bluuebunny/crossref_metadata_2025 huggingface dataset:
A Human Immunodeficiency Virus Type 1 Risk Assessment Tool for Women Aged 15–49 Years in African Countries: A Pooled Analysis Across 15 Nationally Representative Surveys
Authors: Rosenberg Nora E , Shook-Sa Bonnie E , Young Amber M , Zou Yating , Stranix-Chibanda Lynda , Yotebieng Marcel , Sam-Agudu Nadia A , Phiri Sam J , Mutale Wilbroad , Bekker Linda-Gail , Charurat Manhattan E , Moyo Sizulu , Zuma Khangelani , Justman Jessica , Hudgens Michael G , Chi Benjamin H
Published: April 2024

Background

Women in Africa disproportionately acquire human immunodeficiency virus type 1 (HIV-1). Understanding which women are most likely to acquire HIV-1 can guide focused prevention with preexposure prophylaxis (PrEP). Our objective was to identify women at the highest risk of HIV-1 and estimate PrEP efficiency at different sensitivity levels.

Methods

Nationally representative data were collected from 2015 through 2019 from 15 population-based household surveys. This analysis included women aged 15–49 who tested HIV-1 seronegative or had recent HIV-1. Least absolute shrinkage and selection operator regression models were fit with 28 variables to predict recent HIV-1. Models were trained on the full population and internally cross-validated. Performance was evaluated using area under the receiver operating characteristic curve (AUC), sensitivity, and number needed to treat (NNT) with PrEP to avert 1 infection.

Results

Among 209 012 participants, 248 had recent HIV-1 infection, representing 118 million women and 402 000 (95% confidence interval [CI], 309 000–495 000) annual infections. Two variables were retained: living in a subnational area with high HIV-1 viremia and having a sexual partner living outside the home. The full-population AUC was 0.80 (95% CI, .76–.84); cross-validated AUC was 0.79 (95% CI, .75–.84). At 33% sensitivity, 130 000 cases could be averted if 7.9 million women were perfectly adherent to PrEP; NNT would be 61. At 67% sensitivity, 260 000 cases could be averted if 25.1 million women were perfectly adherent; NNT would be 96.

Conclusions

This risk assessment tool was generalizable, predictive, and parsimonious with trade-offs between reach and efficiency.
Prevalence of chronic kidney disease in France: methodological considerations and pitfalls with the use of Health claims databases
Authors: Couchoud Cécile , Raffray Maxime , Lassalle Mathilde , Duisenbekov Zhanibek , Moranne Olivier , Erbault Marie , Lazareth Hélène , Parmentier Cyrielle , Guebre-Egziabher Fitsum , Hamroun Aghiles , Metzger Marie , Mansouri Imene , Goldberg Marcel , Zins Maris , Bayat-Makoei Sahar , Kab Sofiane
Published: April 2024

Background

Health policy-making require careful assessment of chronic kidney disease (CKD) epidemiology to develop efficient and cost-effective care strategies. The aim of the present study was to use the RENALGO-EXPERT algorithm to estimate the global prevalence of CKD in France.

Methods

An expert group developed the RENALGO-EXPERT algorithm based on healthcare consumption. This algorithm has been applied to the French National Health claims database (SNDS), where no biological test findings are available to estimate a national CKD prevalence for the years 2018–2021. The CONSTANCES cohort (+219 000 adults aged 18–69 with one CKD-EPI eGFR) was used to discuss the limit of using health claims data.

Results

Between 2018 and 2021, the estimated prevalence in the SNDS increased from 8.1% to 10.5%. The RENALGO-EXPERT algorithm identified 4.5% of the volunteers in the CONSTANCES as CKD. The RENALGO-EXPERT algorithm had a positive predictive value of 6.2% and negative predictive value of 99.1% to detect an eGFR<60 ml/min/1.73 m². Half of 252 false positive cases (ALGO+, eGFR > 90) had been diagnosed with kidney disease during hospitalization, and the other half based on healthcare consumption suggestive of a ‘high-risk’ profile; 95% of the 1661 false negatives (ALGO−, eGFR < 60) had an eGFR between 45 and 60 ml/min, half had medication and two-thirds had biological exams possibly linked to CKD. Half of them had a hospital stay during the period but none had a diagnosis of kidney disease.

Conclusions

Our result is in accordance with other estimations of CKD prevalence in the general population. Analysis of diverging cases (FP and FN) suggests using health claims data have inherent limitations. Such an algorithm can identify patients whose care pathway is close to the usual and specific CKD pathways. It does not identify patients who have not been diagnosed or whose care is inappropriate or at early stage with stable GFR.
Incidence and predictors of thermal oesophageal and vagus nerve injuries in Ablation Index-guided high-power-short-duration ablation of atrial fibrillation: a prospective study
Authors: Wolff Charlotte , Langenhan Katharina , Wolff Marc , Efimova Elena , Zachäus Markus , Darma Angeliki , Dinov Borislav , Seewöster Timm , Nedios Sotirios , Bertagnolli Livio , Wolff Jan , Paetsch Ingo , Jahnke Cosima , Bollmann Andreas , Hindricks Gerhard , Bode Kerstin , Halm Ulrich , Arya Arash
Published: April 2024

Aims

High-power-short-duration (HPSD) ablation is an effective treatment for atrial fibrillation but poses risks of thermal injuries to the oesophagus and vagus nerve. This study aims to investigate incidence and predictors of thermal injuries, employing machine learning.

Methods and results

A prospective observational study was conducted at Leipzig Heart Centre, Germany, excluding patients with multiple prior ablations. All patients received Ablation Index-guided HPSD ablation and subsequent oesophagogastroduodenoscopy. A machine learning algorithm categorized ablation points by atrial location and analysed ablation data, including Ablation Index, focusing on the posterior wall. The study is registered in clinicaltrials.gov (NCT05709756). Between February 2021 and August 2023, 238 patients were enrolled, of whom 18 (7.6%; nine oesophagus, eight vagus nerve, one both) developed thermal injuries, including eight oesophageal erythemata, two ulcers, and no fistula. Higher mean force (15.8 ± 3.9 g vs. 13.6 ± 3.9 g, P = 0.022), ablation point quantity (61.50 ± 20.45 vs. 48.16 ± 19.60, P = 0.007), and total and maximum Ablation Index (24 114 ± 8765 vs. 18 894 ± 7863, P = 0.008; 499 ± 95 vs. 473 ± 44, P = 0.04, respectively) at the posterior wall, but not oesophagus location, correlated significantly with thermal injury occurrence. Patients with thermal injuries had significantly lower distances between left atrium and oesophagus (3.0 ± 1.5 mm vs. 4.4 ± 2.1 mm, P = 0.012) and smaller atrial surface areas (24.9 ± 6.5 cm2 vs. 29.5 ± 7.5 cm2, P = 0.032).

Conclusion

The low thermal lesion’s rate (7.6%) during Ablation Index-guided HPSD ablation for atrial fibrillation is noteworthy. Machine learning based ablation data analysis identified several potential predictors of thermal injuries. The correlation between machine learning output and injury development suggests the potential for a clinical tool to enhance procedural safety.
Charting the course of pinniped evolution: insights from molecular phylogeny and fossil record integration
Authors: Park Travis , Burin Gustavo , Lazo-Cancino Daniela , Rees Joseph P G , Rule James P , Slater Graham J , Cooper Natalie
Published: April 2024

Pinnipeds (seals, sea lions, walruses, and their fossil relatives) are one of the most successful mammalian clades to live in the oceans. Despite a well-resolved molecular phylogeny and a global fossil record, a complete understanding of their macroevolutionary dynamics remains hampered by a lack of formal analyses that combine these 2 rich sources of information. We used a meta-analytic approach to infer the most densely sampled pinniped phylogeny to date (36 recent and 93 fossil taxa) and used phylogenetic paleobiological methods to study their diversification dynamics and biogeographic history. Pinnipeds mostly diversified at constant rates. Walruses, however, experienced rapid turnover in which extinction rates ultimately exceeded speciation rates from 12 to 6 Ma, possibly due to changing sea levels and/or competition with otariids (eared seals). Historical biogeographic analyses, including fossil data, allowed us to confidently identify the North Pacific and the North Atlantic (plus or minus Paratethys) as the ancestral ranges of Otarioidea (eared seals + walrus) and crown phocids (earless seals), respectively. Yet, despite the novel addition of stem pan-pinniped taxa, the region of origin for Pan-Pinnipedia remained ambiguous. These results suggest further avenues of study in pinnipeds and provide a framework for investigating other groups with substantial extinct and extant diversity.
Multiomics data integration, limitations, and prospects to reveal the metabolic activity of the coral holobiont
Authors: Williams Amanda
Published: April 2024

Since their radiation in the Middle Triassic period ∼240 million years ago, stony corals have survived past climate fluctuations and five mass extinctions. Their long-term survival underscores the inherent resilience of corals, particularly when considering the nutrient-poor marine environments in which they have thrived. However, coral bleaching has emerged as a global threat to coral survival, requiring rapid advancements in coral research to understand holobiont stress responses and allow for interventions before extensive bleaching occurs. This review encompasses the potential, as well as the limits, of multiomics data applications when applied to the coral holobiont. Synopses for how different omics tools have been applied to date and their current restrictions are discussed, in addition to ways these restrictions may be overcome, such as recruiting new technology to studies, utilizing novel bioinformatics approaches, and generally integrating omics data. Lastly, this review presents considerations for the design of holobiont multiomics studies to support lab-to-field advancements of coral stress marker monitoring systems. Although much of the bleaching mechanism has eluded investigation to date, multiomic studies have already produced key findings regarding the holobiont’s stress response, and have the potential to advance the field further.
Variation in processes of care for total hip arthroplasty across high-income countries
Authors: Skopec Laura , Berenson Robert A , Simon Benedikt , Papanicolas Irene
Published: April 2024

Total hip arthroplasty (THA) is among the most commonly performed elective surgeries in high-income countries, and wait times for THA have frequently been cited by US commentators as evidence that countries with universal insurance programs or national health systems “ration” care. This novel qualitative study explores processes of care for hip replacement in the United States and 6 high-income countries with a focus on eligibility, wait times, decision-making, postoperative care, and payment policies. We found no evidence of rationing or government interference in decision-making across high-income countries. Compared with the 6 other high-income countries in our study, the United States has developed efficient care processes that often allow for a same-day discharge. In contrast, THA patients in Germany stay in the hospital 7–9 days and receive 2–3 weeks of inpatient rehabilitation. However, the payment per THA in the United States remains far above other countries, despite far fewer inpatient days.
Chromosome-level genome assembly and population genomics reveals crucial selection for subgynoecy development in chieh-qua
Authors: Wang Min , Cao Zhenqiang , Jiang Biao , Wang Kejian , Xie Dasen , Chen Lin , Shi Shaoqi , Yang Songguang , Lu Hongwei , Peng Qingwu
Published: April 2024

Chieh-qua is an important cucurbit crop and very popular in South China and Southeast Asia. Despite its significance, its genetic basis and domestication history are unclear. In this study, we have successfully generated a chromosome-level reference genome assembly for the chieh-qua ‘A36’ using a hybrid assembly strategy that combines PacBio long reads and Illumina short reads. The assembled genome of chieh-qua is approximately 953.3 Mb in size and is organized into 12 chromosomes, with contig N50 of 6.9 Mb and scaffold N50 of 68.2 Mb. Notably, the chieh-qua genome is comparable in size to the wax gourd genome. Through gene prediction analysis, we have identified a total of 24 593 protein-coding genes in the A36 genome. Additionally, approximately 56.6% (539.3 Mb) of the chieh-qua genome consists of repetitive sequences. Comparative genome analysis revealed that chieh-qua and wax gourd are closely related, indicating a close evolutionary relationship between the two species. Population genomic analysis, employing 129 chieh-qua accessions and 146 wax gourd accessions, demonstrated that chieh-qua exhibits greater genetic diversity compared to wax gourd. We also employed the GWAS method to identify related QTLs associated with subgynoecy, an interested and important trait in chieh-qua. The MYB59 (BhiCQ0880026447) exhibited relatively high expression levels in the shoot apex of four subgynoecious varieties compared with monoecious varieties. Overall, this research provides insights into the domestication history of chieh-qua and offers valuable genomic resources for further molecular research.
Comparative transcriptome and functional analyses provide insights into the key factors regulating shoot regeneration in highbush blueberry
Authors: Omori Masafumi , Yamane Hisayo , Tao Ryutaro
Published: April 2024

Establishing an efficient plant regeneration system is a crucial prerequisite for genetic engineering technology in plants. However, the regeneration rate exhibits considerable variability among genotypes, and the key factors underlying shoot regeneration capacity remain largely elusive. Blueberry leaf explants cultured on a medium rich in cytokinins exhibit direct shoot organogenesis without prominent callus formation, which holds promise for expediting genetic transformation while minimizing somatic mutations during culture. The objective of this study is to unravel the molecular and genetic determinants that govern cultivar-specific shoot regeneration potential in highbush blueberry (Vaccinium corymbosum L.). We conducted comparative transcriptome analysis using two highbush blueberry genotypes: ‘Blue Muffin’ (‘BM’) displaying a high regeneration rate (>80%) and ‘O’Neal’ (‘ON’) exhibiting a low regeneration rate (<10%). The findings revealed differential expression of numerous auxin-related genes; notably, ‘BM’ exhibited higher expression of auxin signaling genes compared to ‘ON’. Among blueberry orthologs of transcription factors involved in meristem formation in Arabidopsis, expression of VcENHANCER OF SHOOT REGENERATION (VcESR), VcWUSCHEL (VcWUS), and VcCUP-SHAPED COTYLEDON 2.1 were significantly higher in ‘BM’ relative to ‘ON’. Exogenous application of auxin promoted regeneration, as well as VcESR and VcWUS expression, whereas inhibition of auxin biosynthesis yielded the opposite effects. Overexpression of VcESR in ‘BM’ promoted shoot regeneration under phytohormone-free conditions by activating the expression of cytokinin- and auxin-related genes. These findings provide new insights into the molecular mechanisms underlying blueberry regeneration and have practical implications for enhancing plant regeneration and transformation techniques.
Independent Transitions to Freshwater Environments Promote Phenotypic Divergence, Not Convergence, in Stingrays
Authors: Magnuson A , Dean M N , Weaver J C , Fontenelle J P , Lovejoy N R , Kolmann M A
Published: April 2024

Synopsis

Instances of convergent or parallel evolution provide a potent model system for exploring contingency and determinism in evolutionary biology. Likewise, the multiple, independent habitat transitions from saltwater to freshwater biomes offer opportunities for studying convergent evolution within and among different vertebrate lineages. For example, stingrays have invaded freshwater habitats multiple times across different continents, sometimes even several times within the same clade (e.g., Dasyatidae). We evaluated the frequency of saltwater–freshwater invasions in stingrays, compared ecological and phenotypic diversification among freshwater and saltwater lineages, and assessed the degree of convergence among freshwater species. Despite not being morphologically distinct from saltwater stingrays, freshwater stingrays do expand the margins of stingray morphological diversity. According to our data, trophic specialists occupied non-overlapping regions of morphospace, with piscivores and molluscivores being distinct from other diet guilds. Freshwater stingrays as a group did not strongly converge morphologically, neither did freshwater rays from different lineages, which shared similar niches. These findings could be explained by there not being enough time for convergence to occur among more ancient and more recent freshwater lineages. Alternatively, the different ancestral bauplans of various freshwater ray lineages and weak selection on optimal phenotypes could promote contingency in the form of evolution along paths of least resistance.
Learning from Civil Society Actors in Turkey: Using Transitional Justice in an Ongoing Conflict
Authors: Alici Nisan
Published: April 2024

ABSTRACT∞

This article examines the role of civil society in the implementation of transitional justice in Turkey’s ongoing Kurdish conflict, which is characterized by historical state violence and a lack of official transitional justice processes. Drawing on 24 interviews, the research reveals the evolution of civil society engagement from its peak during the 2013–2015 peace process to its decline under increasing authoritarianism. The research argues that, despite challenges, civil society retains the potential to drive incremental change in the absence of formal transitional justice mechanisms. However, the authoritarian regime has significantly curtailed its capacity, creating a limited civic space for transitional justice. The article highlights the need for stronger links between civil society in Turkey and international transitional justice scholarship. Such collaboration could empower activists, enabling them to overcome challenges and increase their effectiveness. Turkey offers a unique case for transitional justice scholars and practitioners to learn from civil society actors committed to pursuing justice.
A Construction of Deformations to General Algebras
Authors: Bowman David , Puljić Dora , Smoktunowicz Agata
Published: April 2024

One of the questions investigated in deformation theory is to determine to which algebras can a given associative algebra be deformed. In this paper we investigate a different but related question, namely: for a given associative finite-dimensional ${\mathbb{C}}$-algebra $A$, find algebras $N$, which can be deformed to $A$. We develop a simple method that produces associative and flat deformations to investigate this question. As an application of this method we answer a question of Michael Wemyss about deformations of contraction algebras.
A Facial Order for Torsion Classes
Authors: Hanson Eric J
Published: April 2024

We generalize the “facial weak order” of a finite Coxeter group to a partial order on a set of intervals in a complete lattice. We apply our construction to the lattice of torsion classes of a finite-dimensional algebra and consider its restriction to intervals coming from stability conditions. We give two additional interpretations of the resulting “facial semistable order”: one using cover relations, and one using Bongartz completions of 2-term presilting objects. For $\tau $-tilting finite algebras, this allows us to prove that the facial semistable order is a semidistributive lattice. We then show that, in any abelian length category, our new partial order can be partitioned into a set of completely semidistributive lattices, one of which is the original lattice of torsion classes.
Is it Discriminatory to Mistreat a Migrant Domestic Worker? The Cases of Taiwo and Onu
Authors: Connolly Michael
Published: April 2024

When presented with images of the American plantations, seamstress sweatshops, Morecambe Bay’s Chinese cockle pickers or Qatar’s World Cup stadium builders, a sense of inequality will accompany any normal reaction of shock and revulsion. The exploitation of a group of migrant workers readily is characterised as racist, sexist or both. Yet, when reduced to the sole migrant worker, the legal recognition of discrimination is denied. In such cases, the UK Supreme Court posits a clear distinction between vulnerability and nationality. Not only does this seem somewhat doctrinal and lacking in principle, it produces a likely anomaly between the group and individual exploitation. It also stymies claims for the inevitable psychological harm. This paper presents a brief account of the plight of migrant workers in the UK and the legal landscape regarding trafficking. The main body presents a critical appraisal of the Supreme Court’s denial, in Taiwo v Olaigbe and Onu v Akwiwu, that the mistreatment of a sole migrant worker is not discriminatory. It demonstrates that equality law readily can recognise discrimination in such cases. This is followed by some considerations on policy and alternative remedies.
Maternal pre- and postpartum supplementation of a Bacillus-based DFM enhanced cow and calf performance
Authors: Izquierdo Vinicius S , Cappellozza Bruno I , Silva João V L , Santos Giovanna C M , Miranda André , Bittar João H J , Pickett Autumn , Mackey Shea , Cooke Reinaldo F , Vendramini João M B , Moriel Philipe
Published: April 2024

This study evaluated the effects of maternal supplementation of a Bacillus-based direct-fed microbial (DFM) on the physiology and growth performance of Bos indicus-influenced cow–calf pairs. On day 0 (~139 d before expected calving date), 72 fall-calving, Brangus crossbred beef heifers (20 to 22 mo of age) pregnant with first offspring were stratified by their initial body weight (BW; 431 ± 31 kg) and body condition score (BCS; 6.0 ± 0.36; scale 1 to 9), and randomly allocated into 1 of 12 bahiagrass pastures (1 ha and six heifers per pasture). Treatments were randomly assigned to pastures (six pastures per treatment) and consisted of heifers supplemented with 1 kg/d of soybean hulls (dry matter, DM) that was added (BAC) or not (CON) with DFM containing Bacillus subtilis and B. licheniformis (Bovacillus; Chr. Hansen A/S, Hørsholm, Denmark). Treatments were provided from days 0 to 242 (139 ± 4 d prepartum to 104 ± 4 d postpartum). Calves were weaned on day 242 (96 ± 30 d of age) and then allocated into 1 of 16 drylot pens and fed the same concentrate at 3.25% of BW (DM) until day 319. Maternal treatment effects were not detected (P ≥ 0.29) for herbage allowance and forage chemical composition. Heifer BCS on days 39 and 63 tended (P ≤ 0.09) to be greater for BAC vs. CON heifers, whereas heifer BCS on day 91 was greater (P = 0.01) for BAC vs. CON heifers. Heifer BCS did not differ (P ≥ 0.20) between treatments on days 179 and 242. Plasma glucose concentration did not differ from days 0 to 63 (P ≥ 0.14) but were greater (P < 0.01) on day 179 and tended (P = 0.09) to be greater on day 242 for BAC vs. CON heifers. Calf BW at birth, ADG from birth to weaning, and BW at weaning did not differ (P ≥ 0.19) between treatments, but calf BW at drylot exit (day 319) was greater (P = 0.05) for BAC vs. CON calves. Maternal treatment effects were not detected (P ≥ 0.42) for calf serum concentration of IgG at birth and postvaccination plasma concentrations of glucose, cortisol, and haptoglobin. Serum titers against bovine respiratory syncytial virus (BRSV) were greater (P = 0.04) for BAC vs. CON calves on day 287, whereas seroconversion against parainfluenza-3 virus (PI-3) was greater (P < 0.01) for BAC vs. CON calves on day 271. Thus, maternal supplementation of a Bacillus-based DFM increased prepartum BCS gain and postpartum plasma glucose concentration of heifers and led to positive carryover effects on postweaning BW gain and humoral immune response in their offspring.
COVID-19 pediatric vaccine authorization, FDA authority, and individual misperception of risk
Authors: Sax Joanna K , Doran Neal
Published: April 2024

Vaccines are one component to the public health strategies to alleviate the COVID-19 pandemic. Hesitancy regarding COVID-19 vaccines in the United States has been problematic, which is not surprising given increasing overall vaccine hesitancy in recent decades. Most vaccines are administered during childhood years. Consequently, understanding hesitancy toward administration of vaccines in this age group may provide insight into possible interventions to reduce vaccine hesitancy. The present study analyzed a subset of over 130,000 public comments posted in response to a notice of meeting of the vaccine advisory group to the Food and Drug Administration. The meeting addressed whether to recommend Emergency Use Authorization (‘EUA’) of the COVID-19 vaccine for children ages 5–11. The results of the study demonstrate that most comments opposed EUA and these comments were associated with statements that indicated misperceptions of risk. Findings provide interesting insights regarding the role of public comments generally but also suggest that the public participation process in notice and comment can be modified to serve as an intervention to align individual perceptions of risk more closely with evidence-based assessment of risk. In addition, the findings provide opportunities to consider strategies for public health messaging.
Investigating the Interplay of Polar Nanodomains and Superconductivity in Doped Strontium Titanate through Transmission Electron Microscopy
Authors: Salmani-Rezaie Salva
Published: April 2024

The simultaneous presence of itinerant carriers and polar crystal distortions poses a persistent challenge, especially in polar superconductors such as doped strontium titanate (SrTiO3). This study employs scanning transmission electron microscopy (STEM) to investigate the interplay between ferroelectricity and superconductivity in SrTiO3. Contrary to conventional models, the ferroelectric transition in strained, undoped SrTiO3 exhibits pronounced order-disorder characteristics. Increasing carrier concentration disrupts polar nanodomains, with dopant atoms contributing to the suppression of the ferroelectric transition. The destruction of the global ferroelectric state correlates with the suppression of superconductivity in strained SrTiO3 films, emphasizing the essential role of polar order. The length scale of polar order emerges as a crucial parameter controlling superconductivity in SrTiO3, providing valuable insights into the competition between itinerant carriers and polar crystal distortions.
The discovery of novel noncoding RNAs in 50 bacterial genomes
Authors: Narunsky Aya , Higgs Gadareth A , Torres Blake M , Yu Diane , de Andrade Gabriel Belem , Kavita Kumari , Breaker Ronald R
Published: April 2024

Structured noncoding RNAs (ncRNAs) contribute to many important cellular processes involving chemical catalysis, molecular recognition and gene regulation. Few ncRNA classes are broadly distributed among organisms from all three domains of life, but the list of rarer classes that exhibit surprisingly diverse functions is growing. We previously developed a computational pipeline that enables the near-comprehensive identification of structured ncRNAs expressed from individual bacterial genomes. The regions between protein coding genes are first sorted based on length and the fraction of guanosine and cytidine nucleotides. Long, GC-rich intergenic regions are then examined for sequence and structural similarity to other bacterial genomes. Herein, we describe the implementation of this pipeline on 50 bacterial genomes from varied phyla. More than 4700 candidate intergenic regions with the desired characteristics were identified, which yielded 44 novel riboswitch candidates and numerous other putative ncRNA motifs. Although experimental validation studies have yet to be conducted, this rate of riboswitch candidate discovery is consistent with predictions that many hundreds of novel riboswitch classes remain to be discovered among the bacterial species whose genomes have already been sequenced. Thus, many thousands of additional novel ncRNA classes likely remain to be discovered in the bacterial domain of life.
MutationExplorer: a webserver for mutation of proteins and 3D visualization of energetic impacts
Authors: Philipp Michelle , Moth Christopher W , Ristic Nikola , Tiemann Johanna K S , Seufert Florian , Panfilova Aleksandra , Meiler Jens , Hildebrand Peter W , Stein Amelie , Wiegreffe Daniel , Staritzbichler René
Published: April 2024

The possible effects of mutations on stability and function of a protein can only be understood in the context of protein 3D structure. The MutationExplorer webserver maps sequence changes onto protein structures and allows users to study variation by inputting sequence changes. As the user enters variants, the 3D model evolves, and estimated changes in energy are highlighted. In addition to a basic per-residue input format, MutationExplorer can also upload an entire replacement sequence. Previously the purview of desktop applications, such an upload can back-mutate PDB structures to wildtype sequence in a single step. Another supported variation source is human single nucelotide polymorphisms (SNPs), genomic coordinates input in VCF format. Structures are flexibly colorable, not only by energetic differences, but also by hydrophobicity, sequence conservation, or other biochemical profiling. Coloring by interface score reveals mutation impacts on binding surfaces. MutationExplorer strives for efficiency in user experience. For example, we have prepared 45 000 PDB depositions for instant retrieval and initial display. All modeling steps are performed by Rosetta. Visualizations leverage MDsrv/Mol*. MutationExplorer is available at: http://proteinformatics.org/mutation_explorer/.
D-TERMINED, a phase 1 trial in newly diagnosed high-grade glioma with temozolomide, radiation, and minocycline followed by adjuvant minocycline/temozolomide
Authors: McKean William B , Yang Jingye , Boucher Kenneth , Shrieve Dennis C , Suneja Gita , Salzman Karen , Jensen Randy , Colman Howard , Cohen Adam L
Published: April 2024

Background

Standard treatment for newly diagnosed high-grade gliomas remains suboptimal. Preclinical data indicate that mesenchymal transition and radiation resistance in glioblastoma are driven by NF-κB and microglia activation, which can be inhibited by minocycline. We assessed the safety and efficacy of minocycline combined with standard radiation and temozolomide in newly diagnosed high-grade gliomas.

Methods

Adults with newly diagnosed high-grade glioma were eligible. Minocycline was given with concurrent and adjuvant temozolomide. Minocycline doses were escalated using a 3 + 3 design and expanded to identify the maximum tolerated dose (MTD) and adverse event profile. Individual progression-free survival (PFS) was compared to predicted PFS based on RTOG RPA class using a binomial test. The relationships between mesenchymal and microglial biomarkers were analyzed with immunohistochemistry.

Results

The MTD of minocycline was 150 mg twice per day (N = 20); 1 patient (5%) experienced CTCAE grade 3 + nausea and dizziness, and 2 patients (10%) demonstrated thrombocytopenia requiring temozolomide interruptions. Twelve patients exceeded their predicted PFS (60%), which did not meet the predefined efficacy endpoint of 70%. Symptoms increased during post-radiation treatment but remained mild. No significant correlation was seen between biomarkers and PFS. Expression levels of P-p65, a marker of NF-κB activation, were correlated with the microglia marker IBA-1.

Conclusions

Minocycline at 150 mg twice per day is well tolerated with standard chemoradiation in patients with newly diagnosed high-grade gliomas. PFS was not significantly increased with the addition of minocycline when compared to historical controls. NF-κB activation correlates with microglia levels in high-grade glioma.
Signed Eigenvalue/vector Distribution of Complex Order-Three Random Tensor
Authors: Sasakura Naoki
Published: April 2024

We compute the signed distribution of the eigenvalues/vectors of the complex order-three random tensor by computing a partition function of a four-fermi theory, where signs are from a Hessian determinant associated to each eigenvector. The issue of the presence of a continuous degeneracy of the eigenvectors is properly treated by a gauge fixing. The final expression is compactly represented by a generating function, which has an expansion whose powers are the dimensions of the tensor index spaces. A crosscheck is performed by Monte Carlo simulations. By taking the large-N limit we obtain a critical point where the behavior of the signed distribution qualitatively changes, and also the end of the signed distribution. The expected agreement of the end of the signed distribution with that of the genuine distribution provides a few applications, such as the largest eigenvalue, the geometric measure of entanglement, and the best rank-one approximation in the large-N limit.
Effect of a synthetic hydroxyapatite-based bone grafting material compared to established bone substitute materials on regeneration of critical-size bone defects in the ovine scapula
Authors: Wüster Jonas , Neckel Norbert , Sterzik Florian , Xiang-Tischhauser Li , Barnewitz Dirk , Genzel Antje , Koerdt Steffen , Rendenbach Carsten , Müller-Mai Christian , Heiland Max , Nahles Susanne , Knabe Christine
Published: April 2024

Lately, the potential risk of disease transmission due to the use of bovine-derived bone substitutes has become obvious, demonstrating the urgent need for a synthetic grafting material with comparable bioactive behaviour and properties. Therefore, the effect of a synthetic hydroxyapatite (HA) (Osbone®) bone grafting material on bone regeneration was evaluated 2 weeks, 1 month, and 3, 6, 12 and 18 months after implantation in critical-size bone defects in the ovine scapula and compared to that of a bovine-derived HA (Bio-Oss®) and β-tricalcium phosphate (TCP) (Cerasorb® M). New bone formation and the biodegradability of the bone substitutes were assessed histomorphometrically. Hard tissue histology and immunohistochemical analysis were employed to characterize collagen type I, alkaline phosphatase, osteocalcin, as well as bone sialoprotein expression in the various cell and matrix components of the bone tissue to evaluate the bioactive properties of the bone grafting materials. No inflammatory tissue response was detected with any of the bone substitute materials studied. After 3 and 6 months, β-TCP (Cerasorb® M) showed superior bone formation when compared to both HA-based materials (3 months: β-TCP 55.65 ± 2.03% vs. SHA 49.05 ± 3.84% and BHA 47.59 ± 1.97%; p ≤ 0.03; 6 months: β-TCP 62.03 ± 1.58%; SHA: 55.83 ± 2.59%; BHA: 53.44 ± 0.78%; p ≤ 0.04). Further, after 12 and 18 months, a similar degree of bone formation and bone–particle contact was noted for all three bone substitute materials without any significant differences. The synthetic HA supported new bone formation, osteogenic marker expression, matrix mineralization and good bone-bonding behaviour to an equal and even slightly superior degree compared to the bovine-derived HA. As a result, synthetic HA can be regarded as a valuable alternative to the bovine-derived HA without the potential risk of disease transmission.
Managing Mental Accounts: Payment Cards and Consumption Expenditures
Authors: Gelman Michael , Roussanov Nikolai
Published: April 2024

Does mental accounting matter for total consumption expenditures? We exploit a unique setting in which individuals exogenously receive a new payment card, without requesting one. Using random variation in the time of receipt, we show that individuals temporarily increase total consumption expenditure by making purchases with the new card without reducing spending on the others. We do not observe a corresponding increase in indebtedness. Total consumption expenditure rises even for the least liquidity-constrained individuals. The evidence is consistent with consumers treating methods of payment as nonfungible budget categories, as suggested by models of mental accounting and narrow bracketing.
Fibroblast activation protein inhibitor-positron emission tomography in aortitis: fibroblast pathology in active inflammation and remission
Authors: Röhrich Manuel , Rosales Juan J , Hoppner Jorge , Kvacskay Peter , Blank Norbert , Loi Lisa , Paech Daniel , Schreckenberger Mathias , Giesel Frederik , Kauczor Hans Ulrich , Lorenz Hanns Martin , Haberkorn Uwe , Merkt Wolfgang
Published: April 2024

Objectives

Epigenetically modified fibroblasts contribute to chronicity in inflammatory diseases. Reasons for the relapsing character of large vessel vasculitis (LVV) remain obscure, including the role of fibroblasts, in part due to limited access to biopsies of involved tissue.68Ga FAPI-46 (FAPI)-PET/CT detects activated fibroblasts in vivo. In this exploratory pilot study, we tested the detection of fibroblast activation in vessel walls using FAPI-PET/CT in LVV with aortitis.

Methods

Eight LVV patients with aortitis and eight age- and gender-matched controls were included. The distribution of FAPI uptake was evaluated in the aorta and large vessels. FAPI-uptake was compared with MRI inflammatory activity scores. Imaging results were compared with clinical parameters such as serum inflammatory markers, time of remission and medication.

Results

Three aortitis patients were clinically active and five in remission. Irrespective of activity, FAPI uptake was significantly enhanced in aortitis compared with controls. Patients in remission had a mean duration of remission of 2.8 years (range 1–4 years), yet significant FAPI uptake in the vessel wall was found. In remitted aortitis, MRI inflammatory scores were close to be negative, while in 4/5 patients visually identifiable FAPI uptake was observed.

Conclusions

This pilot feasibility study shows significant tracer uptake in the aortic walls in LVV. FAPI positivity indicates ongoing fibroblast pathology in clinically remitted LVV.
Risk of chronic kidney disease in 260 patients with lupus nephritis: analysis of a nationwide multicentre cohort with up to 35 years of follow-up
Authors: Farinha Filipa , Barreira Sofia , Couto Maura , Cunha Margarida , Fonseca Diogo , Freitas Raquel , Inês Luís , Luís Mariana , Macieira Carla , Prata Ana R , Rodrigues Joana , Santos Bernardo , Torres Rita , Pepper Ruth J , Rahman Anisur , Santos Maria J
Published: April 2024

Objectives

To compare proliferative (PLN) and membranous (MLN) lupus nephritis (LN) regarding clinical and laboratory presentation and long-term outcomes, and to investigate predictors of progression to chronic kidney disease (CKD).

Methods

Multicentre observational study, with retrospective analysis of a prospective cohort, using data from the Rheumatic Diseases Portuguese Registry – Reuma.pt. Patients with biopsy-proven PLN, MLN and mixed LN were included. Cox regression survival analysis was used to investigate predictors of CKD.

Results

A total of 260 patients were included. Median follow-up was 8 years (IQR 11; minimum 1, maximum 35 years). MLN patients presented with significantly lower serum creatinine [0.70 (IQR 0.20; minimum 0.50, maximum 1.30) mg/dl vs 0.80 (IQR 0.31; minimum 0.26, maximum 2.60) in PLN, P = 0.003]. Proteinuria levels did not differ between groups (P = 0.641). Levels of complement were reduced in PLN but nearly normal in MLN patients, and there were fewer patients with positive anti-dsDNA antibodies in the MLN group (P < 0.001). One year after the beginning of treatment, 62% of the patients achieved EULAR/ERA-EDTA complete response, with a further 5% achieving partial response. Patients with lower proteinuria at diagnosis were more likely to achieve a complete renal response at one year; however, proteinuria at diagnosis or at one year did not predict long-term CKD. Estimated glomerular filtration rate (eGFR) ≤75 mL/min/1.73 m2 at one year was the strongest predictor of progression to CKD (HR 23 [95% CI 8–62], P < 0.001). Other possible predictors included the use of azathioprine for induction of remission, older age at diagnosis and male sex.

Conclusion

Proteinuria levels did not predict LN histologic class in our cohort. eGFR cutoff of 75 mL/min/1.73 m2 after one year of treatment was strongly predictive of progression to CKD.
A comprehensive history of injection therapy for erectile dysfunction, 1982-2023
Authors: Porst Hartmut , Lewis Ronald , Virag Ronald , Goldstein Irwin
Published: April 2024

Introduction

Although oral phosphodiesterase 5 inhibitors represent a first choice and long-term option for about half of all patients with erectile dysfunction (ED), self-injection therapy with vasoactive drugs remains a viable alternative for all those who are not reacting or cannot tolerate oral drug therapy. This current injection therapy has an interesting history beginning in 1982.

Objectives

To provide a comprehensive history of self-injection therapy from the very beginnings in 1982 by contemporary witnesses and some members of the International Society for Sexual Medicine’s History Committee, a complete history of injection therapy is prepared from eyewitness accounts and review of the published literature on the subject, as well as an update of the current status of self-injection therapy.

Methods

Published data on injection therapy, as a diagnostic and therapeutic tool for ED, were reviewed thoroughly by PubMed and Medline research from 1982 until June 2023. Early pioneers and witnesses added firsthand details to this historical review. Therapeutic reports of injection therapy were reviewed, and results of side effects and complications were thoroughly reviewed.

Results

The pioneers of the first hours were Ronal Virag (1982) for papaverine, Giles Brindley (1983) for cavernosal alpha-blockade (phentolamine and phenoxybenzamine), Adrian Zorgniotti (1985) for papaverine/phentolamine, and Ganesan Adaikan and N. Ishii (1986) for prostaglandin E1. Moxisylyte (thymoxamine) was originally marketed but later withdrawn. The most common side effect is priapism, with the greatest risk of this from papaverine, which has modified its use for therapy. Currently, prostaglandin E1 and trimixes continue to be the agents of choice for diagnostic and therapeutic use in ED. A recent agent is a mixture of a vasoactive intestinal polypeptide (aviptadil) and phentolamine.

Conclusions

After 40 years, self-injection therapy represents the medication with the highest efficacy and reliability rates and remains a viable option for many couples with ED. The history of this therapy is rich.
Modulatory potential of Bacopa monnieri against aflatoxin B1 induced biochemical, molecular and histological alterations in rats
Authors: Rathour Arti , Gupte Shamli S , Gupta Divya , Singh Shubham , Shrivastava Sadhana , Yadav Deepa , Shukla Sangeeta
Published: April 2024

Oxidative injury is concerned with the pathogenesis of several liver injuries, including those from acute liver failure to cirrhosis. This study was designed to explore the antioxidant activity of Bacopa monnieri (BM) on Aflatoxin B1 (AFB1) induced oxidative damage in Wistar albino rats. Aflatoxin B1 treatment (200 μg/kg/day, p.o.) for 28 days induced oxidative injury by a significant alteration in serum liver function test marker enzymes (AST, ALT, ALP, LDH, albumin and bilirubin), inflammatory cytokines (IL-6, IL-10 and TNF-α), thiobarbituric acid reactive substances (TBARS) along with reduction of antioxidant enzymes (GSH, SOD, CAT), GSH cycle enzymes and drug-metabolizing enzymes (AH and AND). Treatment of rats with B. monnieri (20, 30 and 40 mg/kg for 5 days, p.o.) after 28 days of AFB1 intoxication significantly restored these parameters near control in a dose-dependent way. Histopathological examination disclosed extensive hepatic injuries, characterized by cellular necrosis, infiltration, congestion and sinusoidal dilatation in the AFB1-treated group. Treatment with B. monnieri significantly reduced these toxic effects resulting from AFB1. B. monnieriper se group (40 mg/kg) did not show any significant change and proved safe. The cytotoxic activity of B. monnieri was also evaluated on HepG2 cells and showed a good percentage of cytotoxic activity. This finding suggests that B. monnieri protects the liver against oxidative damage caused by AFB1, which aids in the evaluation of the traditional usage of this medicinal plant.
Single-cell transcriptomics unveiled that early life BDE-99 exposure reprogrammed the gut-liver axis to promote a proinflammatory metabolic signature in male mice at late adulthood
Authors: Lim Joe Jongpyo , Goedken Michael , Jin Yan , Gu Haiwei , Cui Julia Yue
Published: April 2024

Polybrominated diphenyl ethers (PBDEs) are legacy flame retardants that bioaccumulate in the environment. The gut microbiome is an important regulator of liver functions including xenobiotic biotransformation and immune regulation. We recently showed that neonatal exposure to polybrominated diphenyl ether-99 (BDE-99), a human breast milk-enriched PBDE congener, up-regulated proinflammation-related and down-regulated drug metabolism-related genes predominantly in males in young adulthood. However, the persistence of this dysregulation into late adulthood, differential impact among hepatic cell types, and the involvement of the gut microbiome from neonatal BDE-99 exposure remain unknown. To address these knowledge gaps, male C57BL/6 mouse pups were orally exposed to corn oil (10 ml/kg) or BDE-99 (57 mg/kg) once daily from postnatal days 2–4. At 15 months of age, neonatal BDE-99 exposure down-regulated xenobiotic and lipid-metabolizing enzymes and up-regulated genes involved in microbial influx in hepatocytes. Neonatal BDE-99 exposure also increased the hepatic proportion of neutrophils and led to a predicted increase of macrophage migration inhibitory factor signaling. This was associated with decreased intestinal tight junction protein (Tjp) transcripts, altered gut environment, and dysregulation of inflammation-related metabolites. ScRNA-seq using germ-free (GF) mice demonstrated the necessity of a normal gut microbiome in maintaining hepatic immune tolerance. Microbiota transplant to GF mice using large intestinal microbiome from adults neonatally exposed to BDE-99 down-regulated Tjp transcripts and up-regulated several cytokines in large intestine. In conclusion, neonatal BDE-99 exposure reprogrammed cell type-specific gene expression and cell-cell communication in liver towards proinflammation, and this may be partly due to the dysregulated gut environment.