bluuebunny/crossref_metadata_2025 huggingface dataset:
Mutation ofDEFECTIVE EMBRYO SAC1results in a low seed-setting rate in rice by regulating embryo sac development
Authors: Hu Xia , Yu Ping , Zhang Yingxin , Gao Zhiqiang , Sun Bin , Wu Weixun , Deng Chenwei , Abbas Adil , Hong Yongbo , Sun Lianping , Liu Qunen , Xue Pao , Wang Beifang , Zhan Xiaodeng , Cao Liyong , Cheng Shihua
Published: January 2023

The seed-setting rate has a significant effect on grain yield in rice (Oryza sativa L.). Embryo sac development is essential for seed setting; however, the molecular mechanism underlying this process remains unclear. Here, we isolated defective embryo sac1 (des1), a rice mutant with a low seed-setting rate. Cytological examination showed degenerated embryo sacs and reduced fertilization capacity in des1. Map-based cloning revealed a nonsense mutation in OsDES1, a gene that encodes a putative nuclear envelope membrane protein (NEMP)-domain-containing protein that is preferentially expressed in pistils. The OsDES1 mutation disrupts the normal formation of functional megaspores, which ultimately results in a degenerated embryo sac in des1. Reciprocal crosses showed that fertilization is abnormal and that the female reproductive organ is defective in des1. OsDES1 interacts with LONELY GUY (LOG), a cytokinin-activating enzyme that acts in the final step of cytokinin synthesis; mutation of LOG led to defective female reproductive organ development. These results demonstrate that OsDES1 functions in determining the rice seed-setting rate by regulating embryo sac development and fertilization. Our study sheds light on the function of NEMP-type proteins in rice reproductive development.
Degradation of glutathione and glutathione conjugates in plants
Authors: Ito Takehiro , Ohkama-Ohtsu Naoko
Published: January 2023

Glutathione (GSH) is a ubiquitous, abundant, and indispensable thiol for plants that participates in various biological processes, such as scavenging reactive oxygen species, redox signaling, storage and transport of sulfur, detoxification of harmful substances, and metabolism of several compounds. Therefore knowledge of GSH metabolism is essential for plant science. Nevertheless, GSH degradation has been insufficiently elucidated, and this has hampered our understanding of plant life. Over the last five decades, the γ-glutamyl cycle has been dominant in GSH studies, and the exoenzyme γ-glutamyl transpeptidase has been regarded as the major GSH degradation enzyme. However, recent studies have shown that GSH is degraded in cells by cytosolic enzymes such as γ-glutamyl cyclotransferase or γ-glutamyl peptidase. Meanwhile, a portion of GSH is degraded after conjugation with other molecules, which has also been found to be carried out by vacuolar γ-glutamyl transpeptidase, γ-glutamyl peptidase, or phytochelatin synthase. These findings highlight the need to re-assess previous assumptions concerning the γ-glutamyl cycle, and a novel overview of the plant GSH degradation pathway is essential. This review aims to build a foundation for future studies by summarizing current understanding of GSH/glutathione conjugate degradation.
The transcription factor AtMYB12 is part of a feedback loop regulating cell division orientation in the root meristem vasculature
Authors: Wybouw Brecht , Arents Helena E , Yang Baojun , Nolf Jonah , Smet Wouter , Vandorpe Michael , Minne Max , Luo Xiaopeng , De Clercq Inge , Van Damme Daniël , Glanc Matouš , De Rybel Bert
Published: January 2023

Transcriptional networks are crucial to integrate various internal and external signals into optimal responses during plant growth and development. In Arabidopsis thaliana, primary root vasculature patterning and proliferation are controlled by a network centred around the basic Helix-Loop-Helix transcription factor complex, formed by TARGET OF MONOPTEROS 5 (TMO5) and LONESOME HIGHWAY (LHW), which control cell proliferation and division orientation by modulating the cytokinin response and other downstream factors. Despite recent progress, many aspects of the TMO5/LHW pathway are not fully understood. In particular, the upstream regulators of TMO5/LHW activity remain unknown. Here, using a forward genetics approach to identify new factors of the TMO5/LHW pathway, we discovered a novel function of the MYB-type transcription factor, MYB12. MYB12 physically interacts with TMO5 and dampens the TMO5/LHW-mediated induction of direct target gene expression, as well as the periclinal/radial cell divisions. The expression of MYB12 is activated by the cytokinin response, downstream of TMO5/LHW, resulting in a novel MYB12-mediated negative feedback loop that restricts TMO5/LHW activity, to ensure optimal cell proliferation rates during root vascular development.
Shoot-root interaction in control of camalexin exudation in Arabidopsis
Authors: Koprivova Anna , Schwier Melina , Volz Vanessa , Kopriva Stanislav
Published: January 2023

Plants exude secondary metabolites from the roots to shape the composition and function of their microbiome. Many of these compounds are known for their anti-microbial activities and play a role in plant immunity, such as the indole-derived phytoalexin camalexin. Here we studied the dynamics of camalexin synthesis and exudation upon interaction of Arabidopsis thaliana with the plant growth promoting bacteria Pseudomonas sp. CH267 or the bacterial pathogen Burkholderia glumae PG1. We show that while camalexin accumulation and exudation is more rapidly but transiently induced upon interaction with the growth promoting bacteria, the pathogen induces higher and more stable camalexin levels. By combination of experiments with cut shoots and roots, and grafting of wild-type plants with mutants in camalexin synthesis, we showed that while camalexin can be produced and released by both organs, in intact plants exuded camalexin originates in the shoots. We also reveal that the root specific CYP71A27 protein specifically affects the outcome of the interaction with the plant growth promoting bacteria and that its transcript levels are controlled by a shoot derived signal. In conclusion, camalexin synthesis seems to be controlled on a whole plant level and is coordinated between the shoots and the roots.
Exploring the antimicrobial effects of a phenolic-rich extract from jabuticaba depulping waste against enterotoxigenic Escherichia coli
Authors: Lima Maiara da Costa , Magnani Marciane , Lima Marcos dos Santos , Macarisin Dumitru , de Sousa Cristina Paiva , Dubreuil J Daniel , de Souza Evandro Leite
Published: January 2023

This study evaluated the effects of a phenolic-rich extract from jabuticaba [Myrciaria jaboticaba (Vell.) Berg] depulping waste (PEJ) on the survival, antibiotic susceptibility, virulence, and cellular functions of various enterotoxigenic Escherichia coli (ETEC) strains.

The minimum inhibitory concentration of PEJ against the five tested ETEC strains was 125 mg mL−1. PEJ at 125 and 250 mg mL−1 caused reductions in viable cell counts of ≥ 3 and ≥ 5 log CFU mL−1 in ETEC over 24 h, respectively. PEJ at subinhibitory concentrations (31.25 and 62.5 mg mL−1) reduced the viable cell counts of ETEC when exposed to in vitro gastrointestinal conditions, besides decreasing the biofilm formation, cell surface hydrophobicity, mucin adhesion, and swimming and swarming motility. PEJ (31.25 and 62.5 mg mL−1) increased the susceptibility of the tested ETEC strains to various clinically relevant antibiotics. The exposure to PEJ (62.5 and 125 mg mL−1) impaired the membrane permeability and enzymatic and efflux pump activities in ETEC cells. PEJ effectively reduces survival, increases antibiotic susceptibility, and attenuates virulence in ETEC. These effects could be linked to a PEJ multi-target action disturbing various cellular functions in ETEC cells. PEJ could be a candidate for developing innovative solutions to prevent and treat ETEC infections.
Towards 21-cm intensity mapping at z = 2.28 with uGMRT using the tapered gridded estimator – II. Cross-polarization power spectrum
Authors: Elahi Kh Md Asif , Bharadwaj Somnath , Ghosh Abhik , Pal Srijita , Ali Sk Saiyad , Choudhuri Samir , Chakraborty Arnab , Datta Abhirup , Roy Nirupam , Choudhury Madhurima , Dutta Prasun
Published: January 2023

Neutral hydrogen (H i) 21-cm intensity mapping (IM) offers an efficient technique for mapping the large-scale structures in the Universe. We introduce the ‘Cross’ Tapered Gridded Estimator (Cross TGE), which cross-correlates two cross-polarizations (RR and LL) to estimate the multifrequency angular power spectrum Cℓ(Δν). We expect this to mitigate several effects like noise bias, calibration errors, etc., which affect the ‘Total’ TGE that combines the two polarizations. Here, we apply the Cross TGE on $24.4 \text{-} \rm {MHz}$-bandwidth uGMRT (upgraded Giant Metrewave Radio Telescope) Band 3 data centred at $432.8 \, \rm {MHz}$ aiming H i IM at z = 2.28. The measured Cℓ(Δν) is modelled to yield maximum likelihood estimates of the foregrounds and the spherical power spectrum P(k) in several k bins. Considering the mean squared brightness temperature fluctuations, we report a 2σ upper limit $\Delta _{\mathrm{ UL}}^{2}(k) \le (58.67)^{2} \, {\rm mK}^{2}$ at $k=0.804 \, {\rm Mpc}^{-1}$, which is a factor of 5.2 improvement on our previous estimate based on the Total TGE. Assuming that the H i traces the underlying matter distribution, we have modelled Cℓ(Δν) to simultaneously estimate the foregrounds and $[\Omega _{\rm{ H}\, {\small {I}}} b_{\rm{ H}\, {\small {I}}}]$, where $\Omega _{\rm{ H}\, {\small {I}}}$ and $b_{\rm{ H}\, {\small {I}}}$ are the H i density and linear bias parameters, respectively. We obtain a best-fitting value of $[\Omega _{\rm{ H}\, {\small {I}}}b_{\rm{ H}\, {\small {I}}}]^2 = 7.51\times 10^{-4} \pm 1.47\times 10^{-3}$ that is consistent with noise. Although the 2σ upper limit $[\Omega _{\rm{ H}\, {\small {I}}}b_{\rm{ H}\, {\small {I}}}]_{\mathrm{ UL}} \le 0.061$ is ∼50 times larger than the expected value, this is a considerable improvement over earlier works at this redshift.
BD +30°549: a young helium-weak silicon star in the NGC 1333 star-forming region
Authors: Potravnov I , Mashonkina L , Ryabchikova T
Published: January 2023

We present results of the spectroscopic study of the chemically peculiar star BD +30°549, which is a bona fide member of the young NGC 1333 star-forming region. We found that the star possesses negligible rotation and a helium-weak spectroscopic pattern with strongly enhanced Si ii and Si iii lines. The fundamental parameters of the star, Teff = 13 100 K and log (L/L⊙) = 2.1, indicate that its age is about 2.7 Myr and that its position on the Hertzsprung–Russell diagram is at the end of the pre-main-sequence evolutionary track, close to the zero-age main sequence. Abundance analysis reveals the modest deficit of almost all elements, with the exception of Si , Fe , Ca  and P,  which are overabundant. We performed non-local thermodynamic equilibrium (non-LTE) calculations for Si ii/Si iii, Mg ii and Ca ii in order to check the influence of departures from LTE on line formation. Non-LTE calculations lead to much better reproduction of individual silicon line profiles, but do not completely remove the abundance discrepancy between Si ii and Si iii lines. We also investigate the effects of possible chemical stratification in BD +30°549. We suspect that the ‘Si ii/Si iii anomaly’ observed in the BD +30°549 spectrum arises under the combined action of the vertical and horizontal abundance gradients and non-LTE effects. We suppose that the evolutionary status and phenomena observed in BD +30°549 indicate that conditions favourable for the selective diffusion and formation of the surface chemical composition peculiarities (slow rotation and stabilization of the atmosphere) could already be built up at the pre-main-sequence phase.
Depletion of the RNA-binding protein PURA triggers changes in posttranscriptional gene regulation and loss of P-bodies
Authors: Molitor Lena , Klostermann Melina , Bacher Sabrina , Merl-Pham Juliane , Spranger Nadine , Burczyk Sandra , Ketteler Carolin , Rusha Ejona , Tews Daniel , Pertek Anna , Proske Marcel , Busch Anke , Reschke Sarah , Feederle Regina , Hauck Stefanie M , Blum Helmut , Drukker Micha , Fischer-Posovszky Pamela , König Julian , Zarnack Kathi , Niessing Dierk
Published: January 2023

The RNA-binding protein PURA has been implicated in the rare, monogenetic, neurodevelopmental disorder PURA Syndrome. PURA binds both DNA and RNA and has been associated with various cellular functions. Only little is known about its main cellular roles and the molecular pathways affected upon PURA depletion. Here, we show that PURA is predominantly located in the cytoplasm, where it binds to thousands of mRNAs. Many of these transcripts change abundance in response to PURA depletion. The encoded proteins suggest a role for PURA in immune responses, mitochondrial function, autophagy and processing (P)-body activity. Intriguingly, reduced PURA levels decrease the expression of the integral P-body components LSM14A and DDX6 and strongly affect P-body formation in human cells. Furthermore, PURA knockdown results in stabilization of P-body-enriched transcripts, whereas other mRNAs are not affected. Hence, reduced PURA levels, as reported in patients with PURA Syndrome, influence the formation and composition of this phase-separated RNA processing machinery. Our study proposes PURA Syndrome as a new model to study the tight connection between P-body-associated RNA regulation and neurodevelopmental disorders.
8-Oxoguanine targeted by 8-oxoguanine DNA glycosylase 1 (OGG1) is central to fibrogenic gene activation upon lung injury
Authors: Pan Lang , Hao Wenjing , Xue Yaoyao , Wang Ke , Zheng Xu , Luo Jixian , Ba Xueqing , Xiang Yang , Qin Xiaoqun , Bergwik Jesper , Tanner Lloyd , Egesten Arne , Brasier Allan R , Boldogh Istvan
Published: January 2023

Reactive oxygen species (ROS) are implicated in epithelial cell-state transition and deposition of extracellular matrix upon airway injury. Of the many cellular targets of ROS, oxidative DNA modification is a major driving signal. However, the role of oxidative DNA damage in modulation profibrotic processes has not been fully delineated. Herein, we report that oxidative DNA base lesions, 8-oxoG, complexed with 8-oxoguanine DNA glycosylase 1 (OGG1) functions as a pioneer factor, contributing to transcriptional reprogramming within airway epithelial cells. We show that TGFβ1-induced ROS increased 8-oxoG levels in open chromatin, dynamically reconfigure the chromatin state. OGG1 complexed with 8-oxoG recruits transcription factors, including phosphorylated SMAD3, to pro-fibrotic gene promoters thereby facilitating gene activation. Moreover, 8-oxoG levels are elevated in lungs of mice subjected to TGFβ1-induced injury. Pharmacologic targeting of OGG1 with the selective small molecule inhibitor of 8-oxoG binding, TH5487, abrogates fibrotic gene expression and remodeling in this model. Collectively, our study implicates that 8-oxoG substrate-specific binding by OGG1 is a central modulator of transcriptional regulation in response to tissue repair.
Annotation of uORFs in the OMIM genes allows to reveal pathogenic variants in 5′UTRs
Authors: Filatova Alexandra , Reveguk Ivan , Piatkova Maria , Bessonova Daria , Kuziakova Olga , Demakova Victoria , Romanishin Alexander , Fishman Veniamin , Imanmalik Yerzhan , Chekanov Nikolay , Skitchenko Rostislav , Barbitoff Yury , Kardymon Olga , Skoblov Mikhail
Published: January 2023

An increasing number of studies emphasize the role of non-coding variants in the development of hereditary diseases. However, the interpretation of such variants in clinical genetic testing still remains a critical challenge due to poor knowledge of their pathogenicity mechanisms. It was previously shown that variants in 5′-untranslated regions (5′UTRs) can lead to hereditary diseases due to disruption of upstream open reading frames (uORFs). Here, we performed a manual annotation of upstream translation initiation sites (TISs) in human disease-associated genes from the OMIM database and revealed ∼4.7 thousand of TISs related to uORFs. We compared our TISs with the previous studies and provided a list of ‘high confidence’ uORFs. Using a luciferase assay, we experimentally validated the translation of uORFs in the ETFDH, PAX9, MAST1, HTT, TTN,GLI2 and COL2A1 genes, as well as existence of N-terminal CDS extension in the ZIC2 gene. Besides, we created a tool to annotate the effects of genetic variants located in uORFs. We revealed the variants from the HGMD and ClinVar databases that disrupt uORFs and thereby could lead to Mendelian disorders. We also showed that the distribution of uORFs-affecting variants differs between pathogenic and population variants. Finally, drawing on manually curated data, we developed a machine-learning algorithm that allows us to predict the TISs in other human genes.
Trans-cisisomerization kinetics of cyanine dyes reports on the folding states of exogeneous RNA G-quadruplexes in live cells
Authors: Kitamura Akira , Tornmalm Johan , Demirbay Baris , Piguet Joachim , Kinjo Masataka , Widengren Jerker
Published: January 2023

Guanine (G)-rich nucleic acids are prone to assemble into four-stranded structures, so-called G-quadruplexes. Abnormal GGGGCC repeat elongations, and in particular their folding states, are associated with amyotrophic lateral sclerosis and frontotemporal dementia. Due to methodological constraints however, most studies of G quadruplex structures are restricted to in vitro conditions. Evidence of how GGGGCC repeats form into G-quadruplexes in vivo is sparse. We devised a readout strategy, exploiting the sensitivity of trans-cis isomerization of cyanine dyes to local viscosity and sterical constraints. Thereby, folding states of cyanine-labeled RNA, and in particular G-quadruplexes, can be identified in a sensitive manner. The isomerization kinetics, monitored via fluorescence blinking generated upon transitions between a fluorescent trans isomer and a non-fluorescent cis isomer, was first characterized for RNA with GGGGCC repeats in aqueous solution using fluorescence correlation spectroscopy and transient state (TRAST) monitoring. With TRAST, monitoring the isomerization kinetics from how the average fluorescence intensity varies with laser excitation modulation characteristics, we could then detect folding states of fluorescently tagged RNA introduced into live cells.
Dynamic states of eIF6 and SDS variants modulate interactions with uL14 of the 60S ribosomal subunit
Authors: Elliff Jonah , Biswas Aparna , Roshan Poonam , Kuppa Sahiti , Patterson Angela , Mattice Jenna , Chinnaraj Mathivanan , Burd Ryan , Walker Sarah E , Pozzi Nicola , Antony Edwin , Bothner Brian , Origanti Sofia
Published: January 2023

Assembly of ribosomal subunits into active ribosomal complexes is integral to protein synthesis. Release of eIF6 from the 60S ribosomal subunit primes 60S to associate with the 40S subunit and engage in translation. The dynamics of eIF6 interaction with the uL14 (RPL23) interface of 60S and its perturbation by somatic mutations acquired in Shwachman–Diamond Syndrome (SDS) is yet to be clearly understood. Here, by using a modified strategy to obtain high yields of recombinant human eIF6 we have uncovered the critical interface entailing eight key residues in the C-tail of uL14 that is essential for physical interactions between 60S and eIF6. Disruption of the complementary binding interface by conformational changes in eIF6 disease variants provide a mechanism for weakened interactions of variants with the 60S. Hydrogen–deuterium exchange mass spectrometry (HDX-MS) analyses uncovered dynamic configurational rearrangements in eIF6 induced by binding to uL14 and exposed an allosteric interface regulated by the C-tail of eIF6. Disrupting key residues in the eIF6–60S binding interface markedly limits proliferation of cancer cells, which highlights the significance of therapeutically targeting this interface. Establishing these key interfaces thus provide a therapeutic framework for targeting eIF6 in cancers and SDS.
CRISPR-associated type V proteins as a tool for controlling mRNA stability inS. cerevisiaesynthetic gene circuits
Authors: Yu Lifang , Marchisio Mario Andrea
Published: January 2023

Type V-A CRISPR-(d)Cas system has been used in multiplex genome editing and transcription regulation in both eukaryotes and prokaryotes. However, mRNA degradation through the endonuclease activity of Cas12a has never been studied. In this work, we present an efficient and powerful tool to induce mRNA degradation in the yeast Saccharomyces cerevisiae via the catalytic activity of (d)Cas12a on pre-crRNA structure. Our results point out that dFnCas12a, (d)LbCas12a, denAsCas12a and two variants (which carry either NLSs or NESs) perform significant mRNA degradation upon insertion of pre-crRNA fragments into the 5′- or 3′ UTR of the target mRNA. The tool worked well with two more Cas12 proteins—(d)MbCas12a and Casϕ2—whereas failed by using type VI LwaCas13a, which further highlights the great potential of type V-A Cas proteins in yeast. We applied our tool to the construction of Boolean NOT, NAND, and IMPLY gates, whose logic operations are fully based on the control of the degradation of the mRNA encoding for a reporter protein. Compared to other methods for the regulation of mRNA stability in yeast synthetic gene circuits (such as RNAi and riboswitches/ribozymes), our system is far easier to engineer and ensure very high performance.
Systemic structural analysis of alterations reveals a common structural basis of driver mutations in cancer
Authors: Meirson Tomer , Bomze David , Schueler-Furman Ora , Stemmer Salomon M , Markel Gal
Published: January 2023

A major effort in cancer research is to organize the complexities of the disease into fundamental traits. Despite conceptual progress in the last decades and the synthesis of hallmark features, no organizing principles governing cancer beyond cellular features exist. We analyzed experimentally determined structures harboring the most significant and prevalent driver missense mutations in human cancer, covering 73% (n = 168178) of the Catalog of Somatic Mutation in Cancer tumor samples (COSMIC). The results reveal that a single structural element—κ-helix (polyproline II helix)—lies at the core of driver point mutations, with significant enrichment in all major anatomical sites, suggesting that a small number of molecular traits are shared by most and perhaps all types of cancer. Thus, we uncovered the lowest possible level of organization at which carcinogenesis takes place at the protein level. This framework provides an initial scheme for a mechanistic understanding underlying the development of tumors and pinpoints key vulnerabilities.
EEPD1 promotes repair of oxidatively-stressed replication forks
Authors: Jaiswal Aruna S , Kim Hyun-Suk , Schärer Orlando D , Sharma Neelam , Williamson Elizabeth A , Srinivasan Gayathri , Phillips Linda , Kong Kimi , Arya Shailee , Misra Anurag , Dutta Arijit , Gupta Yogesh , Walter Christi A , Burma Sandeep , Narayan Satya , Sung Patrick , Nickoloff Jac A , Hromas Robert
Published: January 2023

Unrepaired oxidatively-stressed replication forks can lead to chromosomal instability and neoplastic transformation or cell death. To meet these challenges cells have evolved a robust mechanism to repair oxidative genomic DNA damage through the base excision repair (BER) pathway, but less is known about repair of oxidative damage at replication forks. We found that depletion or genetic deletion of EEPD1 decreases clonogenic cell survival after oxidative DNA damage. We demonstrate that EEPD1 is recruited to replication forks stressed by oxidative damage induced by H2O2 and that EEPD1 promotes replication fork repair and restart and decreases chromosomal abnormalities after such damage. EEPD1 binds to abasic DNA structures and promotes resolution of genomic abasic sites after oxidative stress. We further observed that restoration of expression of EEPD1 via expression vector transfection restores cell survival and suppresses chromosomal abnormalities induced by oxidative stress in EEPD1-depleted cells. Consistent with this, we found that EEPD1 preserves replication fork integrity by preventing oxidatively-stressed unrepaired fork fusion, thereby decreasing chromosome instability and mitotic abnormalities. Our results indicate a novel role for EEPD1 in replication fork preservation and maintenance of chromosomal stability during oxidative stress.
Longitudinal evaluation of serum microRNAs as biomarkers for neuroblastoma burden and therapeutic p53 reactivation
Authors: Van Goethem Alan , Deleu Jill , Yigit Nurten , Everaert Celine , Moreno-Smith Myrthala , Vasudevan Sanjeev A , Zeka Fjoralba , Demuynck Fleur , Barbieri Eveline , Speleman Frank , Mestdagh Pieter , Shohet Jason , Vandesompele Jo , Van Maerken Tom
Published: January 2023

Accurate assessment of treatment response and residual disease is indispensable for the evaluation of cancer treatment efficacy. However, performing tissue biopsies for longitudinal follow-up poses a major challenge in the management of solid tumours like neuroblastoma. In the present study, we evaluated whether circulating miRNAs are suitable to monitor neuroblastoma tumour burden and whether treatment-induced changes of miRNA abundance in the tumour are detectable in serum. We performed small RNA sequencing on longitudinally collected serum samples from mice carrying orthotopic neuroblastoma xenografts that were exposed to treatment with idasanutlin or temsirolimus. We identified 57 serum miRNAs to be differentially expressed upon xenograft tumour manifestation, out of which 21 were also found specifically expressed in the serum of human high-risk neuroblastoma patients. The murine serum levels of these 57 miRNAs correlated with tumour tissue expression and tumour volume, suggesting potential utility for monitoring tumour burden. In addition, we describe serum miRNAs that dynamically respond to p53 activation following treatment of engrafted mice with idasanutlin. We identified idasanutlin-induced serum miRNA expression changes upon one day and 11 days of treatment. By limiting to miRNAs with a tumour-related induction, we put forward hsa-miR-34a-5p as a potential pharmacodynamic biomarker of p53 activation in serum.
Effectiveness of cold HD for the prevention of HD hypotension and mortality in the general HD population
Authors: Zoccali Carmine , Tripepi Giovanni , Neri Luca , Savoia Matteo , Baró Salvador Maria Eva , Ponce Pedro , Hymes Jeffrey , Maddux Frank , Mallamaci Francesca , Stuard Stefano
Published: January 2023

Background

Cold hemodialysis (HD) prevented intradialysis hypotension (IDH) in small, short-term, randomized trials in selected patients with IDH. Whether this treatments prevents IDH and mortality in the HD population at large is unknown.

Methods

We investigated the relationship between dialysate temperature and the risk of IDH, i.e. nadir blood pressure <90 mmHg (generalized estimating equation model) and all-cause mortality (Cox's regression) in an incident cohort of HD patients (n = 8071). To control for confounding by bias by indication and other factors we applied instrumental variables adjusting for case mix at facility level.

Results

Twenty-seven percent of patients in the study cohort were systematically treated with a dialysate temperature ≤35.5°C. Over a median follow-up of 13.6 months (interquartile range 5.2–26.1 months), a 0.5°C reduction of the dialysate temperature was associated with a small (–2.4%) reduction of the risk of IDH [odds ratio (OR) 0.976, 95% confidence interval (CI) 0.957–0.995, P = .013]. In case-mix, facility-level adjusted analysis, the association became much stronger (OR 0.67, 95% CI 0.63–0.72, risk reduction = 33%, P < .001). In contrast, colder dialysate temperature had no effect on mortality both in the unadjusted [hazard ratio (HR) (0.5°C decrease) 1.074, 95% CI 0.972–1.187, P = .16] and case-mix-adjusted analysis at facility level (HR 1.01, 95% CI 0.88–1.16, P = .84). Similar results were registered in additional analyses by instrumental variables applying the median dialysate temperature or the facility percentage of patients prescribed a dialysate temperature <36°C. Further analyses restricted to patients with recurrent IDH fully confirmed these findings.

Conclusions

Cold HD was associated with IDH in the HD population but had no association with all-cause mortality.
Kidney outcome after mild to moderate COVID-19
Authors: Schmidt-Lauber Christian , Hänzelmann Sonja , Schunk Stefan , Petersen Elina L , Alabdo Ammar , Lindenmeyer Maja , Hausmann Fabian , Kuta Piotr , Renné Thomas , Twerenbold Raphael , Zeller Tanja , Blankenberg Stefan , Fliser Danilo , Huber Tobias B
Published: January 2023

Background

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a remarkable kidney tropism. While kidney effects are common in severe coronavirus disease 2019 (COVID-19), data on non-severe courses are limited. Here we provide a multilevel analysis of kidney outcomes after non-severe COVID-19 to test for eventual kidney sequela.

Methods

This cross-sectional study investigates individuals after COVID-19 and matched controls recruited from the Hamburg City Health Study (HCHS) and its COVID-19 program. The HCHS is a prospective population-based cohort study within the city of Hamburg, Germany. During the COVID-19 pandemic the study additionally recruited subjects after polymerase chain reaction–confirmed SARS-CoV-2 infections. Matching was performed by age, sex and education. Main outcomes were estimated glomerular filtration rate (eGFR), albuminuria, Dickkopf3, haematuria and pyuria.

Results

A total of 443 subjects in a median of 9 months after non-severe COVID-19 were compared with 1328 non-COVID-19 subjects. The mean eGFR was mildly lower in post-COVID-19 than non-COVID-19 subjects, even after adjusting for known risk factors {β = −1.84 [95% confidence interval (CI) −3.16 to −0.52]}. However, chronic kidney disease [odds ratio (OR) 0.90 (95% CI 0.48–1.66)] or severely increased albuminuria [OR 0.76 (95% CI 0.49–1.09)] equally occurred in post-COVID-19 and non-COVID-19 subjects. Haematuria, pyuria and proteinuria were also similar between the two cohorts, suggesting no ongoing kidney injury after non-severe COVID-19. Further, Dickkopf3 was not increased in the post-COVID-19 cohort, indicating no systematic risk for ongoing GFR decline [β = −72.19 (95% CI −130.0 to −14.4)].

Conclusion

While mean eGFR was slightly lower in subjects after non-severe COVID-19, there was no evidence for ongoing or progressive kidney sequela.
The rationale, design and baseline data of FLOW, a kidney outcomes trial with once-weekly semaglutide in people with type 2 diabetes and chronic kidney disease
Authors: Rossing Peter , Baeres Florian M M , Bakris George , Bosch-Traberg Heidrun , Gislum Mette , Gough Stephen C L , Idorn Thomas , Lawson Jack , Mahaffey Kenneth W , Mann Johannes F E , Mersebach Henriette , Perkovic Vlado , Tuttle Katherine , Pratley Richard
Published: January 2023

Background

Chronic kidney disease (CKD) is a common complication of type 2 diabetes (T2D). Glucagon-like peptide-1 receptor agonists (GLP-1RAs) improve glycaemic control and lower body weight in people with T2D, and some reduce the risk of cardiovascular (CV) events in those with high CV risk. GLP-1RAs might also have kidney-protective effects. We report the design and baseline data for FLOW (NCT03819153), a trial investigating the effects of semaglutide, a once-weekly (OW) GLP-1RA, on kidney outcomes in participants with CKD and T2D.

Methods

FLOW is a randomised, double-blind, parallel-group, multinational, phase 3b trial. Participants with T2D, estimated glomerular filtration rate (eGFR) ≥50‒≤75 ml/min/1.73 m2 and urine albumin:creatinine ratio (UACR) >300‒<5000 mg/g or eGFR ≥25‒<50 ml/min/1.73 m2 and UACR >100‒<5000 mg/g were randomised 1:1 to OW semaglutide 1.0 mg or matched placebo, with renin–angiotensin–aldosterone system blockade (unless not tolerated/contraindicated). The composite primary endpoint is time to first kidney failure (persistent eGFR <15 ml/min/1.73 m2 or initiation of chronic kidney replacement therapy), persistent ≥50% reduction in eGFR or death from kidney or CV causes.

Results

Enrolled participants (N = 3534) had a baseline mean age of 66.6 years [standard deviation (SD) 9.0], haemoglobin A1c of 7.8% (SD 1.3), diabetes duration of 17.4 years (SD 9.3), eGFR of 47.0 ml/min/1.73 m2 (SD 15.2) and median UACR of 568 mg/g (range 2‒11 852). According to Kidney Disease: Improving Global Outcomes guidelines categorisation, 68.2% were at very high risk for CKD progression.

Conclusion

FLOW will evaluate the effect of semaglutide on kidney outcomes in participants with CKD and T2D, and is expected to be completed in late 2024.
Safety
Authors: Barling Julian
Published: January 2023

Although not at the forefront of the public imagination, workplace injuries and fatalities remain a daily reality in many workplaces across the world, a concern made worse with more than three thousand health care workers who died from COVID-19 during the first year of the pandemic. There is very little research to guide a discussion on the benefits that might accrue when workplace safety is assured. In sharp contrast, we know that workplace attitudes and employee well-being suffer following safety infractions. Special features of this chapter include a discussion of the extensive financial costs borne by injured workers, their families, and their organizations following workplace injuries and fatalities; and a consideration the disproportionate safety risks faced by foreign correspondents and young workers.
Toward productive, healthy, and safe workplaces
Authors: Barling Julian
Published: January 2023

Fulfilling people’s needs for high-quality leadership, autonomy, belonging, fairness, growth and development, meaningful work, and safety are key to providing productive, healthy, and safe work. As we emerge from the COVID-19 pandemic, the breadth and pace of social change already evident will likely intensify. Internal pressures within organizations for innovations involving remote or hybrid work, as well as the four-day workweek, are already upon us. Social forces promoting gender equity, racial equality, and indigeneity will continue to create tremendous pressure on organizations to adapt, and at the same time organizations will need to provide decisive leadership in responding to the climate crisis. All these internal and external forces will shape the nature of work and organizations in the future. Successful organizations in the future will be those which choose to “build back fairer,” and develop productive, healthy, and safe workplaces.
Questions
Authors: Rufai Sohaib R.
Published: January 2023

This paper covers the full range of core subjects tested in the FRCOphth Part 1 examination: optics, anatomy, physiology, pathology, pharmacology, genetics, investigations, and miscellaneous (biostatistics and evidence-based medicine). As well as ophthalmic subjects, this paper covers general physiology, general pathology, microbiology, biochemistry, and immunology. Several high-yield topics are covered. An anatomical diagram displays the contents of the cavernous sinus. The normal electrocardiogram is explained in a helpful schematic. Histopathological slides are included for temporal arteritis and basal cell carcinoma. Anterior segment optical coherence tomography images of the cornea and iridocorneal angle are included, displaying key anatomical landmarks.
Questions
Authors: Rufai Sohaib R.
Published: January 2023

This paper covers the full range of core subjects tested in the FRCOphth Part 1 examination: optics, anatomy, physiology, pathology, pharmacology, genetics, investigations, and miscellaneous (biostatistics and evidence-based medicine). As well as ophthalmic subjects, this paper covers general physiology, general pathology, microbiology, biochemistry, and immunology. Several high-yield topics are covered. Basic iris anatomy is explained using an external eye photograph. Papilloedema is demonstrated on optical coherence tomography imaging of the optic nerve head. An ultra-widefield scanning laser ophthalmoscopy image of the retina is included, with key anatomical landmarks. T1- and T2-weighted magnetic resonance imaging is explained in a helpful comparative figure.
Concluding Reflections
Authors: Cappelletti Marco
Published: January 2023

Part 4 of the book provides some concluding reflections. First, it emphasizes that while the same argument may be used to justify the imposition of strict liability in a plurality of contexts and a particular context may attract a multitude of arguments, there is no one-to-one relation between any particular context of strict liability and any particular substantive justification. Secondly, Part 4 provides some reflections on the patterns of reasoning in strict liability, highlighting the wide variety of patterns identified in the book, the main types of patterns in relation to the various arguments discussed as well as the problems of clarity that may affect some of them (and, particularly, juxtapositions of arguments). Thirdly, Part 4 provides an overall picture of each legal system’s reasoning by pulling together its constituent parts (the arguments) and by paying attention to the values and goals to which legal actors are committed. This allows us to appreciate and contrast the distinct commitments which shape the role and significance of legal arguments across the four laws and to enhance the understanding of each system’s tort culture. Finally, Part 4 provides some final critical and comparative thoughts on the complexity of legal reasoning in strict liability, emphasizing that there is a plethora of different understandings of the justificatory basis of strict liability within and across legal systems, and that the differences in the legal reasoning on strict liability across the four systems does not trace the distinction between the common law and the civil law tradition.
The ‘Blasted Heath’ and Agrilogistics in Macbeth
Authors: Borlik Todd Andrew
Published: January 2023

The first chapter surveys Macbeth’s ‘blasted heath’ as a battleground between the forces of fertility and sterility to reveal how the play adjudicates disputes over the environmental management of this terrain in Shakespeare’s day. Agrarian improvers in Jacobean Britain wished to convert heaths to enclosed farmland and therefore took a dim view of this landscape as the sinister abode of witches and fortune-telling vagrants. Yet the Scottish play also reflects the Scottish king’s fondness for heathlands as valuable hunting grounds, whose wildfowl needed protection from farmers and poachers. In promoting selective conservation of some avian species such as doves (with whom Duncan, Malcolm, and Macduff are associated) and the persecution of others like the kite (identified with Macbeth), the tragedy espouses an inter-generational but shallow ecology, in contrast to the childless Macbeths, who renounce ‘reproductive futurity’ whilst bestowing a perverse glamour on inhuman wildness.
Caliban and the Fen-Demons of Lincolnshire
Authors: Borlik Todd Andrew
Published: January 2023

Chapter 6 mires The Tempest in the English fens and establishes that the play generates dramatic conflict out of the furore incited by campaigns to drain them. Shakespeare’s romance glances at Ireland and the Americas but Prospero’s magical dominion over his island also mirrors the domestic colonization of England’s wetlands. This claim is buoyed by a number of sources overlooked due to the constraints of periodization and the lacunae of the print archive: medieval legends of a fen-dwelling hermit, a lost play, a manuscript ballad from a fish’s point-of-view, and oral legends of a fen-spirit who acts as a kind of Lorax for the wetlands. Invoking the fens to curse the invading Prospero, Caliban, too, speaks for the fens albeit more loudly for the fen-folk, tapping into their outrage over the confiscation of their aquatic commons and echoing doubts about the feasibility and ethics of controlling nature.
Grace in the Ordinary
Authors: Prevot Andrew
Published: January 2023

This chapter clarifies the contributions of one of the most significant Catholic theological proponents of the mysticism of ordinary life. It discusses Rahner’s understanding of mysticism in relation to his account of the experience of uncreated grace and his retrieval of mystical sources from the Bible and early, medieval, and modern Christianity. It demonstrates that although he draws on scholastic and idealist forms of philosophy to universalize mystical theology, these do not undermine the Christian theological status of his work. It explains different ways that he parses the meaning of ordinary life, while showing his preference for an Ignatian style of ascetical indiferencia. It raises questions about his approach to gender, while noting possibilities for feminist reception. Finally, it interprets his lifelong practice of mystical prayer.
The Divine in Between
Authors: Prevot Andrew
Published: January 2023

This chapter explores the mysticism of ordinary life in the context of U.S. Latino/a theology and philosophy. It features the Chicana theorist Anzaldúa and the Cuban American, mujerista theologian Isasi-Díaz and puts them into dialogue with other scholars who examine how intersecting gender, racial, and socioeconomic aspects of mestizo/a cultures shape the meaning of divine union and everyday life. It draws on Anzaldúa and Isasi-Díaz to develop an interpretation of the mystical significance of cultural mixture (mestizaje) that overcomes the problems in the Mexican philosopher José Vasconcellos’s early twentieth-century account. It emphasizes the ways Anzaldúa and Isasi-Díaz find the empowering presence of the divine in quotidian struggles for justice. It discusses the feminist reception of Juan Diego’s mystical encounter with Our Lady of Guadalupe. It meditates on Latino/a communities’ participation in Jesus’s suffering and death, particularly through Via Crucis celebrations. It argues that these experiences ought to inform contemporary Christian mystical theology.
Divine Darkness Revisited
Authors: Prevot Andrew
Published: January 2023

This chapter turns Christian mystical theology toward the empowering experiences of divine union in Black women’s quotidian lives. It features the womanist novelist and theorist Alice Walker and the Catholic womanist theologian M. Shawn Copeland and puts them into dialogue with other scholars who reflect on intersecting racial, gender, and socioeconomic conditions within African American mystical traditions. It engages with Black studies discourses that offer mystical interpretations of Black “nothingness.” It argues that the mystical conversion stories of nineteenth-century Black female preachers such as Maria Stewart, Zilpha Elaw, Jarena Lee, Sojourner Truth, Rebecca Cox Jackson, and Henriette Delille ought to be included in the Western mystical canon. It demonstrates that mysticism—the union of the divine and the flesh—is a central theme of womanist literature and theology. It highlights the distinctive womanist emphasis on mystical experiences of the body, particularly involving suffering, joy, and freedom. It concludes that the motif of divine darkness in the Christian mystical tradition ought to be rethought in relation to such experiences.
Protecting Workers’ Equal Rights during Crisis and Recovery
Authors: Sprague Aleta , Raub Amy , Heymann Jody
Published: January 2023

This chapter analyses the scope, potential, and early impacts of constitutional protections for equal rights, social protection, and minimum labour standards in safeguarding workers’ health and livelihoods during Covid-19. Across countries, both the pandemic itself and many policies enacted in response (eg economic shutdowns) disproportionately affected marginalized workers due to underlying disparities in terms and conditions of work, social protection coverage, and living conditions. While the right to health has clear relevance during a pandemic, protections for equality and fundamental economic rights also matter to workers’ overall well-being, particularly when policy responses focus narrowly on preventing disease spread through closures without adequately addressing social determinants of health like workplace safety and income. This chapter: (1) draws on a unique global dataset to analyse the extent to which constitutions protect equal rights, decent work, and social insurance in 193 countries; (2) reviews early examples of how these constitutional protections provided tools to support both health and economic needs and uphold foundational equality amidst a crisis; and (3) identifies gaps likely to leave workers vulnerable if unaddressed. It finds that explicit constitutional protections for almost all aspects of equal rights, decent work, and social insurance have become more common over time; moreover, courts from wide-ranging countries have cited these protections in decisions addressing workers’ rights and households’ material needs amidst Covid-19. Nevertheless, most countries lack constitutional provisions specifically addressing safe working conditions or income protection during illness and unemployment—areas that matter to equality both during pandemics and more typical years.
Responding to Exponential Inequalities in AustraliaBeyond the Limits of Equality and Discrimination Law
Authors: Gaze Beth
Published: January 2023

This chapter discusses the Covid-19 pandemic in Australia and the effects on equity of the pandemic and the government response. Vulnerable groups such as the elderly, and low paid, precarious workers and the people they cared for were the most affected and exposed to risk. The pandemic’s impact on already disadvantaged groups was partially ameliorated by the government’s public health response, although selective government responses left many vulnerable groups inadequately protected. Public health is not adequately dealt with in the equality and discrimination laws. The chapter argues for dual reforms: first to fill the gaps in Australia’s anti-discrimination laws, and secondly, more broadly, to adopt an approach that recognizes universal vulnerability to social, economic, and health risks, where government’s role includes providing basic protection for everyone regardless of protected attributes.
Equal Access to Vaccines
Authors: O’Regan Catherine
Published: January 2023

The Covid-19 pandemic has caused millions of deaths since 2020. The virus’ capacity to produce variants that evade immunity has meant that the best way to prevent further deaths is through ensuring that as many people as possible worldwide are vaccinated. Production of vaccines is reaching the point where it could meet global demand, if vaccines were equitably distributed. So far, however, vaccination rates have been highest in the developed world, and people in developing countries, especially Africa, remain woefully under-vaccinated. This article considers whether international human rights law can contribute to ensuring equal access to vaccines. It concludes that although the provisions of the International Covenant on Economic, Social and Cultural Rights would support equal access to vaccines, there are various reasons why international human rights law may not be effective in securing equal access to vaccines. These include not only the state-centric approach of international human rights law and its weak enforcement mechanisms, but also the strong international law protection for patents under the World Trade Organization (WTO)’s Agreement on Trade-related Aspects of Intellectual Property Rights (TRIPs). Nevertheless, important steps have been taken by new institutions of global health governance, such as the Global Agency for Access to Vaccines (GAVI) and Coalition for Epidemic Preparedness Innovations (CEPI), to ensure equal access to vaccines but much work still needs to be done. The chapter concludes that the Covid-19 pandemic has illustrated how inequality between countries, as well as within them, can be exacerbated by a global health crisis.