP2A A and B subunits directly dephosphorylate PIF3-MYC in vitro. An RNA-sequencing analysis shows that B″α and B″β alter global gene expression in response to red light. PIFs (PIF1, PIF3, PIF4, and PIF5) are epistatic to these B subunits in regulating hypocotyl elongation under red light. Collectively, these data show an essential function of PP2A in dephosphorylating PIF3 to modulate photomorphogenesis in Arabidopsis.
Biparental graph strategy to represent and analyze hybrid plant genomes
Authors: Kong Qianqian , Jiang Yi , Sun Mingfei , Wang Yunpeng , Zhang Lin , Zeng Xing , Wang Zhiheng , Wang Zijie , Liu Yuting , Gan Yuanxian , Liu Han , Gao Xiang , Yang Xuerong , Song Xinyuan , Liu Hongjun , Shi Junpeng
Published: July 2024

Hybrid plants are found extensively in the wild, and they often demonstrate superior performance of complex traits over their parents and other selfing plants. This phenomenon, known as heterosis, has been extensively applied in plant breeding for decades. However, the process of decoding hybrid plant genomes has seriously lagged due to the challenges associated with genome assembly and the lack of appropriate methodologies for their subsequent representation and analysis. Here, we present the assembly and analysis of 2 hybrids, an intraspecific hybrid between 2 maize (Zea mays ssp. mays) inbred lines and an interspecific hybrid between maize and its wild relative teosinte (Z. mays ssp. parviglumis), utilizing a combination of PacBio High Fidelity sequencing and chromatin conformation capture sequencing data. The haplotypic assemblies are well phased at chromosomal scale, successfully resolving the complex loci with extensive parental structural variations (SVs). By integrating into a biparental genome graph, the haplotypic assemblies can facilitate downstream short-read–based SV calling and allele-specific gene expression analysis, demonstrating outstanding advantages over a single linear genome. Our work offers a comprehensive workflow that aims to facilitate the decoding of numerous hybrid plant genomes, particularly those with unknown or inaccessible parentage, thereby enhancing our understanding of genome evolution and heterosis.
The alternative fairytale: how personal history shapes identity and resilience in medicine
Authors: Kurdi Hibba
Published: July 2024

In “The Alternative Fairytale,” I explore my journey as a cardiology registrar/fellow, a path influenced deeply by my early displacement from war-torn Sudan. This piece reflects on the interplay between my professional choices and personal identity amidst the backdrop of a male-dominated field and societal expectations. It examines how my roots in a family that once fled conflict have shaped my approach to medicine—emphasizing community, empathy, and a leadership style that diverges from traditional norms. Through this narrative, I aim to redefine and help others to reflect on what success looks like in cardiology and medicine; advocating for diversity in leadership styles and highlight the importance of personal background in shaping professional paths.
The prescription and monitoring of conventional synthetic disease-modifying anti-rheumatic drugs: British Society for Rheumatology guideline scope
Authors: Mercer Louise , Abhishek Abhishek , Kavirayani Akhila , Ahmed Alison , Davidson Alan , Foulkes Amy , Jones Claire , Nash Clare , Rose-Parfitt Emily , Dhillon Emmandeep , Zabate Genevieve , Twohig Helen , De Vere Hope , Scott Jennifer , Reynolds John , Holmes Julia , Hartley Karen , Warrier Kishore , Nowak Kataryzna , Parsons Kate , Bechman Katie , Bray Lisa , Adikari Madura , Wood Natasha , Faithfull Nicola , Gullick Nicola , Saha Pratyasha , Heaton Rebecca , Deepak Samundeeswari , Hider Samantha , Khalid Sameena , Said Sanaa Suleiman , Ryan Sarah , Kyle Stuart , Raghuvanshi Subhra , Tan Su-Yin , Shivamurthy Vinay , Galloway James ,   British Society for Rheumatology Guidelines Steering Group
Published: July 2024

This guideline will provide up-to-date, evidence-based recommendations on the safe use of non-biologic DMARDs, also called conventional synthetic DMARDs (csDMARD), across the full spectrum of autoimmune rheumatic diseases. The guideline will update the guideline published in 2017 and will be expanded to include people of all ages. Updated information on the monitoring of DMARDs and vaccinations will be included. The guideline will be developed using the methods and processes described in the British Society for Rheumatology’s ‘Creating clinical guidelines: our protocol’, updated 2023.
Qualified kidney injury biomarkers demonstrate value during early clinical drug development
Authors: Ravindra Kodihalli C , Fader Kelly A , Potter David , Radi Zaher A , Friedman Gary S , Brenneman Karrie A , Amin Neeta B , Weiss Roberta , Danto Spencer I , Page Karen , Ramaiah Shashi K , Vaidya Vishal S
Published: July 2024

Drug-induced kidney injury (DIKI) is of significant concern, both during drug development and in clinical practice. We report a patient-centric approach for clinical implementation of the FDA-qualified kidney safety biomarker panel, highlighting Phase 1 and 2 trials for candidate therapeutics in Pfizer’s portfolio (PFE-1 and PFE-2, respectively) that induced kidney tubular injury in rat toxicity studies. Clusterin (CLU), cystatin-C (CysC), kidney injury molecule-1 (KIM-1), N-acetyl-beta-d-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), and osteopontin (OPN) were measured in urine samples from (i) Phase 1 healthy volunteers (HVs; n = 12) dosed with PFE-1, (ii) Phase 2 rheumatoid arthritis (RA) patients (n = 266) dosed with PFE-2, (iii) lupus patients on standard-of-care therapies (n = 121), and (iv) healthy volunteers (n = 60). The FDA-defined composite measure (CM), calculated as the geometric mean response across the 6 biomarkers, was increased ∼30% in HVs administered 100 mg PFE-1 relative to placebo, providing evidence of DIKI. In contrast, the CM for RA patients dosed with PFE-2 was comparable to placebo controls, helping to de-risk the concern for DIKI at clinically relevant doses. Comparing individual biomarker concentrations across disease states revealed that CLU, KIM-1, NAG, NGAL, and OPN are elevated in the urine of RA and lupus patients (those without severe active proliferative lupus nephritis) relative to HVs. Overall, these case studies demonstrate the value of using the FDA-qualified kidney biomarker panel to guide risk assessment, dose selection, and clinical decision making for novel therapeutics, both in HVs and patient populations.
Quantitative label-free proteomic analysis of mouse ovarian antral follicles following oral exposure to a human-relevant mixture of three phthalates
Authors: Miller Kara L , Liu Xiaosong , McSwain Maile G , Jauregui Estela J , Langlais Paul R , Craig Zelieann R
Published: July 2024

Dibutyl phthalate (DBP), di-2-ethylhexyl phthalate (DEHP), and benzyl butyl phthalate (BBP) are used in personal and medical care products. In the ovary, antral follicles are essential for steroidogenesis and ovulation. DBP, BBP, and DEHP are known to inhibit mouse antral follicle growth and ovulation in vitro, and associate with decreased antral follicle counts in women. Given that the in vivo effects of a three-phthalate mixture on antral follicles are unknown, we evaluated the effects of a human-relevant mixture of DBP, BBP, and DEHP on ovarian follicles through proteome profiling analysis. Adult CD-1 female mice were fed corn oil (vehicle), or two dose levels of a phthalate mixture based on estimated exposures in general (32 µg/kg/d; PHT 32) and occupationally exposed (500 µg/kg/d; PHT 500) populations for 10 d. Antral follicles (>250 µm) were isolated and subjected to proteome profiling via label-free tandem mass spectrometry. A total of 5,417 antral follicle proteins were detected, of which 194 were differentially abundant between vehicle and PHT 32, and 136 between vehicle and PHT 500. Bioinformatic analysis revealed significantly different responses between the two phthalate doses. Protein abundance differences in the PHT 32 exposure mapped to cytoplasm, mitochondria, and lipid metabolism; whereas those in the PHT 500 exposure mapped to cytoplasm, nucleus, and phosphorylation. When both doses altered proteins mapped to common processes, the associated predicted transcription factors were different. These findings provide novel mechanistic insight into phthalate-associated, ovary-driven reproductive outcomes in women.