bluuebunny/crossref_metadata_2025 huggingface dataset:
Phylogenetic diversity of the carbon monoxide-utilizing prokaryotes and their divergent carbon monoxide metabolisms in the human gut microbiome
Authors: Katayama Yuka Adachi , Kamikawa Ryoma , Yoshida Takashi
Published: October 2023

Although the production of toxic CO within the human body has been detected, only a few CO-utilizing prokaryotes (CO utilizers) have been reported in the human gut, and their phylogenetic and physiological diversity remains unclear. Here, we unveiled more than thousand representative genomes originating from previously unexplored potential CO-utilizing prokaryotes, which contain CO dehydrogenase (CODH) genes. More than half of CODH-bearing prokaryotes possess genes for the autotrophic Wood–Ljungdahl pathway (WLP). However, 79% of these prokaryotes commonly lack a key gene for WLP, which encodes enzyme that synthesizes formate from CO2and reductants such as H2, suggesting that they share a degenerated WLP. Instead, many were predicted to possess an alternative way of synthesizing formate from pyruvate, which is a product of glycolysis. In addition to degenerated WLP, seven genes neighboring the CODH gene were found, which may reflect diverse utilization of CO in the human gut. Our findings reveal the unique and diverse nature of CO metabolism in the human gut microbiome, suggesting its potential contribution to CO consumption and gut homeostasis.

Impact statement

Carbon monoxide (CO)-utilizing prokaryotes mitigate the toxic impact of CO by consuming it as energy and/or carbon sources. In addition to various environments, CO is also produced via multiple routes, such as heme degradation, in the human body and accumulates in the gut. Revealing CO-utilizing prokaryotes and their CO metabolisms in the human gut would contribute to gaining insight into how microbial community functions are involved in maintaining human gut homeostasis. Nevertheless, the limited number of CO utilizers in the human gut microbiome have been reported. In our study, a significant proportion of human gut microbial genomes belonging to diverse phyla were revealed to be of potential CO-utilizing prokaryotes. Additionally, the majority of CO-utilizing prokaryote genomes in the human gut have potentially remodeled the Wood– Ljungdahl pathway (WLP), one of the most well-known autotrophic pathways, to the degenerated, heterotrophic form. Moreover, there were seven other genes neighboring CODH in the human gut CO-utilizers, suggesting various CO utilization. Our findings would pave the way for future explorations into microbial metabolic adaptations and their implications for human health.

Data summary

The human gut prokaryote genomes were downloaded from HumGut database (Hiseni et al. 2021;https://arken.nmbu.no/~larssn/humgut/). The accession numbers of CODH/ACS-bearing genomes from environments without host-association (Inoueet al., 2022) are listed in Table S1. Metatranscriptomic datasets were downloaded from the NCBI Sequence Read Archive (SRA) under the Bioproject accession numbers PRJNA354235 and PRJNA707065 and their accession IDs are listed in Table S2.
Data-driven regularisation lowers the size barrier of cryo-EM structure determination
Authors: Kimanius Dari , Jamali Kiarash , Wilkinson Max E , Lövestam Sofia , Velazhahan Vaithish , Nakane Takanori , Scheres Sjors H.W.
Published: October 2023

Macromolecular structure determination by electron cryo-microscopy (cryo-EM) is limited by the alignment of noisy images of individual particles. Because smaller particles have weaker signals, alignment errors impose size limitations on its applicability. Here, we explore how image alignment is improved by the application of deep-learning to exploit prior knowledge about biological macromolecular structures that would otherwise be difficult to express mathematically. We train a denoising convolutional neural network on pairs of half-set reconstructions from the electron microscopy data bank (EMDB) and use this denoiser as an alternative to a commonly used smoothness prior. We demonstrate that this approach, which we call Blush regularisation, yields better reconstructions than existing algorithms, in particular for data with low signal-to-noise ratios. The reconstruction of a protein-nucleic acid complex with a molecular weight of 40 kDa, which was previously intractable, illustrates that regularisation through denoising will expand the applicability of cryo-EM structure determination for a wide range of biological macromolecules.
A previously-unrecognized motif of transcription factor RYBP, hotspot of cancer-related mutations, is essential for the integrity ofPolycombrepressive complex 1
Authors: Silva Catarina S. , Pérez Laura Mariño , Ferrer Irene Garcia , Dieryck Ines , Pessey Ombeline , Erba Elisabetta Boeri , Jensen Malene Ringkjøbing , Marcia Marco
Published: October 2023

Polycombrepressive complex 1 (PRC1) catalyzes monoubiquitination of histone H2A on Lys119, promoting gene silencing. Cells at different developmental stages and in different tissues express different PRC1 isoforms. All isoforms share the same catalytic core (subunits RING1B and PCGF) and vary in the composition of regulatory subunits, clustering in two major classes. Canonical isoforms (cPRC1) are regulated by CBX-like subunits, while variant isoforms (vPRC1) are regulated by RYBP-like subunits. The molecular bases for how regulatory subunits affect the structural assembly of the complex and its catalytic activity are still largely unknown. To fill this knowledge gap, here we have specifically studied how RYBP regulates vPRC1 structure and function. Integrating the machine-learning algorithm AlphaFold2 and NMR, we have identified novel vPRC1 structural motifs in RING1B and RYBP. While the new RING1B motif is dispensable for vPRC1 assembly, the RYBP motif is essential for mediating inter-subunit interactions between RYBP and the catalytic RING1B-PCGF4 heterodimer. Importantly, the RYBP motif harbors cancer-related mutations systematically positioned on the same face of a putative transiently-forming α-helix. Biochemical, biophysical and enzymatic characterization of purified cancer-related mutants confirm that this region is crucial for the structural stability of the complex. Overall, our data offer novel insights into the molecular architecture of vPRC1 and the effects of its regulatory subunit on the biochemical, structural, enzymatic, and physio-pathological properties of the complex.
A new abundant nitrite-oxidizing phylum in oligotrophic marine sediments
Authors: Zhao Rui , Jørgensen Steffen L. , Babbin Andrew R.
Published: October 2023

Nitrite-oxidizing bacteria (NOB) are important nitrifiers whose activity regulates the availability of nitrite and links reduced ammonium and oxidized nitrate in ecosystems. In oxic marine sediments, ammonia-oxidizing archaea (AOA) and NOB together catalyze the oxidation of ammonium to nitrate, but the observed abundance ratios of AOA to canonical NOB are significantly higher than the theoretical ratio predicted from microbial physiology, indicating that many novel NOBs are yet to be discovered. Here we report a new bacterial phylumCandidatusNitrosediminicolota, members of which are more abundant than canonical NOBs and are widespread across global oligotrophic sediments.Ca.Nitrosediminicolota members have the functional potential to oxidize nitrite, in addition to other accessory functions such as urea hydrolysis and thiosulfate reduction. While one recovered species (Ca.Nitrosediminicola aerophilis) is generally confined within the oxic zone, another (Ca.Nitrosediminicola anaerotolerans) can additionally thrive in anoxic sediments. CountingCa.Nitrosediminicolota as a nitrite-oxidizer resolves the apparent abundance imbalance between AOA and NOB in oxic marine sediments, and thus its activity may exert a critical control on the nitrite budget.
Transposable elements acquire time- and sex-specific transcriptional and epigenetic signatures along mouse fetal gonad development
Authors: Stévant Isabelle , Gonen Nitzan , Poulat Francis
Published: October 2023

Gonadal sex determination in mice is a complex and dynamic process, crucial for the development of functional reproductive organs. The expression of genes involved in this process is regulated by a variety of genetic and epigenetic mechanisms. Recently, there has been increasing evidence that transposable elements (TEs), which are a class of mobile genetic elements, play a significant role in regulating gene expression during embryogenesis and organ development. In this study, we aimed to investigate the involvement of TEs in the regulation of gene expression during mouse embryonic gonadal development. Through bioinformatic analysis, we aimed to identify and characterize specific TEs acting as regulatory elements for sex-specific genes, as well as their potential mechanisms of regulation. We identified TE loci expressed in a time- and sex-specific manner along fetal gonad development that correlate positively and negatively with nearby gene expression, suggesting that their expression is integrated to the gonadal regulatory network. Moreover, chromatin accessibility and histone post-transcriptional modification analyses in the differentiating supporting cells revealed that TEs are acquiring sex-specific signature for promoter-, enhancer-, and silencer-like elements with some of them being proximal to critical sex determining genes. Altogether, our study introduces TEs as new potential players of the gene regulatory network controlling gonadal development in mammals.
Micrococcin cysteine-to-thiazole conversion through transient interactions between a scaffolding protein and two modification enzymes
Authors: Calvopina-Chavez Diana G , Bursey Devan M , Tseng Yi-Jie , Patil Leena M , Bewley Kathryn D , Bennallack Philip R , McPhie Josh M , Wagstaff Kimberly B , Daley Anisha , Miller Susan M , Moody James D , Price John C , Griffitts Joel S
Published: October 2023

Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a broad group of compounds mediating microbial competition in nature. Azole/azoline heterocycle formation in the peptide backbone is a key step in the biosynthesis of many RiPPs. Heterocycle formation in RiPP precursors is often carried out by a scaffold protein, an ATP-dependent cyclodehydratase, and an FMN-dependent dehydrogenase. It has generally been assumed that the orchestration of these modifications is carried out by a stable complex including the scaffold, cyclodehydratase and dehydrogenase. The antimicrobial RiPP micrococcin begins as a precursor peptide (TclE) with a 35-amino acid N-terminal leader and a 14-amino acid C-terminal core containing six Cys residues that are converted to thiazoles. The putative scaffold protein (TclI) presumably presents the TclE substrate to a cyclodehydratase (TclJ) and a dehydrogenase (TclN) to accomplish the two-step installation of the six thiazoles. In this study, we identify a minimal TclE leader region required for thiazole formation, we demonstrate complex formation between TclI, TclJ and TclN, and further define regions of these proteins required for complex formation. Our results point to a mechanism of thiazole installation in which TclI associates with the two enzymes in a mutually exclusive fashion, such that each enzyme competes for access to the peptide substrate in a dynamic equilibrium, thus ensuring complete modification of each Cys residue in the TclE core.

IMPORTANCE

Thiopeptides are a family of antimicrobial peptides characterized for having sulfur-containing heterocycles and for being highly post-translationally modified. Numerous thiopeptides have been identified; almost all of which inhibit protein synthesis in gram-positive bacteria. These intrinsic antimicrobial properties make thiopeptides promising candidates for the development of new antibiotics. The thiopeptide micrococcin is synthesized by the ribosome and undergoes several post-translational modifications (PTMs) to acquire its bioactivity. In this study, we identify key interactions within the enzymatic complex that carries out cysteine to thiazole conversion in the biosynthesis of micrococcin.
Honey varietals differentially impactBifidobacterium animalisssplactissurvivability in yogurt through simulatedin vitrodigestion
Authors: Alvarado David A. , Ibarra-Sánchez Luis Alberto , Mysonhimer Annemarie R. , Khan Tauseef A. , Cao Rong , Miller Michael J. , Holscher Hannah D.
Published: October 2023

Background

Bifidobacterium animalis ssp. lactisDN-173 010/CNCM I-2494 (B. animalis) is a probiotic strain commonly added to yogurt. Yogurt and honey are a popular culinary pairing. Honey improves bifidobacteria survivalin vitro. However, probiotic survival in yogurt with honey duringin vitrodigestion has not been investigated.

Objective

The study aimed to evaluate the effects of different honey varietals and concentrations onB. animalissurvivability in yogurt throughin vitrodigestion.

Methods

Yogurt with honey or control-treated samples underwentin vitrosimulated oral, gastric, and intestinal digestion.B. animaliscells were enumerated on MRS medium followed by an overlay with a modified selective MRS medium; all underwent anaerobic incubation.B. animaliswere enumerated pre-digestion and after oral, gastric, and intestinal digestion. There were two study phases: phase 1 tested four honey varietals at 20% w/w per 170g yogurt, and phase 2 tested seven dosages of clover honey (20, 14, 10, 9, 8, 6, and 4% w/w) per 170g yogurt.

Results

SimilarB. animaliscounts were observed between all treatments after oral and gastric digestion (<1 Log CFU/g probiotic reduction). HigherB. animalissurvivability was observed in yogurt with clover honey after exposure to simulated intestinal fluids (∼3.5 Log CFU/g reduction;P< 0.05) compared to all control treatments (∼5.5 Log CFU/g reduction;P< 0.05). Yogurt with 10 to 20% w/w clover honey increasedB. animalissurvivability after simulatedin vitrodigestion (up to ∼4.7 Log CFU/g survival;P< 0.05).

Conclusion

Yogurt with added honey improves probiotic survivability duringin vitrodigestion. The effective dose of clover honey in yogurt was 10 to 20% w/w per serving (1 – 2 tablespoons per 170g yogurt) for increased probiotic survivability duringin vitrodigestion.
Genome Editing Outcomes Reveal Mycobacterial NucS Participates in a Short-Patch Repair of DNA Mismatches
Authors: Islam Tanjina , Josephs Eric A.
Published: October 2023

In the canonical DNA mismatch repair (MMR) mechanism in bacteria, if during replication a nucleotide is incorrectly mis-paired with the template strand, the resulting repair of this mis-pair can result in the degradation and re-synthesis of hundreds or thousands of nucleotides on the newly-replicated strand (long-patch repair). While mycobacteria, which include important pathogens such asMycobacterium tuberculosis, lack the otherwise highly-conserved enzymes required for the canonical MMR reaction, it was found that disruption of a mycobacterial mismatch-sensitive endonuclease NucS results in a hyper-mutative phenotype, which has led to the idea that NucS might be involved in a cryptic, independently-evolved DNA MMR mechanism. It has been proposed that nuclease activity at a mismatch might result in correction by homologous recombination (HR) with a sister chromatid. Using oligonucleotide recombination, which allows us to introduce mismatches during replication specifically into the genomes of a model forM. tuberculosis, Mycobacterium smegmatis, we find that NucS participates in a direct repair of DNA mismatches where the patch of excised nucleotides is largely confined to within ∼5 - 6 bp of the mis-paired nucleotides, which is inconsistent with mechanistic models of canonical mycobacterial HR or other double-strand break (DSB) repair reactions. The results presented provide evidence of a novel NucS-associated mycobacterial MMR mechanism occurringin vivoto regulate genetic mutations in mycobacteria.
HumanO-linked Glycosylation Site Prediction Using Pretrained Protein Language Model
Authors: Pakhrin Subash C. , Chauhan Neha , Khan Salman , Upadhyaya Jamie , Keller Charles , Neuman Laurie N. , Beck Moriah R. , Blanco Eduardo
Published: October 2023

O-linked glycosylation of proteins is an essential post-translational modification process inHomo sapiens, where the attachment of a sugar moiety occurs at the oxygen atom of serine and/or threonine residues. This modification plays a pivotal role in various biological and cellular functions. While threonine or serine residues in a protein sequence are potential sites forO-linked glycosylation, not all threonine or serine residues areO-linked glycosylated. Furthermore, the modification is reversible. Hence, it is of vital importance to characterize if and whenO-linked glycosylation occurs. We propose a multi-layer perceptron-based approach termed OglyPred-PLM which leverages the contextualized embeddings produced from the ProtT5-XL-UniRef50 protein language model that significantly improves the prediction performance of humanO-linked glycosylation sites. OglyPred-PLM surpassed the performance of other indispensableO-linked glycosylation predictors on the independent benchmark dataset. This demonstrates that OglyPred-PLM is a powerful and unique computational tool to predictO-linked glycosylation sites in proteins and thus will accelerate the discovery of unknownO-linked glycosylation sites in proteins.
Recurrent gene flow events shaped the diversification of the clownfish skunk complex
Authors: Marcionetti Anna , Bertrand Joris A. M. , Cortesi Fabio , Donati Giulia F. A. , Heim Sara , Huyghe Filip , Kochzius Marc , Pellissier Loïc , Salamin Nicolas
Published: October 2023

Clownfish (subfamily Amphiprioninae) are an iconic group of coral reef fish that evolved a mutualistic interaction with sea anemones, which was shown to have triggered the adaptive radiation of the group. Within clownfishes, the skunk complex is particularly interesting as, besides ecological speciation, gene flow between species and hybrid speciation are suggested to have shaped the diversification of the group. We investigated, for the first time, the mechanisms underlying the diversification of this complex. By taking advantage of their disjunct geographical distribution, we obtained whole-genome data of sympatric and allopatric populations of the three main species of the complex (Amphiprion akallopisos,A. perideraionandA. sandaracinos). We examined the population structure, genomic divergence patterns and introgression signals, and performed demographic modeling to identify the most realistic diversification scenario. We excluded scenarios of strict isolation, of hybrid origin ofA. sandaracinos, and ruled out the presence of extensive gene flow in sympatry. We discovered moderate gene flow fromA. perideraionto the ancestor ofA. akallopisos + A. sandaracinosand weak gene flow between the species in the Indo-Australian Archipelago throughout the diversification process of the group. We identified introgressed regions inA. sandaracinosand detected two large regions of high divergence inA. perideraion, likely maintained by the disruption of recombination. Altogether, our results show that ancestral hybridization events shaped the group’s diversification. However, more recent gene flow is less pervasive than initially thought and suggests a role of host repartition or behavioral barriers in maintaining the genetic identity of the species in sympatry.
Resource configurations among digital academic spin-offs: finding the technology-market fit
Authors: Evertsen Phuc Huynh , Rasmussen Einar
Published: October 2023

Purpose

Managing resources is crucial for firms to gain competitive advantages and succeed, particularly for startups with limited resources. It is important to understand how digital startups in general and digital academic spin-offs (ASOs) in particular may orchestrate their resources to optimize value. This paper integrates the resource-based perspective with digital entrepreneurship to analyze the resource configurations leading to success of digital ASOs.

Design/methodology/approach

The paper adopts an inductive approach and applies qualitative comparative analysis (QCA) on a longitudinal dataset of digital ASOs to identify the resource configurations for a successful outcome.

Findings

The authors' paper identifies two main paths to success among digital ASOs, consisting of five distinct resource configurations. The first path is termed “market exploiters” that operate in favorable market conditions where specific technological resources and research collaboration resources are lacking. The second path involves “technology explorers” that combines both technological and commercial resources to achieve success.

Research limitations/implications

By outlining distinct pathways to the success of digital ASOs, this paper contributes to the digital academic entrepreneurship literature and the resource-based view of entrepreneurial firms. The paper also suggests implications for policymakers and managers in managing resources for the success of digital ventures.

Originality/value

By exploring the resource configurations leading to the success of ASOs commercializing digital technologies, the paper shows that favorable market conditions and complementary resource configurations can be alternative pathways to success.
Numerical investigations on the lubrication characteristics of involute harmonic gears
Authors: Shen Yi , He Tao , Gong Xiaoya
Published: October 2023

Purpose

Harmonic gears always work under different operating conditions and may usually break down due to lubrication failures, while its lubrication mechanism is still not clearly understood. This paper aims to present a lubrication model comprehensively considering the influence of contact geometry, lubrication properties and three-dimensional (3D) real surface roughness to analyze the lubrication performance under different conditions.

Design/methodology/approach

Based on the discrete convolution-fast Fourier transformation with duplicated padding and quasi-system numerical methods, the lubrication model for harmonic gears is developed, which is verified by comparing results with available lubrication data.

Findings

The effects of meshing process, working conditions and 3D roughness on the lubrication characteristics are discussed. From the calculated cases, the increase in rotational speed and decrease of applied torque may increase the film thickness, enhancing the lubrication performance of harmonic gears. It is also observed that proper surface roughness can be used for lubrication design.

Originality/value

The research results can provide theoretical guidance for improving lubrication performance and reducing friction/wear of the harmonic gear interfaces. This study can be promoted to various engineering scenarios of harmonic gears, such as industrial robots, space-driven agencies and precision measuring instruments.
Recent developments in freezing of fruits and vegetables: Striving for controlled ice nucleation and crystallization with enhanced freezing rates
Authors: Grover Yashmita , Negi Pradeep Singh
Published: October 2023

Fruits and vegetables are rich in essential nutrients such as minerals, vitamins, and antioxidants; however, they have short shelf life. Freezing is a superior method of preservation compared to other techniques with respect to nutrient retention and maintenance of sensory attributes. However, several physical and textural quality changes associated with freezing and thawing pose a serious problem to the quality of frozen products. Some of the disadvantages associated with the currently employed methods for freezing fruits and vegetables include low rates of heat exchange in blast freezers, shape limitation in plate freezers, high cost of operation in cryogenic freezing, and freezing solution dilution in immersion freezing. Therefore, novel freezing technologies have been developed to achieve controlled ice nucleation and crystallization, enhanced freezing rate, decreased phase transition time, and maintained temperature stability. This review discusses some of the most recent approaches employed in freezing and points to their adoption for maintaining the quality of fruits and vegetables with extended storage.
Practical application of the linkage disequilibrium method for estimating contemporary effective population size: A review
Authors: Waples Robin S.
Published: October 2023

The method to estimate contemporary effective population size (Ne) based on patterns of linkage disequilibrium (LD) at unlinked loci has been widely applied to natural and managed populations. The underlying model makes many simplifying assumptions, most of which have been evaluated in numerous studies published over the last two decades. Here, these performance evaluations are reviewed and summarized, with a focus on information that facilitates practical application to real populations in nature. Potential sources of bias that are discussed include calculation of r2 (a measure of LD), adjustments for sampling error, physical linkage, age structure, migration and spatial structure, mutation and selection, mating systems, changes in abundance, rare alleles, missing data, genotyping errors, data filtering choices and methods for combining multiple Ne estimates. Factors that affect precision are reviewed, including pseudoreplication that limits the information gained from large genomics datasets, constraints imposed by small samples of individuals, and the challenges in obtaining robust estimates for large populations. Topics that merit further research include the potential to weight r2 values by allele frequency, lump samples of individuals, use genotypic likelihoods rather than called genotypes, prune large LD values and apply the method to species practising partial monogamy.
The heritages of forced opening: The treaty‐port history and institutions in modern China
Authors: Liu Yuan , Zhang Lei
Published: October 2023

Treaty ports attracted most of colonial China's foreign enterprise and introduced western institutions that would shape property rights and the judicial system. Political change and economic reconstruction after 1949 depressed this tradition, but its effects lingered and became more active after reform and opening. Using cross‐sectional data for cities combining the treaty‐port history and the investment climate, we document the impact of this heritage on the institutional quality and economic development of modern China.
The pregnant traveller: An overview of common preventable infections
Authors: Lee Wen Jie Isaac , Giles Michelle L. , Cole Stephen , Krishnaswamy Sushena
Published: October 2023

Pregnant travellers are often unaware of the various infections that can be acquired during travel and that pregnant people may be at increased risk of severe disease compared to their non‐pregnant counterparts. Pregnant people often seek pre‐travel counselling from their obstetrician or primary care physicians, who may not be well versed in travel medicine. This paper aims to provide information for maternity care providers regarding important travel‐related food, water and mosquito‐borne illnesses, including their prevention and treatment methods, equipping maternity care providers to confidently counsel prospective travellers during pregnancy.
Retinal vein occlusion as an age‐dependent marker of incident dementia in a long‐term Danish national cohort
Authors: Clausen Anna Rebien , Stokholm Lonny , Frederiksen Katrine Hartmund , Möller Sören , Blaabjerg Morten , Pedersen Frederik Nørregaard , Grauslund Jakob
Published: October 2023

Purpose

The aim of this study was to investigate retinal vein occlusion (RVO) as an independent marker of incident dementia.

Methods

In a prospective nationwide cohort study, we identified 2 225 568 individuals through the Danish national health registers. Individuals older than 65 years, without unspecified retinal vascular occlusion or dementia were included from 1998 to 2020 and followed until 2022. We calculated the incidence rate (IR) and performed a Cox regression analysis with a hazard ratio (HR) and 95% confidence interval (CI) for RVO (exposure) as a marker of all‐cause dementia adjusted for systemic comorbidity.

Results

We identified 19 669 individuals with RVO who had a higher prevalence of systemic comorbidity at inclusion compared to those without RVO (n = 2 185 483). We performed a Cox regression analysis for age‐dependent exposure due to non‐proportional hazards in the pre‐planned analysis. Exposed individuals younger than 75 years had an increased risk of all‐cause dementia (adjusted HR 1.09, 95% CI 1.01–1.18), whereas individuals older than 75 years had a decreased risk of all‐cause dementia (adjusted HR 0.92, 95% CI 0.86–0.98).

Conclusion

Individuals with RVO had an age‐dependent risk of dementia, with a 9% increased risk in individuals with RVO younger than 75 years and an 8% decreased risk in individuals older than 75 years at the time of exposure.
Vascular imaging findings in retinopathy of prematurity
Authors: Rowe Lucas W. , Belamkar Aditya , Antman Gal , Hajrasouliha Amir R. , Harris Alon
Published: October 2023

Retinopathy of prematurity (ROP) is a vascular disease among preterm infants involving incomplete or abnormal retinal vascularization and is a leading cause of preventable blindness globally. Measurements of ocular blood flow originating from a variety of imaging modalities, including colour Doppler imaging (CDI), fluorescein angiography (FA) and ocular coherence tomography angiography (OCTA), have been associated with changes in ROP patients. Herein, we discuss and summarize the relevant current literature on vascular imaging and ROP reviewed through December 2022. Differences in vascular imaging parameters between ROP patients and healthy controls are reviewed and summarized. The available data identify significantly increased peak systolic velocity (PSV) in the central retinal artery and ophthalmic artery as measured by CDI, increased vascular tortuosity as measured by FA, smaller foveal avascular zone (FAZ) as measured by FA and OCTA, and increased foveal vessel density (VD) and reduced parafoveal VD as measured by OCTA in ROP patients compared with controls. None of the above findings appear to reliably correlate with visual acuity. The studies currently available, however, are inconclusive and lack robust longitudinal data. Vascular imaging demonstrates the potential to aid in the diagnosis, management and monitoring of ROP, alongside retinal examination via indirect ophthalmoscopy and fundus photography.
Exploring the challenges faced by foundation doctors when prescribing high risk medicines safely during the on‐call period: A qualitative study
Authors: Alanzi Mahdi A. , Tully Mary P. , Lewis Penny J.
Published: October 2023

Aims

Errors with prescribing high‐risk medicines (HRMs) have a greater propensity to cause harm than with non‐HRMs. Prescribing errors arise due to multiple factors and it can be particularly challenging for junior doctors to prescribe safely during the on‐call period. Knowledge regarding the challenges of prescribing HRM during the on‐call period would be useful to target preventative interventions. The aim of this study was to explore the challenges encountered by foundation doctors (doctors who have graduated medical school within the last 2 years) when prescribing specific HRMs (anticoagulants, insulin and opioids) safely during the on‐call period.

Methods

Six focus groups exploring the challenges of prescribing HRMs safely during the on‐call period were conducted, 3 with foundation year 1 and 3 with foundation year 2 doctors from across 3 different hospitals. A thematic framework analysis based on the London Protocol was conducted.

Results

Doctors described multiple challenges to prescribing HRMs safely during the on‐call period including a lack of prescribing support, nursing pressure, complex prescribing tasks, unknown patients as well as individual factors such as lack of knowledge and tiredness. Many of these factors exist to some extent during the day, yet the nature of the on‐call period as a fast‐paced environment heightened the challenges that prescribers faced.

Conclusion

There are multiple challenges experienced by foundation doctors when prescribing HRMs during the on‐call period. The potentially devastating consequences of errors with HRMs means that closer attention and more concern from healthcare professionals, researchers and policymakers is required to improve safe prescribing of HRMs in hospitals.
Drug clustering to anticipate new aspects of drug safety profile: Application to gabapentinoids and other voltage‐gated calcium channel ligand drugs
Authors: Viguier Thibault , Agier Marie‐Sara , Jonville‐Béra Annie‐Pierre , Giraudeau Bruno , Largeau Bérenger
Published: October 2023

Aims

Gabapentin and pregabalin bind to α2‐δ subunit of voltage‐gated calcium channels (Cav). Other drugs targeting Cav include cardiovascular calcium channel blockers (CCBs) and anticonvulsants (levetiracetam, ethosuximide and zonisamide). In addition to pharmacodynamics, the safety profile of gabapentinoids seems to overlap with the one of cardiovascular CCBs (oedema) and Cav‐blocking anticonvulsants (suicide and ataxia). The objective of this study was to cluster the safety profile of different Cav‐ligand drugs by focusing on whether gabapentinoids present a distinct adverse drug reaction (ADR) signature from cardiovascular CCBs and anticonvulsants.

Methods

We extracted all ADRs with at least one significant disproportionate reporting (reporting odds ratio) related to gabapentinoids, CCBs or anticonvulsants in VigiBase. After principal component analysis preprocessing, a hierarchical ascendent classification was performed to cluster gabapentinoids and other Cav‐ligand drugs that share a similar ADR signature. The robustness of the results was determined through four sensitivity analyses, varying on the dataset or the clustering method.

Results

A total of 16 drugs and 65 ADRs were included. Gabapentinoids were in Cluster #1, which included eight other drugs (isradipine, nicardipine, lacidipine, lercanidipine, ethosuximide, levetiracetam, zonisamide and nimodipine). Cluster #2 contained two drugs (diltiazem and verapamil) and Cluster #3 contained four drugs (amlodipine, felodipine, nifedipine and nitrendipine). The clustering results were consistent in all sensitivity analyses.

Conclusions

The safety profile of gabapentinoids overlaps with those of some dihydropyridine CCBs and Cav‐blocking anticonvulsants. These results could be used to anticipate some unidentified ADRs of gabapentinoids from information accumulated with older drugs and sharing a common molecular target and ADR signature.
Population pharmacokinetics of mirvetuximab soravtansine in patients with folate receptor‐α positive ovarian cancer: The antibody–drug conjugate, payload and metabolite
Authors: Tu Ya‐Ping , Hanze Eva , Zhu Fengying , Lagraauw H. Maxime , Sloss Callum M. , Method Michael , Esteves Brooke , Westin Eric H. , Berkenblit Anna
Published: October 2023

Aims

Mirvetuximab soravtansine is a first‐in‐class antibody–drug conjugate recently approved for the treatment of folate receptor‐α positive ovarian cancer. The aim of this study was to develop a population pharmacokinetic model to describe the concentration–time profiles of mirvetuximab soravtansine, the payload (DM4) and a metabolite (S‐methyl‐DM4).

Methods

Mirvetuximab soravtansine was administered intravenously from 0.15 to 7 mg/kg to 543 patients with predominantly platinum‐resistant ovarian cancer in 3 clinical studies, and the plasma drug concentrations were analysed using a nonlinear mixed‐effects modelling approach. Stepwise covariate modelling was performed to identify covariates.

Results

We developed a semi‐mechanistic population pharmacokinetic model that included linear and nonlinear routes for the elimination of mirvetuximab soravtansine and a target compartment for the formation and disposition of the payload and metabolite in tumour cells. The clearance and volume of the central compartment were 0.0153 L/h and 2.63 L for mirvetuximab soravtansine, 8.83 L/h and 3.67 L for DM4, and 2.04 L/h and 6.3 L for S‐methyl‐DM4, respectively. Body weight, serum albumin and age were identified as statistically significant covariates. Exposures in patients with renal or hepatic impairment and who used concomitant cytochrome P450 (CYP) 3A4 inhibitors were estimated.

Conclusion

There is no need for dose adjustment due to covariate effects for mirvetuximab soravtansine administered at the recommended dose of 6 mg/kg based on adjusted ideal body weight. Dose adjustment is not required for patients with mild or moderate renal impairment, mild hepatic impairment, or when concomitant weak and moderate CYP3A4 inhibitors are used.
Post‐COVID‐19 thrombotic sequelae: The potential role of persistent platelet hyperactivity
Authors: Schieppati Francesca
Published: October 2023

Postacute COVID‐19 sequelae affect millions of individuals, and active research into the pathophysiological mechanisms and potential treatments is underway. The report by Nara and colleagues shows persistent platelet hyperactivity in the chronic phase of the infection, suggesting a possible role of platelets in post‐COVID‐19 complications and, consequently, a possible therapeutic target.

Commentary on: Nara et al. Prolonged platelet hyperactivity after COVID‐19 infection. Br J Haematol 2024;204:492‐496.
Drug discovery: In silico dry data can bypass biological wet data?
Authors: Tognolini Massimiliano , Lodola Alessio , Giorgio Carmine
Published: October 2023

The recent and extraordinary increase in computer power, along with the availability of efficient algorithms based on artificial intelligence, has prompted a large number of inexperienced scientists to challenge the complex and yet competitive world of drug discovery, by pretending to identify new hits through the sole use of computer aided drug design (CADD). Does the golden era of dry data run the risk of overshadowing the importance of wet data and, in doing so, forget that in silico and biological data need each other in successful preclinical drug discovery programmes?
Leveraging corporate sustainability through responsible innovation: Capacity building with exploration and exploitation
Authors: Beger Gizem Aras , Sağlam Bayram Bilge , Turker Duygu
Published: October 2023

The growing literature on corporate sustainability suggests its positive implications for organizations and stakeholders. Based on the social identity approach, the current study aims to investigate whether responsible innovation can leverage these sustainability advantages of companies to improve organizational commitment and competitiveness. Responsible innovation has been integrated into an original model as a construct that translates corporate sustainability into organizational outcomes to meet stakeholders' needs and to frame and solve the sustainability‐related tensions in an ethical way. The study also attempts to examine the mediating impacts of exploration and exploitation orientations on the proposed link between corporate sustainability and responsible innovation. The model was validated by using the partial least squares structural equation modelling method on a sample of 196 middle managers in small businesses in Turkey. The findings reveal that responsible innovation has a significant mediation effect on the proposed links, and both exploration and exploitation elicit the innovation capacity in sustainability practices. The study also supports the argument on the positive impact of exploitation on exploration.
AZD9567 versus prednisolone in patients with active rheumatoid arthritis: A phase IIa, randomized, double‐blind, efficacy, and safety study
Authors: van Laar Jacob M. , Lei Alejhandra , Safy‐Khan Mary , Almquist Joachim , Belfield Graham , Edman Karl , Öberg Lisa , Angermann Bastian R. , Dillmann Inken , Berntsson Pia , Etal Damla , Dainty Ian , Astbury Carol , Belvisi Maria G. , Nemes Szilárd , Platt Adam , Prothon Susanne , Samuelsson Sara , Svanberg Petter , Keen Christina ,   the SEMRA study group
Published: October 2023

Oral corticosteroid use is limited by side effects, some caused by off‐target actions on the mineralocorticoid receptor that disrupt electrolyte balance. AZD9567 is a selective, nonsteroidal glucocorticoid receptor modulator. The efficacy, safety, and tolerability of AZD9567 and prednisolone were assessed in a phase IIa study. Anti‐inflammatory mechanism of action was also evaluated in vitro in monocytes from healthy donors. In this randomized, double‐blind, parallel‐group, multicenter study, patients with active rheumatoid arthritis were randomized 1:1 to AZD9567 40 mg or prednisolone 20 mg once daily orally for 14 days. The primary end point was change from baseline in DAS28‐CRP at day 15. Secondary end points included components of DAS28‐CRP, American College of Rheumatology (ACR) response criteria (ACR20, ACR50, and ACR70), and safety end points, including serum electrolytes. Overall, 21 patients were randomized to AZD9567 (n = 11) or prednisolone (n = 10), and all completed the study. As anticipated, AZD9567 had a similar efficacy profile to prednisolone, with no clinically meaningful (i.e., >1.0) difference in change from baseline to day 15 in DAS28‐CRP between AZD9567 and prednisolone (least‐squares mean difference: 0.47, 95% confidence interval: −0.49 to 1.43). Similar results were observed for the secondary efficacy end points. In vitro transcriptomic analysis showed that anti‐inflammatory responses were similar for AZD9567, prednisolone, and dexamethasone. Unlike prednisolone, AZD9567 had no effect on the serum sodium:potassium ratio. The safety profile was not different from that of prednisolone. Larger studies of longer duration are required to determine whether AZD9567 40 mg may in the future be an alternative to prednisolone in patients with inflammatory disease.
Cytologic features of meningioma: An analysis of common and uncommon subtypes and diagnostic difficulties during intraoperative procedures
Authors: Rodríguez‐García Ana M. , Esteban‐Rodríguez Isabel , Jiménez‐Heffernan José A. , Bárcena Carmen , López‐Muñoz Samuel , López‐Ferrer Pilar
Published: October 2023

Despite common histogenesis meningiomas have a wide morphologic spectrum, and the World Health Organization (WHO) recognizes 15 subtypes. They are the most common brain tumour in adults and typically have an extra‐axial location. Although there have been important advances in the molecular biology of meningiomas its diagnosis is based on histopathologic features. The great majority are benign WHO grade 1 tumours. There are specific criteria for assigning WHO grade 2 and 3 that can be applied to all meningioma subtypes. Regardless of these criteria, chordoid and clear cell morphologic subtypes are considered grade 2. WHO grade 3 tumours exhibit a very high mitotic index, frank anaplasia or specific molecular abnormalities. The impressive morphologic diversity shown by meningiomas makes them a diagnostic challenge, which can be even greater in intraoperative studies. The focus of this article is to describe and illustrate their main cytologic features, with emphasis on the most infrequent subtypes.
Do gender stereotypes play a role in the process of identifying gifted students in Western Balkan countries? – Case study Bosnia and Herzegovina
Authors: Milic Sanja , Simeunovic Vlado
Published: October 2023

Gender stereotypes, as a cause and consequence of deeply rooted attitudes, values and norms, directly affect the discovery and development of gifted potentials. Given the fact that high abilities are most successfully identified and properly developed in early school age, the aim of the study is to investigate the existence of gender differences in the perception of different abilities in boys and girls by teachers, parents, peers and self‐perception in multiple intelligences. The research was conducted on 115 lower primary school students in Bosnia and Herzegovina. Mann–Whitney U test was used to determine differences in various domains of giftedness between girls and boys throughout groups of evaluators. Statistically significant difference was found in 11 of the 36 variables analysed. Most statistically significant differences were found in parents' assessments (5), while 3 were found in teachers' assessments, 2 in peers' assessments, and only one in self‐assessments. Although the cultural factors, customs and traditions of the Balkan country of Bosnia and Herzegovina have a great influence on gender stereotypes, the results of research on gender discrimination in the process of identifying giftedness are largely similar to the results of developed European countries. The results of the study can be used in the context of general education as a basis for critical re‐examination of negative attitudes towards females in the direction of a particular professional orientation.
Hemispheric epilepsy surgery for hemimegalencephaly: The UCLA experience
Authors: Goel Keshav , Phillips H. Westley , Chen Jia‐Shu , Ngo Jacqueline , Edmonds Benjamin , Ha Phong X. , Wang Andrew , Weil Alexander G. , Russell Bianca E. , Salamon Noriko , Nariai Hiroki , Fallah Aria
Published: October 2023

Objectives

Hemimegalencephaly (HME) is a rare congenital brain malformation presenting predominantly with drug‐resistant epilepsy. Hemispheric disconnective surgery is the mainstay of treatment; however, little is known about how postoperative outcomes compare across techniques. Thus we present the largest single‐center cohort of patients with HME who underwent epilepsy surgery and characterize outcomes.

Methods

This observational study included patients with HME at University of California Los Angeles (UCLA) from 1984 to 2021. Patients were stratified by surgical intervention: anatomic hemispherectomy (AH), functional hemispherectomy (FH), or less‐than‐hemispheric resection (LTH). Seizure freedom, functional outcomes, and operative complications were compared across surgical approaches. Regression analysis identified clinical and intraoperative variables that predict seizure outcomes.

Results

Of 56 patients, 43 (77%) underwent FH, 8 (14%) underwent AH, 2 (4%) underwent LTH, 1 (2%) underwent unknown hemispherectomy type, and 2 (4%) were managed non‐operatively. At median last follow‐up of 55 months (interquartile range [IQR] 20–92 months), 24 patients (49%) were seizure‐free, 17 (30%) required cerebrospinal fluid (CSF) shunting for hydrocephalus, 9 of 43 (21%) had severe developmental delay, 8 of 38 (21%) were non‐verbal, and 15 of 38 (39%) were non‐ambulatory. There was one (2%) intraoperative mortality due to exsanguination earlier in this cohort. Of 12 patients (29%) requiring revision surgery, 6 (50%) were seizure‐free postoperatively. AH, compared to FH, was not associated with statistically significant improved seizure freedom (hazard ratio [HR] = .48, p = .328), although initial AH trended toward greater odds of seizure freedom (75% vs 46%, p = .272). Younger age at seizure onset (HR = .29, p = .029), lack of epilepsia partialis continua (EPC) (HR = .30, p = .022), and no contralateral seizures on electroencephalography (EEG) (HR = .33, p = .039) independently predicted longer duration of seizure freedom.

Significance

This study helps inform physicians and parents of children who are undergoing surgery for HME by demonstrating that earlier age at seizure onset, absence of EPC, and no contralateral EEG seizures were associated with longer postoperative seizure freedom. At our center, initial AH for HME may provide greater odds of seizure freedom with complications and functional outcomes comparable to those of FH.