bluuebunny/crossref_metadata_2025 huggingface dataset:
Cross-species applicability of an adverse outcome pathway network for thyroid hormone system disruption
Authors: Haigis Ann-Cathrin , Vergauwen Lucia , LaLone Carlie A , Villeneuve Daniel L , O’Brien Jason M , Knapen Dries
Published: July 2023

Thyroid hormone system disrupting compounds are considered potential threats for human and environmental health. Multiple adverse outcome pathways (AOPs) for thyroid hormone system disruption (THSD) are being developed in different taxa. Combining these AOPs results in a cross-species AOP network for THSD which may provide an evidence-based foundation for extrapolating THSD data across vertebrate species and bridging the gap between human and environmental health. This review aimed to advance the description of the taxonomic domain of applicability (tDOA) in the network to improve its utility for cross-species extrapolation. We focused on the molecular initiating events (MIEs) and adverse outcomes (AOs) and evaluated both their plausible domain of applicability (taxa they are likely applicable to) and empirical domain of applicability (where evidence for applicability to various taxa exists) in a THSD context. The evaluation showed that all MIEs in the AOP network are applicable to mammals. With some exceptions, there was evidence of structural conservation across vertebrate taxa and especially for fish and amphibians, and to a lesser extent for birds, empirical evidence was found. Current evidence supports the applicability of impaired neurodevelopment, neurosensory development (eg, vision) and reproduction across vertebrate taxa. The results of this tDOA evaluation are summarized in a conceptual AOP network that helps prioritize (parts of) AOPs for a more detailed evaluation. In conclusion, this review advances the tDOA description of an existing THSD AOP network and serves as a catalog summarizing plausible and empirical evidence on which future cross-species AOP development and tDOA assessment could build.
Effect of paracetamol on the storage cells of Hypsibius exemplaris—ultrastructural analysis
Authors: Wieczorkiewicz Filip , Sojka Julia , Poprawa Izabela
Published: July 2023

Tardigrades in their natural environment are exposed to various environmental toxicants, including non-steroidal anti-inflammatory drugs (NSAIDs) or antipyretics such as paracetamol. This drug can enter the animal’s body through the body wall or the digestive system with food and can affect the biology of organisms. In this paper, we report for the first time the effects of paracetamol on tardigrade storage cells. We analyzed the effects of short-term (7 days) and long-term (28 days) exposure of Hypsibius exemplaris storage cells to three paracetamol concentrations (0.2 µgxL−1, 230 µgxL−1, 1 mgxL−1). Our results showed that increasing paracetamol concentration and incubation time increases the number of damaged mitochondria in storage cells, and autophagy is activated and intensified. Moreover, the relocation of some organelles and cell deformation may indicate cytoskeleton damage.
Pain Management in the Postoperative Period for People With Dementia: An Integrative Review
Authors: Neville Emily K. , Stolic Snezana , Wagstaff Ruth A. , Neville Christine C.
Published: July 2023

Objective:

With the increased global prevalence of older people with dementia, more will present for surgery over the coming decades. Therefore, the objective of this study was to synthesize the existing research about how pain in managed for people with dementia in the postoperative period and discuss the implications for clinical practice.

Methods:

For this integrative review, the Cumulative Index to Nursing and Allied Health literature, Medline/Pubmed, ProQuest, ERIC, and Health Source Nursing were searched to identify original empirical research published between 2000 and 2021. Tasks were divided between reviewers to ensure independent study selection, data extraction, and risk of bias assessment.

Results:

Eleven articles were eligible. The evidence is incompletely developed therefore the review focused on pain assessment, the types and amount of pain relief, that people with dementia receive less analgesia than people without dementia and the challenges for effective pain management. Most studies were surgery for hip fracture so there is scope to look at outcomes for other types of surgery. Analgesia was administered but it was noted that even over a 20-year period, people with dementia received less than cognitively intact people. Pain management could have a stronger evidence-base with more psychometric development of pain assessment tools. Challenges are due to the impaired ability of the person with dementia to communicate pain and that clinicians have difficulty understanding pain behavior in people with dementia.

Conclusion:

Adequate pain management for people with dementia in the postoperative period is important for a faster and better recovery.
Vascularized pronator quadratus pedicled bone grafting versus iliac crest bone grafting in the treatment of scaphoid nonunion: a retrospective study
Authors: Zandrahimi Farshad , Aazami Maryam , Sarhadi Zade Alireza , Saied Alireza
Published: July 2023

Background:

Vascularized pronator quadratus pedicled bone grafting is a viable procedure for the treatment of scaphoid nonunion. However, its superiority over iliac crest bone grafting is unknown. In this study, we compare the union rate and outcomes of these procedures in the treatment of scaphoid nonunion.

Methods:

The medical profiles of the patients with scaphoid nonunion that were treated with either pronator quadratus pedicled bone grafting (n=23) or iliac crest bone grafting procedure (n=31) were retrospectively reviewed. Patients with avascular necrosis of the scaphoid and those with the involvement of the proximal pole were excluded. The outcome measures were the union rate and time, active wrist range of motion, pinch, and grip strength.

Results:

The mean age of the patients was 30±8.1 yr. Bony union was achieved in all patients of the study groups. The mean time to union was 9.1±2.8 wk in the pronator quadratus group and 8.7±3.5 wk in the iliac crest groups (P=0.14). The mean active flexion, extension, radial deviation, ulnar deviation, pinch, and grip strength of the involved wrist averaged 87.3%, 86.2%, 80.2%, 89.1%, 84.3%, and 85.6% of the contralateral wrist in the pronator quadratus group and 85.5%, 87%, 77.8%, 85.1%, 88.8%, and 87.8% of the contralateral wrist in the iliac crest group, respectively. These differences were not statistically significant.

Conclusion:

Pronator quadratus pedicled bone grafting provides a similar union rate and outcomes compared to the iliac crest bone grafting in the treatment of scaphoid nonunion.

Level of Evidence:

IV
A randomized comparative study of flexible ureterorenoscopy versus mini-percutaneous nephrolithotomy for treatment of renal stones 2 cm or less
Authors: Darwish Amr E. , Abdel Moneim Alaa E. , Ahmed Abdelfatah I. , Hamdy Seif M. , Abolella Hassan A. , Reda Ahmed
Published: July 2023

Background

Flexible ureterorenoscopy (fURS) and mini-percutaneous nephrolithotomy (mPCNL) have been increasingly used for the treatment of renal stones. However, current guidelines do not recommend one modality over the other. The aim of this study is to compare the safety and efficacy of treatment with fURS versus mPCNL for renal stones sized 2 cm or less.

Materials and methods

A prospective, randomized, comparative study was conducted between January 2019 and July 2021 at 3 tertiary care urology centers. Inclusion criteria were adult patients with renal stone(s) ≤ 2 cm with inappropriateness or failure of extracorporeal shock-wave lithotripsy. Subjects were assigned to 1 of 2 treatment groups, either mPCNL or fURS. Two primary outcomes were assessed: (1) initial success rate, defined as the absence of clinically significant residual fragments (>2 mm) on kidney ureter bladder X-ray and ultrasound on the first postoperative day; and (2) complications, which were reported according to the Modified Clavien-Dindo classification system. Secondary outcomes included final success rate, defined as the absence of clinically significant residual fragments on noncontrast computed tomography on the 90th postoperative day; operative time; auxiliary procedures and blood transfusion rates; hemoglobin drop; and length of hospital stay.

Results

One hundred and eighteen procedures were analyzed (59 in each group). The initial success rate of the mPCNL group (93%) was significantly higher than that of the fURS group (70%). Complications occurred more frequently with mPCNL than fURS (44.1% vs. 18.6%, respectively). Final success rate, operative time, and length of hospital stay were comparable between the 2 groups.

Conclusions

Mini-percutaneous nephrolithotomy is more effective than fURS as a single-step treatment for renal stones <2 cm because of its higher initial success rate and lower auxiliary procedure rate. However, mPCNL results in significantly higher complication rates than fURS.
Radiation and Dose-densification of R-CHOP in Aggressive B-cell Lymphoma With Intermediate Prognosis: The UNFOLDER Study
Authors: Thurner Lorenz , Ziepert Marita , Berdel Christian , Schmidt Christian , Borchmann Peter , Kaddu-Mulindwa Dominic , Viardot Andreas , Witzens-Harig Mathias , Dierlamm Judith , Haenel Mathias , Metzner Bernd , Wulf Gerald , Lengfelder Eva , Keller Ulrich B. , Frickhofen Norbert , Nickelsen Maike , Gaska Tobias , Griesinger Frank , Mahlberg Rolf , Marks Reinhard , Shpilberg Ofer , Lindemann Hans-Walter , Soekler Martin , Fischer von Weikersthal Ludwig , Kiehl Michael , Roemer Eva , Bentz Martin , Krammer-Steiner Beate , Trappe Ralf , de Nully Brown Peter , Federico Massimo , Merli Francesco , Engelhard Marianne , Glass Bertram , Schmitz Norbert , Truemper Lorenz , Bewarder Moritz , Hartmann Frank , Murawski Niels , Stilgenbauer Stephan , Rosenwald Andreas , Altmann Bettina , Schmidberger Heinz , Fleckenstein Jochen , Loeffler Markus , Poeschel Viola , Held Gerhard ,   on behalf of German Lymphoma Alliance (GLA)
Published: July 2023

UNFOLDER (Unfavorable Young Low-Risk Densification of R-Chemo Regimens) is an international phase-3 trial in patients 18–60 years with aggressive B-cell lymphoma and intermediate prognosis defined by age-adjusted International Prognostic Index (aaIPI) of 0 and bulky disease (≥7.5 cm) or aaIPI of 1. In a 2 × 2 factorial design patients were randomized to 6× R-CHOP-14 or 6× R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prediso[lo]ne) and to consolidation radiotherapy to extralymphatic and bulky disease or observation. Response was assessed according to the standardized response criteria published in 1999, not including F-18 fluordesoxyglucose positron emission tomography/computed tomography (FDG-PET). Primary endpoint was event-free survival (EFS). A total of 695 of 700 patients were eligible for the intention-to-treat analysis. Totally 467 patients qualified for radiotherapy of whom 305 patients were randomized to receive radiotherapy (R-CHOP-21: 155; R-CHOP-14: 150) and 162 to observation (R-CHOP-21: 81, R-CHOP-14: 81). Two hundred twenty-eight patients not qualifying for radiotherapy were randomized for R-CHOP-14 versus R-CHOP-21. After a median observation of 66 months 3-year EFS was superior in the radiotherapy-arm versus observation-arm (84% versus 68%; P = 0.0012), due to a lower rate of partial responses (PR) (2% versus 11%). PR often triggered additional treatment, mostly radiotherapy. No significant difference was observed in progression-free survival (PFS) (89% versus 81%; P = 0.22) and overall survival (OS) (93% versus 93%; P = 0.51). Comparing R-CHOP-14 and R-CHOP-21 EFS, PFS and OS were not different. Patients randomized to radiotherapy had a superior EFS, largely due to a lower PR rate requiring less additional treatment (NCT00278408, EUDRACT 2005-005218-19).
Ocular Surface Disease as Extraesophageal Gastroesophageal Reflux Disease Manifestation: A Specific Therapeutic Strategy
Authors: Di Zazzo Antonio , Micera Alessandra , Surico Pier Luigi , Balzamino Bijorn Omar , Luccarelli Vitaliana , Antonini Marco , Coassin Marco , Bonini Stefano
Published: July 2023

Purpose:

Gastroesophageal reflux disease (GERD) and laryngopharyngeal reflux (LPR) are common gastrointestinal disorders with extraesophageal manifestations (EGERD). Studies showed a correlation between GERD/LPR and ocular discomfort. Our aim was to report the prevalence of ocular involvement in patients with GERD/LPR, describe clinical and biomolecular manifestations, and provide a treatment strategy for this novel EGERD comorbidity.

Methods:

Fifty-three patients with LPR and 25 healthy controls were enrolled in this masked randomized controlled study. Fifteen naive patients with LPR were treated with magnesium alginate eye drops and oral therapy (magnesium alginate and simethicone tablets) with a 1-month follow-up. Clinical ocular surface evaluation, Ocular Surface Disease Index questionnaire, tear sampling, and conjunctival imprints were performed. Tear pepsin levels were quantified by ELISA. Imprints were processed for human leukocyte antigen-DR isotype (HLA-DR) immunodetection and for HLA-DR, IL8, mucin 5AC (MUC5AC), nicotine adenine dinucleotide phosphate (NADPH), vasoactive intestinal peptide (VIP), and neuropeptide Y (NPY) transcript expression (PCR).

Results:

Patients with LPR had significantly increased Ocular Surface Disease Index (P < 0.05), reduced T-BUT (P < 0.05), and higher meibomian gland dysfunction (P < 0.001) compared with controls. After treatment, tear break-up time (T-BUT) and meibomian gland dysfunction scores improved to normal values. Pepsin concentration increased in patients with EGERD (P = 0.01) and decreased with topical treatment (P = 0.0025), significantly. HLA-DR, IL8, and NADPH transcripts were significantly increased in the untreated versus controls and comparable significant values were obtained after treatment (P < 0.05). MUC5AC expression significantly increased with treatment (P = 0.005). VIP transcripts were significantly higher in EGERD than in controls and decreased with the topical treatment (P < 0.05). No significant changes were observed in NPY.

Conclusions:

We report an increase in prevalence of ocular discomfort in patients with GERD/LPR. The observations of VIP and NPY transcripts demonstrate the potential neurogenic nature of the inflammatory state. Restoration of the ocular surface parameters suggests the potential usefulness of topical alginate therapy.
Measurement of Anions in Tear Fluid Using Ion Chromatography
Authors: Saito Tomohiko , Suzuki Takashi , Nakayama Chika , Kato Yukina , Kakisu Koji , Itokawa Takashi , Hori Yuichi , Ushida Kiminori
Published: July 2023

Purpose:

Tear fluid (TF) contains a variety of electrolytes that exhibit a strong correlation with its osmotic pressure. These electrolytes are also related to the etiology of diseases on ocular surfaces such as dry eye syndromes and keratopathy. Although positive ions (cations) in TF have been investigated to understand their roles, negative ions (anions) have hardly been studied because applicable analytical methods are restricted to a few kinds. In this study, we established a method to analyze the anions involved in a sufficiently small amount of TF for in situ diagnosis of a single subject.

Methods:

Twenty healthy volunteers (10 men and 10 women) were recruited. Anions in their TF were measured on a commercial ion chromatograph (IC-2010, Tosoh, Japan). Tear fluid (5 μL or more) was collected from each subject with a glass capillary, diluted with 300 μL of pure water, and conveyed to the chromatograph. We successfully monitored the concentrations of bromide, nitrate, phosphate, and sulfate anions (Br−, NO3
−, HPO4
2−, and SO4
2−, respectively) in TF.

Results:

Br− and SO4
2− were universally detected in all samples, whereas NO3
− was found in 35.0% and HPO4
2− in 30.0% of them. The mean concentrations (mg/L) of each anion were Br−, 4.69 ± 0.96; NO3
−, 0.80 ± 0.68; HPO4
2−, 17.48 ± 7.60; and SO4
2−, 3.34 ± 2.54. As for SO4
2−, no sex differences or diurnal variations were observed.

Conclusions:

We established an efficient protocol to quantitate various inorganic anions involved in a small amount of TF using a commercially available instrument. This is the first step to elucidate the role of anions in TF.
Phacoemulsification Under the Complex Dua Layer–Descemet–Endothelium for Combined Cataract Surgery and Penetrating Keratoplasty After Failed Deep Anterior Lamellar Keratoplasty
Authors: Lucisano Andrea , Scorcia Vincenzo , Rossi Costanza , Scalia Giovanni , Giannaccare Giuseppe
Published: July 2023

Purpose:

The aim of this study was to report the surgical management of an eye with a cataract and a failed deep anterior lamellar keratoplasty (DALK) graft. Given the null visualization of the anterior chamber, instead of performing penetrating keratoplasty (PK) combined with open-sky extracapsular extraction, the cleavage plane of the previous DALK was used to expose the transparent complex including Dua layer (DL)–Descemet membrane (DM)–endothelium and to perform phacoemulsification in a closed system; then, PK was completed after the surgical removal of the complex DL–DM–endothelium.

Methods:

This study is a case report.

Results:

A 45-year-old woman with corneal opacity due to Acanthamoeba keratitis underwent multiple (n = 2) DALK surgeries. The second DALK graft underwent failure, with the development of severe corneal edema; a dense opacity of the lens was also present. The patient was scheduled for combined PK and cataract surgery. Because the cornea was too opaque to allow closed-system cataract surgery, a partial trephination was performed with the purpose of reopening the old donor–host junction and finding the deep cleavage plane. This maneuver permitted the exposition of the complex DL–DM–endothelium that was completely transparent, thus allowing standard phacoemulsification using the phaco-chop technique. A full-thickness corneal graft was then positioned and sutured.

Conclusions:

This case confirms the toughness of the complex DL–DM–endothelium and reveals the transparency of this complex even in the presence of a failed endothelium, thus highlighting distinct advantages of our surgical approach over the conventional one involving PK combined with open-sky extracapsular extraction.
Severe Mpox Infection of the Eye and Periocular Region
Authors: Bacorn Colin , Majidi Shahriyar , Schultz Hannah , Sulewski Michael E. , Eberhart Charles G. , Mahoney Nicholas R.
Published: July 2023

Mpox is an emerging zoonotic infection with potentially severe ocular and periocular consequences, particularly in immunocompromised patients. This report summarizes 2 cases of fulminant mpox presenting in patients with AIDS. In the first case, confluent lesions resulted in orbital compartment syndrome and total eyelid necrosis. In the second case, eyelid involvement was accompanied by corneal melt and perforation. Despite aggressive medical and surgical treatment, both patients developed permanent loss of vision and ultimately expired.
Isolated Orbital Apex Mucocele: A Case Study and Literature Review
Authors: Cancio Lorenzo Maria , Chin Michael , Tumuluri Krishna
Published: July 2023

Isolated orbital mucocele without connection between the mass and paranasal sinuses is extremely rare and poorly understood. Literature review of these cases are very few and present more anteriorly in the orbit. Here, the authors present a 33-year-old female with an isolated left orbital apex mucocele without direct communication with the adjacent paranasal sinuses and other vital orbital structures. Endoscopic sinus surgery with marsupialization was performed, and an orbital mucocele was confirmed on histopathology. Although uncommon, previously reported cases, including our patient have remained disease free of recurrence for at least 1 year post-operatively.
Techniques and outcomes of percutaneous tumour ablation for small renal masses
Authors: Pecoraro Angela , Campi Riccardo , Marchioni Michele
Published: July 2023

Purpose of review

Small renal masses suspected to be malignant have little potential for metastasis and disease-related mortality. Surgery remains the standard care but represents overtreatment in many cases. Percutaneous ablative technique, especially thermal ablation has emerged as a valid alternative.

Recent findings

The increased availability of cross-sectional imaging has led to a large number of incidentally detected small renal masses (SRMs), many of which are of low grade and exhibit indolent behaviour. Since 1996, ablative techniques such as cryoablation, radiofrequency ablation, and microwave ablation have gained widespread acceptance for treatment of SRMs in patients who are not surgical candidates. In this review article, we provide an overview of each of the commonly used percutaneous ablative treatments for SRMs and summarize the current literature regarding the advantages and disadvantages of each technique.

Although partial nephrectomy (PN) represents the standard treatment of SRMs, Thermal ablation techniques have been increasingly used showing acceptable efficacy, low complication rate, and equivalent survival. Cryoablation seems to be superior to radiofrequency ablation in terms of local tumour control and retreatment rates. However, selection criteria for thermal ablation are still under refinement.
Metastasis-directed treatment in kidney cancer
Authors: Jackson Jamaal C. , Franco Antonio , Wang Dian , Autorino Riccardo , Vourganti Srinivas
Published: July 2023

Purpose of review

To provide a critical overview of the latest evidence on the role of metastasis-direct treatment (MDT) in the management of metastatic renal cell carcinoma (mRCC).

Recent findings

This is a nonsystematic review of the English language literature published since January 2021. A PubMed/MEDLINE search using various search terms was conducted, including only original studies. After title and abstract screening, selected articles were grouped into two main areas which mirror the main treatment options in this setting: surgical metastasectomy (MS) and stereotactic radiotherapy (SRT). While a limited number of retrospective studies have been reported on surgical MS, the consensus of these reports is that extirpation of metastasis should be part of a multimodal management strategy for carefully selected cases. In contrast, there have been both retrospective studies and a small number of prospective studies on the use of SRT of metastatic sites.

As the management of mRCC rapidly evolves, and evidence on MDT – both in the form of MS and SRT – has continued to build over the past 2 years. Overall, there is growing interest in this therapeutic option, which is increasingly being implemented and seems to be safe and potentially beneficial in well selected disease scenarios.
TP53 as a Diagnostic Aid in the Distinction of Ovarian Mucinous Borderline Tumors From Mucinous Carcinoma
Authors: Kang Eun Young , Terzic Tatjana , Ghatage Prafull , Woo Lawrence , Gorringe Kylie L. , Karnezis Anthony N. , Lee Cheng H. , Köbel Martin
Published: July 2023

Ovarian mucinous borderline tumors (MBTs) are clinically managed as benign neoplasms while the management of ovarian mucinous carcinomas (MC) is dependent on tumor stage. Despite the standardization of sampling of ovarian mucinous neoplasms, limited interobserver reproducibility between MBT and MC persists. Based on our recent finding that abnormal TP53 expression is associated with unfavorable outcome in MBT, we hypothesized that TP53 status might improve the reproducible distinction of MBT from MC. A virtual slide set of 85 consecutive ovarian mucinous neoplasms received at a single institution, with each case represented by 3 full sections, were reviewed by 3 pathologists in 2 iterations. The initial assessment was based solely on morphologic review, while the second iteration was performed with knowledge of TP53 status. The reproducibility of a trinary categorization (MBT, MBT with intraepithelial carcinoma [IEC], MC) significantly improved from a κ of 0.60 based on the initial morphologic assessment to a κ of 0.76 (t-test, P=0.0042) after consideration of TP53 immunohistochemistry (IHC) results. Six out of 85 patients died of disease, and in 2 of them, at least 1 pathologist assessed MBT with IEC and not MC even after integration of TP53 IHC. With the integration of TP53 IHC, substantial interobserver agreement for MBT and MC can be reached, particularly in cases with an uncertain degree of confluent growth. TP53 IHC can also be used to highlight and support the presence of IEC in MBT, however, discordances remained in 2 cases with adverse outcome.
Salivary Ductal Carcinoma
Authors: Mu Si-Qi , Zhang Xi , Chen Jie
Published: July 2023

Salivary ductal carcinoma is an extremely rare tumor located in the parotid gland. This case details a salivary ductal carcinoma within the parotid gland of a 59-year-old man and its management.
Histone acetyltransferases and external demands influence task switching in
Temnothorax
ants
Authors: Kohlmeier Philip , Feldmeyer Barbara , Foitzik Susanne
Published: July 2023

In social hymenopterans, workers specialize in different tasks. Whether a worker nurses the brood or forages is influenced by the responsiveness for task-related cues which in turn is determined by gene expression. Task choice is dynamic and changes throughout a worker's life, e.g. with age or in response to increased demands for certain tasks. Behavioural switches require the ability to adjust gene expression but the mechanisms regulating such transcriptional adaptations remain elusive. We investigated the role of histone acetylation in task specialization and behavioural flexibility in
Temnothorax longispinosus
ants. By inhibiting p300/CBP histone acetyltransferases (HAT) and manipulating colony composition, we found that HAT inhibition impairs the ability of older workers to switch to brood care. Yet, HAT inhibition increased the ability of young workers to accelerate their behavioural development and switch to foraging. Our data suggest that HAT in combination with social signals indicating task demands play an important role in modulating behaviour. Elevated HAT activity may contribute to keeping young brood carers from leaving the nest, where they would be exposed to high mortality. These findings shed light on the epigenetic processes underlying behavioural flexibility in animals and provide insight into the mechanisms of task specialization in social insects.
Sex and gender in infection and immunity: addressing the bottlenecks from basic science to public health and clinical applications
Authors: Pasin Chloé , Consiglio Camila R. , Huisman Jana S. , de Lange Ann-Marie G. , Peckham Hannah , Vallejo-Yagüe Enriqueta , Abela Irene A. , Islander Ulrika , Neuner-Jehle Nadia , Pujantell Maria , Roth Olivia , Schirmer Melanie , Tepekule Burcu , Zeeb Marius , Hachfeld Anna , Aebi-Popp Karoline , Kouyos Roger D. , Bonhoeffer Sebastian
Published: July 2023

Although sex and gender are recognized as major determinants of health and immunity, their role is rarely considered in clinical practice and public health. We identified six bottlenecks preventing the inclusion of sex and gender considerations from basic science to clinical practice, precision medicine and public health policies. (i) A terminology-related bottleneck, linked to the definitions of sex and gender themselves, and the lack of consensus on how to evaluate gender. (ii) A data-related bottleneck, due to gaps in sex-disaggregated data, data on trans/non-binary people and gender identity. (iii) A translational bottleneck, limited by animal models and the underrepresentation of gender minorities in biomedical studies. (iv) A statistical bottleneck, with inappropriate statistical analyses and results interpretation. (v) An ethical bottleneck posed by the underrepresentation of pregnant people and gender minorities in clinical studies. (vi) A structural bottleneck, as systemic bias and discriminations affect not only academic research but also decision makers. We specify guidelines for researchers, scientific journals, funding agencies and academic institutions to address these bottlenecks. Following such guidelines will support the development of more efficient and equitable care strategies for all.
Gaussian process deconvolution
Authors: Tobar Felipe , Robert Arnaud , Silva Jorge F.
Published: July 2023

Let us consider the deconvolution problem, i.e. to recover a latent sourcex(⋅)from the observationsy=[y1,…,yN]of a convolution processy=x⋆h+η, whereηis an additive noise, the observations inymight have missing parts with respect toy, and the filterhcould be unknown. We propose a novel strategy to address this task whenxis a continuous-time signal: we adopt a Gaussian process prior on the sourcex, which allows for closed-form Bayesian non-parametric deconvolution. We first analyse the direct model to establish the conditions under which the model is well-defined. Then, we turn to the inverse problem, where we study (i) some necessary conditions under which Bayesian deconvolution is feasible and (ii) to which extent the filterhcan be learned from data or approximated for the blind deconvolution case. The proposed approach, termed Gaussian process deconvolution, is compared to other deconvolution methods conceptually, via illustrative examples, and using real-world datasets.
The effects of mutations on gene expression and alternative splicing
Authors: Snyman Marelize , Xu Sen
Published: July 2023

Understanding the relationship between mutations and their genomic and phenotypic consequences has been a longstanding goal of evolutionary biology. However, few studies have investigated the impact of mutations on gene expression and alternative splicing on the genome-wide scale. In this study, we aim to bridge this knowledge gap by utilizing whole-genome sequencing data and RNA sequencing data from 16 obligately parthenogenetic
Daphnia
mutant lines to investigate the effects of ethyl methanesulfonate-induced mutations on gene expression and alternative splicing. Using rigorous analyses of mutations, expression changes and alternative splicing, we show that trans-effects are the major contributor to the variance in gene expression and alternative splicing between the wild-type and mutant lines, whereas cis mutations only affected a limited number of genes and do not always alter gene expression. Moreover, we show that there is a significant association between differentially expressed genes and exonic mutations, indicating that exonic mutations are an important driver of altered gene expression.
Gender shapes the formation of review paper collaborations in microbiology
Authors: Wheatley Rachel M. , Ogunlana Lois
Published: July 2023

Women are underrepresented in senior academic positions within microbiology globally. Studies show that gender bias affects the progression of women in academia, but there is evidence that improving conscious awareness of bias can improve equity in this regard. Here we analyse the publication data associated with review articles within the microbiology field to investigate the statistical associations with author gender. We analyse the data from review articles published between 2010 and 2022 in three leading microbiology review journals:
Nature Reviews Microbiology
,
Trends in Microbiology
and
Annual Review of Microbiology
. We find a significant association between the gender of the lead author and the gender of co-authors in multi-author publications. Review articles with men lead authors have a significantly reduced proportion of women co-authors compared to reviews with women lead authors. Given the existing differences in the proportions of men and women in lead author positions, this association may have important consequences for the relative visibility of women in microbiology, along with negative impacts on scientific output relating to reduced collaboration diversity.
Rampant asexual reproduction and limited dispersal in a mangrove population of the coral
Porites divaricata
Authors: Lord Karina Scavo , Lesneski Kathryn C. , Buston Peter M. , Davies Sarah W. , D'Aloia Cassidy C. , Finnerty John R.
Published: July 2023

Corals are critical to marine biodiversity. Reproduction and dispersal are key to their resilience, but rarely quantified in nature. Exploiting a unique system—a fully censused, longitudinally characterized, semi-isolated population inhabiting mangroves—we used 2bRAD sequencing to demonstrate that rampant asexual reproduction most likely via parthenogenesis and limited dispersal enable the persistence of a natural population of thin-finger coral (
Porites divaricata
). Unlike previous studies on coral dispersal, knowledge of colony age and location enabled us to identify plausible parent–offspring relationships within multiple clonal lineages and develop tightly constrained estimates of larval dispersal; the best-fitting model indicates dispersal is largely limited to a few metres from parent colonies. Our results explain why this species is adept at colonizing mangroves but suggest limited genetic diversity in mangrove populations and limited connectivity between mangroves and nearby reefs. As
P. divaricata
is gonochoristic, and parthenogenesis would be restricted to females (whereas fragmentation, which is presumably common in reef and seagrass habitats, is not), mangrove populations likely exhibit skewed sex ratios. These findings suggest that coral reproductive diversity can lead to distinctly different demographic outcomes in different habitats. Thus, coral conservation will require the protection of the entire coral habitat mosaic, and not just reefs.
Glycoprotein VI is Critical for the Detection and Progression of Abdominal Aortic Aneurysms
Authors: Benson Tyler W. , Pike Mindy M. , Spuzzillo Anthony , Hicks Sarah M. , Pham Michael , Mix Doran S. , Brunner Seth I. , Wadding-Lee Caris , Conrad Kelsey A. , Russell Hannah M. , Jennings Courtney , Coughlin Taylor M. , Aggarwal Anu , Lyden Sean , Mani Kevin , Björck Martin , Wanhainen Anders , Bhandari Rohan , Lipworth-Elliot Loren , Robinson-Cohen Cassianne , Caputo Francis J. , Shim Sharon , Edwards Todd L. , Tranter Michael , Gardiner Elizabeth E. , Mackman Nigel , Cameron Scott J. , Owens A. Phillip
Published: July 2023

A common feature in patients with abdominal aortic aneurysms (AAA) is the formation of a nonocclusive intraluminal thrombus (ILT) in regions of aortic dilation. Platelets are known to maintain hemostasis and propagate thrombosis through several redundant activation mechanisms, yet the role of platelet activation in the pathogenesis of AAA associated ILT is still poorly understood. Thus, we sought to investigate how platelet activation impacts the pathogenesis of AAA. Using RNA-sequencing, we identify that the platelet-associated transcripts are significantly enriched in the ILT compared to the adjacent aneurysm wall and healthy control aortas. We found that the platelet specific receptor glycoprotein VI (GPVI) is among the top enriched genes in AAA ILT and is increased on the platelet surface of AAA patients. Examination of a specific indicator of platelet activity, soluble GPVI (sGPVI), in two independent AAA patient cohorts is highly predictive of a AAA diagnosis and associates more strongly with aneurysm growth rate when compared to D-dimer in humans. Finally, intervention with the anti-GPVI antibody (J) in mice with established aneurysms blunted the progression of AAA in two independent mouse models. In conclusion, we show that levels of sGPVI in humans can predict a diagnosis of AAA and AAA growth rate, which may be critical in the identification of high-risk patients. We also identify GPVI as a novel platelet-specific AAA therapeutic target, with minimal risk of adverse bleeding complications, where none currently exist.

KEY POINTS

Soluble glycoprotein VI, which is a platelet-derived blood biomarker, predicts a diagnosis of AAA, with high sensitivity and specificity in distinguishing patients with fast from slow-growing AAA.

Blockade of glycoprotein VI in mice with established aneurysms reduces AAA progression and mortality, indicating therapeutic potential.
Fertility care among people with primary ciliary dyskinesia
Authors: Schreck Leonie D , Goutaki Myrofora , Jörger Philippa , Dexter Katie , Manion Michele , Christin-Maitre Sophie , Maitre Bernard ,   COVID-PCD patient advisory group, Kuehni Claudia E , Pedersen Eva SL
Published: July 2023

Introduction

Fertility care is important for people living with primary ciliary dyskinesia (PCD) who are at increased risk of fertility problems. We investigated fertility care in an international participatory study.

Methods

Participants of the COVID-PCD study completed an online questionnaire addressing fertility issues. We used logistic regression to study factors associated with fertility specialist visits.

Results

Among 384 respondents (response rate 53%), 266 were adults [median age 44 years, interquartile range (IQR) 33–54), 68% female], 16 adolescents, and 102 parents of children with PCD. Half adult participants (128; 48%) received care from fertility specialists at a median age of 30 years (IQR 27–33)—a median of 10 years after PCD diagnosis. Fertility specialist visits were reported more often by adults with pregnancy attempts [odds ratio (OR) 9.1, 95% confidence interval (CI) 3.8–23.6] and among people who reported fertility as important for them (OR 5.9, 95% CI 2.6–14.6) and less often by females (OR 0.4, 95% CI 0.2–0.8). Only 56% of participants who talked with healthcare professionals about fertility were satisfied with information they received. They expressed needs for more comprehensive fertility information and reported dissatisfaction with physician knowledge about PCD and fertility.

Conclusion

People with PCD are inconsistently referred to fertility specialists. We recommend care from fertility specialists become standard in routine PCD care, and that PCD physicians provide initial fertility information either at diagnosis or no later than transition to adult care.
Accelerated somatic mutation calling for whole-genome and whole-exome sequencing data from heterogenous tumor samples
Authors: Ji Shuangxi , Zhu Tong , Sethia Ankit , Wang Wenyi
Published: July 2023

Accurate detection of somatic mutations in DNA sequencing data is a fundamental prerequisite for cancer research. Previous analytical challenge was overcome by consensus mutation calling from four to five popular callers. This, however, increases the already nontrivial computing time from individual callers. Here, we launch MuSE2.0, powered by multi-step parallelization and efficient memory allocation, to resolve the computing time bottleneck. MuSE2.0 speeds up 50 times than MuSE1.0 and 8-80 times than other popular callers. Our benchmark study suggests combining MuSE2.0 and the recently expedited Strelka2 can achieve high efficiency and accuracy in analyzing large cancer genomic datasets.
Somatic mutation of Afadin leads to anchorage independent survival and metastatic growth of breast cancer through αE-catenin dependent destabilization of the adherens junction
Authors: Ratze Max A.K. , Enserink Lotte N.F.L. , Ishiyama Noboru , Veltman Christina H.J. , Nijman Isaac J. , Bernards Rene , van Diest Paul J. , Christgen Matthias , Derksen Patrick W.B.
Published: July 2023

Loss of E-cadherin (CDH1) and the adherens junction (AJ) drive development and progression of invasive lobular breast cancer (ILC). However, approximately 40% retain wild typeCDH1alleles, indicating that modulation of other genes attenuates the AJ during ILC etiology. To identify alternative drivers, we performed targeted sequencing inCDH1wild type samples, based on a defined set of 100 AJ, tight junction, and desmosome genes we designated as the ‘Adhesome’. In 146 ILC samples, we identified 62 cases (43%) with wild typeCDH1alleles in which we detected a total of 284 mutations in 36 Adhesome genes. After selection based on occurrence and potential loss of function, we identified an inactivating frameshift mutation in Afadin (AFDN; p.Lys630fs).

Functional studies in E-cadherin-expressing breast cancer cells showed that Afadin knockout leads to immature AJs, and a non-cohesive phenotype accompanied by actomyosin dependent anoikis resistance, which are classical ILC hallmarks. Afadin reconstitutions show that F-actin organization critically depends on the ⍰E-catenin binding CC domain. Afadin loss in intraductal xenograft mouse breast cancer models leads to ILC-type morphologies and overt lung metastases.AFDNtruncate reconstitutions revealed that deletion of the C-terminal ⍰E-catenin binding CC domain is sufficient to drive metastatic ILC. In conclusion, we identified and functionally coupled a somatic frameshiftAFDNmutation in breast cancer to destabilization the epithelial AJ and the development of ILC hallmarks such as actomyosin-dependent anoikis resistance and single cell invasion. As such, Afadin represents a candidate tumor suppressor for E-cadherin-positive ILC development and progression.
Basal MET Phosphorylation is an Indicator of Hepatocyte Dysregulation in Liver Disease
Authors: Burbano de Lara Sebastian , Kemmer Svenja , Biermayer Ina , Feiler Svenja , Vlasov Artyom , D’Alessandro Lorenza A. , Helm Barbara , Dieter Yannik , Ghallab Ahmed , Hengstler Jan G. , Hoffmann Katrin , Schilling Marcel , Timmer Jens , Klingmüller Ursula
Published: July 2023

Chronic liver diseases are worldwide on the rise. Due to the rapidly increasing incidence, in particular in Western countries, Non-alcoholic fatty liver disease (NAFLD) is gaining importance as the disease can develop into hepatocellular carcinoma. Lipid accumulation in hepatocytes has been identified as the characteristic structural change in NAFLD development, but molecular mechanisms responsible for disease progression remained unresolved. Here, we uncover in primary hepatocytes from a preclinical model fed with a Western diet (WD) a strong downregulation of the PI3K-AKT pathway and an upregulation of the MAPK pathway. Dynamic pathway modeling of hepatocyte growth factor (HGF) signal transduction combined with global proteomics identifies that an elevated basal MET phosphorylation rate is the main driver of altered signaling leading to increased proliferation of WD-hepatocytes. Model-adaptation to patient-derived hepatocytes reveal patient-specific variability in basal MET phosphorylation, which correlates with patient outcome after liver surgery. Thus, dysregulated basal MET phosphorylation could be an indicator for the health status of the liver and thereby inform on the risk of a patient to suffer from liver failure after surgery.
Ubiquitin-derived artificial binding proteins targeting oncofetal fibronectin reveal scaffold plasticity by β-strand slippage
Authors: Katzschmann Anja , Haupts Ulrich , Reimann Anja , Settele Florian , Gloser-Bräunig Manja , Fiedler Erik , Parthier Christoph
Published: July 2023

Affilin proteins (artificial binding proteins based on the ubiquitin scaffold) were generated using directed protein evolution to yieldde-novovariants that bind the extra-domain B (EDB) of oncofetal fibronectin, an abundant tumor marker in fetal and neoplastic tissues. Structures of two EDB-specific Affilin molecules reveal striking structural plasticity of the ubiquitin scaffold, characterized by β-strand slippage, leading to diverse register shifts of the β5 strands. This recruits residues from β5 to a loop region, enhancing the target-binding interface. The observed β-strand rearrangements, manifested by pressure of selection for target binding, challenge the accepted paradigm that directed evolution of binding proteins should base on rigid frameworks. Fold plasticity allowing β-strand slippages enhances the evolutionary potential of proteins beyond “simple” mutations significantly and provides a general mechanism to generate residue insertions/deletions in proteins. They are however difficult to predict, underlining the need for caution in interpretation of structure-activity relationships of evolved proteins.
Robust prediction of patient outcomes with immune checkpoint blockade therapy for cancer using common clinical, pathologic, and genomic features
Authors: Chang Tia-Gen , Cao Yingying , Sfreddo Hannah J. , Dhruba Saugato Rahman , Lee Se-Hoon , Valero Cristina , Yoo Seong-Keun , Chowell Diego , Morris Luc G. T. , Ruppin Eytan
Published: July 2023

Despite the revolutionary impact of immune checkpoint blockade (ICB) in cancer treatment, accurately predicting patients’ responses remains elusive. We analyzed eight cohorts of 2881 ICB-treated patients across 18 solid tumor types, the largest dataset to date, examining diverse clinical, pathologic, and genomic features. We developed the LOgistic Regression-based Immunotherapy-response Score (LORIS) using a transparent, compact 6-feature logistic regression model. LORIS outperforms previous signatures in ICB response prediction and can identify responsive patients, even those with low tumor mutational burden or tumor PD-L1 expression. Importantly, LORIS consistently predicts both objective responses and short-term and long-term survival across most cancer types. Moreover, LORIS showcases a near-monotonic relationship with ICB response probability and patient survival, enabling more precise patient stratification across the board. As our method is accurate, interpretable, and only utilizes a few readily measurable features, we anticipate it will help improve clinical decision-making practices in precision medicine to maximize patient benefit.
Disregarding multimappers leads to biases in the functional assessment of NGS data
Authors: Almeida da Paz Michelle , Warger Sarah , Taher Leila
Published: July 2023

Standard ChIP-seq and RNA-seq processing pipelines typically disregard sequencing reads whose origin is ambiguous (“multimappers”). This usual practice has potentially important consequences for the functional interpretation of the data: genomic elements belonging to clusters composed of highly similar members are left unexplored. In particular, disregarding multimappers leads to the systematic underrepresentation in epigenetic studies of recently active transposons, such as AluYa5 and L1HS. Furthermore, this common strategy also has implications for transcriptomic analysis: members of repetitive gene families, such the ones including major histocompatibility complex (MHC) class I and II genes, are systematically underquantified. Based on these findings, we strongly advocate for the implementation of multimapper-aware bioinformatic genomic analyses.
Witnessed trauma exposure induces fear in mice through a reduction in endogenous neurosteroid synthesis
Authors: Evans-Strong Aidan , Walton Najah , Roper Abby , Donaldson S. Tiffany , Lewis Mike , Maguire Jamie
Published: July 2023

Neurosteroids have been implicated in the pathophysiology of post-traumatic stress disorder (PTSD). Allopregnanolone is reduced in subsets of individuals with PTSD and has been explored as a novel treatment strategy. Both direct trauma exposure and witnessed trauma are risk factors for PTSD; however, the role of neurosteroids in the behavioral outcomes of these unique experiences has not been explored. Here we investigate whether observational fear is associated with a reduced capacity for endogenous neurosteroidogenesis and the relationship with behavioral outcomes. We demonstrate that both mice directly subjected to the threat (foot shocks) and those witnessing the threat have decreased plasma levels of allopregnanolone. The expression of a key enzyme involved in endogenous neurosteroid synthesis, 5α-reductase type 2, is decreased in the basolateral amygdala (BLA), which is a major emotional processing hub implicated in PTSD. We demonstrate that knockdown of 5α-reductase type 2 exaggerates the behavioral expression of fear in response to witnessed trauma, whereas treatment with an exogenous, synthetic neuroactive steroid GABAAreceptor PAM with molecular pharmacology similar to allopregnanolone (SGE-516 [tool compound]) decreases the behavioral response to observational fear. These data implicate impaired endogenous neurosteroidogenesis in the pathophysiology of threat exposure, both direct and witnessed. Further, these data suggest that treatment with exogenous 5α-reduced neurosteroids or targeting endogenous neurosteroidogenesis may be beneficial for the treatment of individuals with PTSD, whether resulting from direct or witnessed trauma.