bluuebunny/crossref_metadata_2025 huggingface dataset:
A review of Peyronie’s disease insurance coverage
Authors: Hricz Nicholas , Schlidt Kevin , Ha Michael , Er Seray , Stark Katarina , Jung Esther , Liang Fan , Rasko Yvonne M
Published: October 2024

Background

Peyronie’s disease (PD) is a fibroproliferative disorder that causes an abnormal curve of the penis resulting in pain, discomfort, and erectile dysfunction with management options including correctional surgery, penile external/internal devices, shock wave therapy (SWT), intralesional Verapamil (IV), and collagenase Clostridium histolyticum injections.

Aim

To investigate the insurance coverage of these treatment options.

Methods

The authors performed a cross-sectional analysis of the top US insurance policies for coverage of PD. Companies were chosen based on their market share and enrollment. Their policies were identified through a Web-based search and telephone interviews, and the companies’ medical necessity criteria were defined. The online policies were then re-examined for interval change 3 years later.

Outcomes

There are significant discrepancies for in coverage for the different modalities of Peyronie’s treatment.

Results

Of the 100 companies examined, only 54% of companies had a policy that directly addressed the treatment coverage for PD. The most covered treatment was CCH injections with 37 companies providing unanimous coverage (n = 37, 100%). Within this category, all companies required a palpable plaque as a requirement. Additionally, external/internal devices were unanimous covered by 18 companies (n = 18, 100%). Surgical treatment was covered by eight companies with six companies denying coverage (n = 8 vs. n = 6, 57.1% vs. 42.9%). IV was covered by two companies. The least covered treatment option was SWT which was universally denied by 19 companies (n = 19, 100%).

Clinical Implications

Insurance coverage of PD should be aligned with current medical literature to better increase access to care.

Strengths & Limitations

This study is limited by the updated policies of insurance companies and future applicability. Additionally, this study assumes that a written policy will provide coverage and may overestimate the actual extent of coverage. Finally, this study only addressed some of the common treatment options of PD and did not expand on all possible treatment options.

Conclusion

Differing rates for modalities of treatment may present a barrier for patients to receive individualized and adequate treatment for PD.
A sustainable nutritional solution for fattening pigs based on 25-hydroxycholecalciferol and triterpenoids added to a low Ca diet containing phytase improves growth performance via the activation of muscle protein synthesis without compromising bone mineralization
Authors: Pérez-Calvo Estefania , McCormack Ursula M , Muns Ramon , Mulvenna Christina , Payling Laura , Romero Luis , Roger Laurent , Walsh Maria C
Published: October 2024

In the current climate of sustainable animal agriculture, nutritional strategies that support fattening swine growth performance and bone mineralization whilst reducing environmental impacts are much sought after. This study evaluated the effect of supplementing 25(OH)D3 with triterpenoids to a Ca-reduced diet containing phytase during the grower-finisher phase. Growth performance, bone composition, plasma metabolites and muscle gene expression were evaluated. Sixty crossbreed boar pigs (initial body weight (BW) 42.0 ± 5.1 kg at 12 wk of age) were assigned to three treatments with 20 pigs/treatment in a completely randomized design. Treatments comprised: 1) a standard commercial grower-finisher diet (positive control (PC)) containing 1,500 IU/kg vitamin D3 [3,585 kcal/kg digestible energy, 16.19% CP, 0.70% Ca, 0.29% standardized total tract digestible P]; 2) a negative control (NC) based on the PC with reduction in Ca and P (minus 30% and 10%, respectively); 3) the NC with vitamin D3 replaced by a commercially available compounds combination containing 25(OH)D3 and triterpenoids, dosed at 500 mg per kg of feed (TRT). All diets were provided ad libitum for 7 wk, and feed intake was recorded individually via electronic feeder stations. For the overall period, average daily gain and average daily feed intake were increased (P < 0.05) in TRT vs. NC or PC (+ 13.0% and + 8.3%, respectively, vs. NC); final BW was 7.8% higher vs. NC (+ 5.2% vs. PC; P < 0.05). Whole-body DXA-scanning at 19 wk of age showed that bone mineral density, content and percentage were reduced in NC vs. PC and equivalent to PC in TRT. Plasma 25(OH)D3 and P levels were raised in TRT (+ 33 ng/ml or 2.6-fold and + 0.55 mg/dL or 5.9%, respectively, vs. NC). The combination of 25(OH)D3 with triterpenoids was found to activate several biological pathways involved in muscle growth, including pathways that activate mTOR, a key central regulator of cell metabolism, growth, proliferation and survival when the gene expression was measured in the muscle tissue at 19 wk of age. These results suggest that the dietary combination of 25(OH)D3 with triterpenoids has the potential for use, alongside phytase, in supporting a reduction in Ca and P in the diet to reduce nutrient waste and improve the sustainability of production by promoting muscle growth and maintaining bone composition.
Pathophysiological Markers of Acute Respiratory Distress Syndrome Severity Are Correlated With Ventilation-Perfusion Mismatch Measured by Electrical Impedance Tomography
Authors: Spinelli Elena , Perez Joaquin , Chiavieri Valentina , Leali Marco , Mansour Nadia , Madotto Fabiana , Rosso Lorenzo , Panigada Mauro , Grasselli Giacomo , Vaira Valentina , Mauri Tommaso
Published: October 2024

OBJECTIVES:

Pulmonary ventilation/perfusion (V/Q) mismatch measured by electrical impedance tomography (EIT) is associated with the outcome of patients with the acute respiratory distress syndrome (ARDS), but the underlying pathophysiological mechanisms have not been fully elucidated. The present study aimed to verify the correlation between relevant pathophysiological markers of ARDS severity and V/Q mismatch.

DESIGN:

Prospective observational study.

SETTING:

General ICU of a university-affiliated hospital.

PATIENTS:

Deeply sedated intubated adult patients with ARDS under controlled mechanical ventilation.

INTERVENTIONS:

Measures of V/Q mismatch by EIT, respiratory mechanics, gas exchange, lung imaging, and plasma biomarkers.

MEASUREMENTS AND MAIN RESULTS:

Unmatched V/Q units were assessed by EIT as the fraction of ventilated nonperfused plus perfused nonventilated lung units. At the same time, plasma biomarkers with proven prognostic and mechanistic significance for ARDS (carbonic anhydrase 9 [CA9], hypoxia-inducible factor 1 [HIF1], receptor for advanced glycation endproducts [RAGE], angiopoietin 2 [ANG2], gas exchange, respiratory mechanics, and quantitative chest CT scans were measured. Twenty-five intubated ARDS patients were included with median unmatched V/Q units of 37.1% (29.2–49.2%). Unmatched V/Q units were correlated with plasma levels of CA9 (rho = 0.47; p = 0.01), HIF1 (rho = 0.40; p = 0.05), RAGE (rho = 0.46; p = 0.02), and ANG2 (rho = 0.42; p = 0.03). Additionally, unmatched V/Q units correlated with plateau pressure (r = 0.38; p = 0.05) and with the number of quadrants involved on chest radiograph (r = 0.73; p < 0.01). Regional unmatched V/Q units were correlated with the corresponding fraction of poorly aerated lung tissue (r = 0.62; p = 0.01) and of lung tissue weight (rho: 0.51; p = 0.04) measured by CT scan.

CONCLUSIONS:

In ARDS patients, unmatched V/Q units are correlated with pathophysiological markers of lung epithelial and endothelial dysfunction, increased lung stress, and lung edema. Unmatched V/Q units could represent a comprehensive marker of ARDS severity, reflecting the complex organ pathophysiology and reinforcing their prognostic significance.
Mitochondrial quality control in alcohol-associated liver disease
Authors: Thoudam Themis , Gao Hui , Jiang Yanchao , Huda Nazmul , Yang Zhihong , Ma Jing , Liangpunsakul Suthat
Published: October 2024

Excessive alcohol consumption is a leading cause of alcohol-associated liver disease (ALD), a significant global health concern with limited therapeutic options. Understanding the key factors contributing to ALD pathogenesis is crucial for identifying potential therapeutic targets. Central to ALD pathogenesis is the intricate interplay between alcohol metabolism and cellular processes, particularly involving mitochondria. Mitochondria are essential organelles in the liver, critical for energy production and metabolic functions. However, they are particularly vulnerable to alcohol-induced damage due to their involvement in alcohol metabolism. Alcohol disrupts mitochondrial function, impairing ATP production and triggering oxidative stress, which leads to cellular damage and inflammation. Mitochondrial quality control mechanisms, including biogenesis, dynamics, and mitophagy, are crucial for maintaining optimal mitochondrial function. Chronic alcohol consumption disrupts mitochondrial quality control checkpoints, leading to mitochondrial dysfunction that impairs fatty acid oxidation and contributes to hepatic steatosis in ALD. Moreover, alcohol promotes the accumulation of damaged mitochondria and the release of proinflammatory components, exacerbating liver damage and inflammation. Preserving mitochondrial health presents a promising therapeutic approach to mitigate ALD progression. In this review, we provide a comprehensive overview of the effects of alcohol on mitochondrial function and quality control mechanisms, highlighting their role in ALD pathogenesis. Understanding these mechanisms may pave the way for the development of novel therapeutic interventions for ALD.
Differences in sex and age response to single pill combination based antihypertensive therapy reflecting in blood pressure and arterial stiffness
Authors: Brguljan Hitij Jana , Gaciong Zbigniew , Simić Dragan , Vajer Péter , Zelveian Parounak , Chazova Irina E. , Jelaković Bojan ,   Precious trial investigators
Published: October 2024

Objective:

There are noticeable sex differences in the treatment response to antihypertensives, with limited data on the response to single pill combinations. The aim of the PRECIOUS trial was to assess the treatment response to perindopril/amlodipine and perindopril/amlodipine/indapamide dual and triple single-pill combination in men and women.

Methods:

Four hundred and forty adults with essential hypertension were assessed in the 16-week interventional, open-label, prospective, international, multicentre trial. Based on the previous antihypertensive therapy, patients were assigned to either perindopril/amlodipine 4/5 mg or perindopril/amlodipine/indapamide 4/5/1.25 mg, with the initial dose up-titrated in 4-week intervals in case of uncontrolled blood pressure. An additional analysis was performed for sex- and age-related differences on the blood pressure response and arterial stiffness in men and women aged 35–74 years.

Results:

Women achieved better overall blood pressure control in all age groups, except for the 35–44 age group. Women presented higher average 24 h aortic augmentation indexes than men, but had more pronounced decreasing trends. The pulse wave velocity was only age-dependent, with reductions slightly greater in women. Both the aortic augmentation index and pulse wave velocity were significantly decreased in all groups compared to baseline.

Conclusions:

The results of the PRECIOUS trial contribute significant data to the expanding body of evidence on sex differences in hypertension, including the aspect of age-related changes during the life course of women. The differences between same-aged men and women tend to be smaller with advancing age, but with a greater treatment response in women in all age groups for all observed blood pressure parameters and arterial stiffness.

Trial registration:

ClinicalTrials.gov identifier NCT03738761
Giant lipomas: A 130-year literature review, case series, and introduction of an intuitive management algorithm
Authors: Marcasciano Marco , Greto Ciriaco Antonio , Fiorillo Maria Antonia , Cutuli Salvatore , Thom Douglas , Stagno D’ Alcontres Francesco , Delia Gabriele , Fanelli Benedetta , Luridiana Gianluigi , Casella Donato , Chang Chad , Greco Manfredi
Published: October 2024

Background:

Lipomas are the most common benign mesenchymal tumors in adults. On the other hand, giant lipomas, defined as lipomas over >10 cm in length of over 1000 g in weight, are less frequently seen, can be clinically challenging to manage, and require careful attention. While most cases are benign, soft, asymptomatic masses, there is potential for functional limitation, nerve compression syndromes, and sarcomatous changes in such lesions.

Methods:

A case series is presented and an extensive review of the literature was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) declaration, since the first description of a giant lipoma reported in 1894, with the aim of providing an updated and comprehensive “state-of-the-art” on the management, diagnosis, and treatment of this entity. PubMed, Scopus, and Google Scholar databases were queried for relevant articles using the search terms “Giant lipoma” and “Massive lipoma” from 1894 to 2024.

Results:

Five consecutive clinical cases were reported. A total of 79 patients were identified from the 65 collected reports. Clinical characteristics of the lesions, surgical details, and patient characteristics are obtained and summarized. Preoperative/postoperative radiological/histological features are reported.

Conclusion:

Surgical excision remains the gold standard treatment for giant lipomas. According to existing literature, most recommendations are based on expert opinions and there is a paucity of guidelines or universal consensus on a treatment pathway for standardized, multidisciplinary management of such a challenging clinical condition.
Lifestyle modifications and environmental risk factors for glaucoma
Authors: Elhusseiny Abdelrahman M. , Aref Ahmad A.
Published: October 2024

Purpose of review

To summarize recent evidence about the association between different lifestyle modifications and environmental risk factors and glaucoma.

Recent findings

Incorporating moderate exercise into the routine of glaucoma patients may help slow the progression of the condition. However, caution should be taken when using swim goggles, and it may be advisable to avoid certain yoga positions and heavy weight-lifting exercises, as they have been linked to intraocular pressure (IOP) spikes and potential risks for glaucoma patients. Various relaxation techniques may lower IOP. The evidence remains inconclusive about the association between vitamins intake and glaucoma. Dietary nitric oxide has been associated with a lower risk of glaucoma. Higher smoking intensity has been linked to faster visual field decline and retinal nerve fiber layer thinning. Additionally, there is currently insufficient evidence to support the use of marijuana in managing glaucoma, with side effects outweighing the proposed benefits. A significant association has been found between air pollutants and ganglion cell layer thinning, as well as a greater burden of glaucoma.

Lifestyle and environmental factors are increasingly recognized as significant contributors to glaucoma development and progression. These modifications should be integrated into a comprehensive treatment approach alongside medications or surgical interventions.
Traumatic cataract with iridodialysis
Authors: Chee Soon-Phaik , Weikert Mitchell P. , Wallace Ryan , De Francesco Ticiana , Ahmed Ike , Fram Nicole , McCabe Cathleen M.
Published: October 2024

A 56-year-old woman presented with left blurring of vision for 6 months. She gave a history of previous left eye trauma for which she had undergone suturing of a corneal laceration. The right eye was 20/20 and normal. Her left visual acuity was hand motion. A linear corneal scar was present extending obliquely from 5 to 9 o'clock. In addition, there were iridodialysis from 8 to 1 o'clock, a fixed dilated pupil, and extensive zonulysis with displacement of a dense nuclear sclerotic cataract temporally (Figures 1 and 2

JOURNAL/jcrs/04.03/02158034-202411000-00015/figure1/v/2024-10-18T161301Z/r/image-tiff

JOURNAL/jcrs/04.03/02158034-202411000-00015/figure2/v/2024-10-18T161301Z/r/image-tiff

). There was no vitreous in the anterior chamber. The posterior segment appeared normal, as were the intraocular pressures.

Ultrasound biomicroscopy of the anterior segment of the left eye confirmed the absence of zonular fibers from 6 to 12 o'clock. Optical coherence tomography was unable to capture any image of the macular or optic nerve. Corneal topography showed irregular astigmatism. The endothelial cell density was 1650 cells/mm2.

Describe how you would manage this case surgically, given that her financial resources were limited, and she was unable to afford a prosthetic iris.
PROTACs in platelets: emerging antithrombotic strategies and future perspectives
Authors: Trory Justin S. , Vautrinot Jordan , May Carl J. , Hers Ingeborg
Published: October 2024

Purpose of review

Proteolysis-targeted chimeras (PROTACs) are heterobifunctional compounds that selectively target proteins for degradation and are an emerging therapeutic modality to treat diseases such as cancer and neurodegenerative disorders. This review will widen the area of application by highlighting the ability of PROTACs to remove proteins from the anucleate platelets and evaluate their antithrombotic potential.

Recent findings

Proteomic and biochemical studies demonstrated that human platelets possess the Ubiquitin Proteasomal System as well as the E3 ligase cereblon (CRBN) and therefore may be susceptible to PROTAC-mediated protein degradation. Recent findings confirmed that CRBN ligand-based PROTACs targeting generic tyrosine kinases, Btk and/or Fak lead to efficacious and selective protein degradation in human platelets. Downregulation of Btk, a key player involved in signalling to thrombosis, but not haemostasis, resulted in impaired in-vitro thrombus formation.

Platelets are susceptible to targeted protein degradation by CRBN ligand-based PROTACs and have limited ability to resynthesise proteins, ensuring long-term downregulation of target proteins. Therefore, PROTACs serve as an additional research tool to study platelet function and offer new therapeutic potential to prevent thrombosis. Future studies should focus on enhancing cell specificity to avoid on-target side effects on other blood cells.
Imaging for upper tract urothelial carcinoma: update of the evidence and a glimpse into the future
Authors: Laukhtina Ekaterina , Muin Dina , Shariat Shahrokh F.
Published: October 2024

Purpose of review

Upper tract urothelial carcinoma (UTUC) is a rare malignancy posing significant diagnostic and management challenges. This review provides an overview of the evidence supporting various imaging modalities and offers insights into future innovations in UTUC imaging.

Recent findings

With the growing use of advancements in computed tomography (CT) technologies for both staging and follow-up of UTUC patients, continuous innovations aim to enhance performance and minimize the risk of excessive exposure to ionizing radiation and iodinated contrast medium. In patients unable to undergo CT, magnetic resonance imaging serves as an alternative imaging modality, though its sensitivity is lower than CT. Positron emission tomography, particularly with innovative radiotracers and theranostics, has the potential to significantly advance precision medicine in UTUC. Endoscopic imaging techniques including advanced modalities seem to be promising in improved visualization and diagnostic accuracy, however, evidence remains scarce. Radiomics and radiogenomics present emerging tools for noninvasive tumor characterization and prognosis.

The landscape of imaging for UTUC is rapidly evolving, with significant advancements across various modalities promising improved diagnostic accuracy, patient outcomes, and safety.
Intracranial aneurysm coexisting with pituitary adenoma: a systematic review
Authors: de Sena Barbosa Mateus Gonçalves , Otávio da Silva Vinícius , Santos Ferreira Luiz Henrique , de Souza Rafaela Luiza Vilela , Pipek Leonardo Zumerkorn , de Oliveira Almeida Gustavo , Figueiredo Eberval Gadelha , Rabelo Nicollas Nunes , Chaurasia Bipin
Published: October 2024

Introduction:

The simultaneous occurrence of intracranial aneurysms (IA) and primary brain tumors (BT) is frequently reported, with an estimated incidence of 0.5–7.4%. Among the tumor types associated with IA, pituitary adenomas (PA) are the most prevalent.

Methods:

The authors selected articles, published from 1960 to December 2023, on the Medline, Embase, Scopus, Cochrane Library, and Web of Science databases. The extraction form contains information specific to the aneurysm and tumor, rupture of the aneurysm, treatment proposal for both and order of treatment and outcome.

Results:

The study evaluated 118 patients from 25 articles. The most frequent types of tumors were non-functioning hormone (NFA) producers, present in 45.8% (n=54) of the cases, and growth hormone (GH) secretors, which represent 23.0% (n=27) of the cases. The main treatment used was surgery, with subtotal resection (STR) performed in 4.2% (n=5) of cases, gross total resection (GTR) in 3.4% (n=4), and transsphenoidal resection (TSR) in 7.6% (n=9). 16.0% (n=19) of patients had two or more aneurysms concomitant with the adenoma. IA treatment was performed before PA surgery in 25 patients (21.2%) and 15 patients received simultaneous treatment to IA and PA (12.7%).

Conclusion:

Patients with PAs have a considerable prevalence of IAs. Hormonal imbalances and mechanical changes induced by tumor growth, particularly influenced by GH and IGF-1, contribute to this coexistence. Surgical intervention is common, requiring meticulous precautions to avoid complications. More longitudinal studies including close follow-up with a description of outcomes are necessary to guide treatment protocols for this condition.
Thoracic irrigation for prevention of secondary intervention after thoracostomy tube drainage for hemothorax: A Western Trauma Association multicenter study
Authors: Carver Thomas W. , Berndtson Allison E. , McNickle Allison G. , Boyle Kelly A. , Haan James M. , Campion Eric M. , Biffl Walter L. , Carroll Alyssa N. , Sise Michael J. , Berndt Kelsey S. , Burris Jennifer M. , Kopelman Tammy R. , Blank Jaqueline J. , Seamon Mark J. , Peschman Jacob R. , Morris Rachel S. , Kugler Nathan W. , Conrardy Ryan D. , Szabo Aniko , de Moya Marc A.
Published: October 2024

BACKGROUND

Retained hemothorax (rHTX) requiring intervention occurs in up to 20% of patients who undergo chest tube (TT) placement for a hemothorax (HTX). Thoracic irrigation at the time of TT placement decreases the need for secondary intervention in this patient group but those findings are limited because of the single-center design. A multicenter study was conducted to evaluate the effectiveness of thoracic irrigation.

METHODS

A multicenter, prospective, observational study was conducted between June 2018 and July 2023. Eleven sites contributed patients. Patients were included if they had a TT placed for a HTX and were excluded if: younger than 18 years, TT for pneumothorax, thoracotomy or video-assisted thoracoscopic surgery performed within 6 hours of TT, TT >24 hours after injury, TT removed <24 hours, or death within 48 hours. Thoracic irrigation was performed at the discretion of the attending. Each hemithorax was considered separately if bilateral HTX. The primary outcome was secondary intervention for HTX-related complications (rHTX, effusion, or empyema). Secondary intervention was defined as: TT placement, instillation of thrombolytics, video-assisted thoracoscopic surgery, or thoracotomy. Irrigated and nonirrigated hemithoraces were compared using a propensity weighted analysis with age, sex, mechanism of injury, Abbreviated Injury Scale chest, and TT size as predictors.

RESULTS

Four hundred ninety-three patients with 462 treated hemothoraces were included, 123 (25%) had thoracic irrigation at TT placement. There were no significant demographic differences between the cohorts. Fifty-seven secondary interventions were performed, 10 (8%) and 47 (13%) in the irrigated and non-irrigated groups, respectively (p = 0.015). Propensity weighted analysis demonstrated a reduction in secondary interventions in the irrigated cohort (odds ratio, 0.56 (0.34–0.85); p = 0.005).

CONCLUSION

This Western Trauma Association multicenter study demonstrates a benefit of thoracic irrigation at the time of TT placement for a HTX. Thoracic irrigation reduces the odds of a secondary intervention for rHTX-related complications by 44%.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level II.
The involvement of lidocaine in amyloid-β1-42-dependent mitochondrial dysfunction and apoptosis in hippocampal neurons via nerve growth factor-protein kinase B pathway
Authors: Guo Jianlian , Xu Yong , Liu Jie , Hou Xueqi
Published: October 2024

This project is conceived to reveal the role of lidocaine in the process of Alzheimer’s disease (AD) and its possible downstream targets. After the employment of AD cell model in mice hippocampal neuronal HT-22 cells in the presence of amyloid-β1-42 (Aβ1-42), Cell Counting Kit-8 method investigated cell viability. Oxidative damage was assayed based on a dichloro-dihydro-fluorescein diacetate fluorescent probe and commercially available kits. The 5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethylbenzimidazolocarbocyanine iodide fluorescent probe estimated mitochondrial function. Terminal-deoxynucleotidyl transferase mediated nick end labeling, western blotting, and immunofluorescence appraised the apoptotic level. Western blot also ascertained the alternations of nerve growth factors (NGF)-protein kinase B (Akt) pathway-related proteins. Aβ1-42 concentration dependently triggered the viability loss, oxidative damage, and apoptosis in HT-22 cells. Lidocaine promoted the viability and reduced the mitochondrial impairment and mitochondria-dependent apoptosis in Aβ1-42-treated HT-22 cells in a concentration-dependent manner. Besides, lidocaine activated the NGF-Akt pathway and NGF absence blocked NGF-Akt pathway, aggravated mitochondrial dysfunction as well as mitochondria-dependent apoptosis in lidocaine-administrated HT-22 cells in response to Aβ1-42. Altogether, these observations concluded that lidocaine might stimulate NGF-Akt pathway to confer protection against mitochondrial impairment and apoptosis in Aβ1-42-mediated cellular model of AD.
Genomic biosurveillance of the kiwifruit pathogen Pseudomonas syringae pv. actinidiae biovar 3 reveals adaptation to selective pressures in New Zealand orchards
Authors: Hemara Lauren M. , Hoyte Stephen M. , Arshed Saadiah , Schipper Magan M. , Wood Peter , Marshall Sergio L. , Andersen Mark T. , Patterson Haileigh R. , Vanneste Joel L. , Peacock Linda , Jayaraman Jay , Templeton Matthew D.
Published: October 2024

In the late 2000s, a pandemic ofPseudomonas syringaepv.actinidiaebiovar 3 (Psa3) devastated kiwifruit orchards growing susceptible yellow-fleshed cultivars. New Zealand’s kiwifruit industry has since recovered, following the deployment of the tolerant cultivar ‘Zesy002’. However, little is known about the extent to which the Psa population is evolving since its arrival. Over 500 Psa3 isolates from New Zealand kiwifruit orchards were sequenced between 2010 and 2022, from commercial monocultures and diverse germplasm collections. While effector loss was previously observed on Psa-resistant germplasm vines, effector loss appears to be rare in commercial orchards, where the dominant cultivars lack Psa resistance. However, a new Psa3 variant, which has lost the effectorhopF1c, has arisen. The loss ofhopF1cappears to have been mediated by the movement of integrative conjugative elements introducing copper resistance into this population. Following this variant’s identification,in plantapathogenicity and competitive fitness assays were performed to better understand the risk and likelihood of its spread. WhilehopF1closs variants had similarin plantagrowth to wild-type Psa3, a lab-generated ΔhopF1cstrain could outcompete wild-type on select hosts. Further surveillance was conducted in commercial orchards where these variants were originally isolated, with 6.6% of surveyed isolates identified ashopF1closs variants. These findings suggest that the spread of these variants is currently limited, and they are unlikely to cause more severe symptoms than the current population. Ongoing genome biosurveillance of New Zealand’s Psa3 population is recommended to enable early detection and management of variants of interest.
Transcriptional pattern enriched for synaptic signaling is associated with shorter survival of patients with high-grade serous ovarian cancer
Authors: Bhattacharya Arkajyoti , Stutvoet Thijs S , Perla Mirela , Loipfinger Stefan , Jalving Mathilde , Reyners Anna K.L. , Vermeer Paola D. , Drapkin Ronny , de Bruyn Marco , de Vries Elisabeth G.E. , de Jong Steven , Fehrmann Rudolf S.N.
Published: October 2024

Background: Bulk transcriptomic analyses of high-grade serous ovarian cancer (HGSOC) so far have not uncovered potential drug targets, possibly because subtle, disease-relevant transcriptional patterns are overshadowed by dominant, non-relevant ones. Our aim was to uncover disease-outcome-related patterns in HGSOC transcriptomes that may reveal novel drug targets. Method: Using consensus-independent component analysis, we dissected 678 HGSOC transcriptomes of systemic therapy naive patients, sourced from public repositories, into statistically independent transcriptional components (TCs). To enhance c-ICA's robustness, we added 447 transcriptomes from non-serous histotypes, low-grade serous, and non-cancerous ovarian tissues. Cox regression and survival tree analysis were performed to determine the association between TC activity and overall survival (OS). Finally, we determined the activity of the OS-associated TCs in 11 publicly available spatially resolved ovarian cancer transcriptomes. Results: We identified 374 TCs, capturing prominent and subtle transcriptional patterns linked to specific biological processes. Six TCs, age, and tumor stage stratified patients with HGSOC receiving platinum-based chemotherapy into ten distinct OS groups. Three TCs were linked to copy-number alterations affecting expression levels of genes involved in replication, apoptosis, proliferation, immune activity, and replication stress. Notably, the TC identifying patients with the shortest OS captured a novel transcriptional pattern linked to synaptic signaling, which was active in tumor regions within all spatially resolved transcriptomes. Conclusion: The association between a synaptic signaling-related TC and OS supports the emerging role of neurons and their axons as cancer hallmark-inducing constituents of the tumor microenvironment. These constituents might offer a novel drug target for patients with HGSOC. Keywords: high-grade serous ovarian cancer (HGSOC), synaptic signaling, consensus independent component analysis, transcriptome
Optimizing information transmission in neural induction constrains cell surface contacts of ascidian embryos
Authors: Bettoni Rossana , Dupont Genevieve , Walczak Aleksandra M. , de Buyl Sophie
Published: October 2024

The onset of neural induction in the anterior ectoderm of ascidian embryos is regulated at the extracellular level by FGF signaling molecules, which control the acquisition of neural fate through the activation of the ERK pathway. Among the anterior ectoderm cells exposed to FGF, only a fraction will acquire neural fate. The selection of neural precursors depends on the quasi-invariant geometry of the embryo, which imposes upon each ectoderm cell a precise area of cell surface contact with underlying FGF-expressing (mesendoderm) cells. Here, we investigate information transmission between FGF and activated ERK and how this depends on the geometry of the system. Optimizing information transmission with the constraint that the total FGF-emitting surface area is restricted, as in the embryo, we find that the surface contacts with FGF that maximize information transmission are close to those observed experimentally. This information optimal solution is compatible with the anterior ectoderm cells having different areas of cell surface exposure to FGF, allowing the embryo to use cell surface areas as a regulatory mechanism for differentiating the outcome of cells that sense a constant FGF concentration.
Estimating and correcting index hopping misassignments in single-cell RNA-seq data
Authors: Miao Lingling , Collado Loren , Barkdull Savannah , Saito Yoshine , Jo Jay-Hyun , Han Jungmin , Dell’Orso Stefania , Kelly Michael C. , Kong Heidi H. , Brownell Isaac
Published: October 2024

Background

Index hopping causes read assignment errors in data from multiplexed sequencing libraries. This issue has become more prevalent with the widespread use of high-capacity sequencers and highly multiplexed single-cell RNA sequencing (scRNA- seq).

Results

We conducted deep, plate-based scRNA-seq on a mixed population of mouse skin cells. Analysis of transcriptomes from 1152 cells identified four distinct cell types. To estimate the error rate in sample assignment due to index hopping, we employed differential expression analysis to identify signature genes that were highly and specifically expressed in each cell type. We quantified the proportion of misassigned reads by examining the detection rates of signature genes in other cell types. Remarkably, regardless of gene expression levels, we estimated that 0.65% of reads per gene were assigned to incorrect cell across our data. To computationally compensate for index hopping, we developed a simple correction method wherein, for each gene, 0.65% of the library’s average expression level was subtracted from the expression in each cell. This correction had notable effects on transcriptome analyses, including increased cell-cell clustering distance and alterations in intermediate state assignments of cell differentiation.

Conclusions

Index hopping misassignments are measurable and can impact the experimental interpretation of sequencing results. We devised a straightforward method to estimate and correct for the index hopping rate by quantifying misassigned genes in distinct cell types within an scRNA-seq library. This approach can be applied to any barcoded, multiplexed scRNA-seq library containing cells with distinct expression profiles, allowing for correction of the expression matrix before conducting biological analysis.
Phase Behavior and Dissociation Kinetics of Lamins in a Polymer Model of Progeria
Authors: Hameed Hadiya Abdul , Paturej Jaroslaw , Erbas Aykut
Published: October 2024

One of the key structural proteins in the eukaryotic cell nucleus is lamin. Lamins can assemble into a two–dimensional protein meshwork at the nuclear periphery, referred to as the nuclear lamina, which provides rigidity and shape to the nucleus. Mutations in lamin proteins that affect the structure of the nuclear lamina underlie laminopathic diseases, including Hutchinson–Gilford Progeria Syndrome (HGPS). Experiments have shown that, compared to healthy cells, lamin supramolecular structures (e.g., protofilaments) assemble into a thicker lamina structure in HGPS, where lamins form highly stable nematic microdomains at the nuclear periphery, reminiscent of liquid crystals. This significantly alters the morphological and mechanical properties of the nucleus. In this study, we investigate the aggregation of lamin fibrous structures and their dissociation kinetics from the nuclear periphery by modeling them as coarse–grained, rod–like polymer chains confined in a rigid spherical shell. Our model recapitulates the formation of multidirectional nematic domains at the nuclear surface and the reduced lamin dissociation observed in HGPS nuclei by adjusting lamin concentration, lamin–lamin (specifically head–tail), and lamin–shell association strengths. While nematic phase formation requires relatively strong lamin-shell affinity under any non–vanishing inter–lamin attraction, the thickness of this layer is primarily controlled by head–tail association strength in the model. Furthermore, the dissociation kinetics of lamin chains from the chain aggregates at the periphery (lamina) exhibits a concentration–dependent dissociation (facilitated dissociation) pattern governed by weak lamin–lamin interactions, reminiscent of healthy nuclei. Overall, our calculations demonstrate how an interplay between molecular interactions altered by mutations and lamin concentration can lead to an abnormal nuclear lamina in laminopathic diseases.
Multigenerational Proteolytic Inactivation of Restriction Upon Subtle Genomic Hypomethylation
Authors: Shmidov Esther , Villani Alexis , Mendoza Senén D. , Avihu Ellay , Lebenthal-Loinger Ilana , Karako-Lampert Sarit , Shoshani Sivan , Ye Chang , Wang Yiding , Yan Hao , Tang Weixin , Bondy-Denomy Joseph , Banin Ehud
Published: October 2024

Restriction-modification (R-M) systems, present in most bacterial genomes, protect against phage infection by detecting and degrading invading foreign DNA. However, like many prokaryotic anti-phage systems, R-M systems pose a significant risk of auto-immunity, exacerbated by the presence of hundreds to thousands of potential cleavage sites in the bacterial genome. InPseudomonas aeruginosa, restriction inactivation upon growth at high temperatures was previously described, however, which system is being inactivated, the underlying mechanism, as well as the timing of recovery, remain unknown. Here, we report thatP. aeruginosaType I methyltransferase (HsdMS) and restriction endonuclease (HsdR) components are degraded by two Lon-like proteases when replicating above 41 °C, which induces partial genome hypomethylation and simultaneously prevents self-targeting, respectively. Interestingly, upon return to 37 °C, methyltransferase activity returns gradually, with restriction activity not fully recovering for over 60 bacterial generations, representing the longest bacterial memory to our knowledge. Forced expression of HsdR over the first 45 generations is toxic, demonstrating the fitness benefit of HsdR inactivation. Our findings demonstrate that type I R-M is tightly regulated post-translationally with a remarkable memory effect to ensure genomic stability and emphasize the importance of mitigating auto-toxicity for bacterial defense systems.
Urinary biochemical ecology reveals microbiome-metabolite interactions and metabolic markers of recurrent urinary tract infection
Authors: Neugent Michael L. , Hulyalkar Neha V. , Ghosh Debasish , Zimmern Philippe E. , Shulaev Vladimir , De Nisco Nicole J.
Published: October 2024

Recurrent urinary tract infections (rUTIs) are a major clinical challenge in postmenopausal women and their increasing prevalence underscores the need to define interactions between the host and the urinary microbiome that may underlie rUTI susceptibility. A body of work has identified the taxonomic profile of the female urinary microbiome associate with aging, menopause, and urinay disease. However, how this microbial community engages with the host niche, including the local biochemical environment of the urogenital tract, in health and disease is yet to be fully defined. This study directly assesses differences in the biochemical environment of the urine, or biochemical ecology, associated with recurrent urinary tract infection (UTI) and defines a microbe-metabolite association network of the female urinary microbiome. By integrating metagenomic and metabolomic data collected from a controlled cohort of women with rUTI, we find that distinct metabolites, such as methionine sulfoxide (Met-SO) and trimethylamine oxide (TMAO), are associated with differences in urinary microbiome diversity. We observe associations between microbial and biochemical beta diversity and unique metabolic networks of uropathogenicEscherichia coliand uroprotectiveLactobacillusspecies, highlighting potential metabolite-driven ecological shifts that may influence UTI susceptibility. We identify a urinary lipid signature of active rUTI that can accurately distinguish (AUC = 0.987) cases controls. Finally, using time-to-relapse data we identify deoxycholic acid (DCA) as a new prognostic indicator for rUTI recurrence. Together these findings suggest that systemic metabolic processes may influence susceptibility, opening new avenues for therapeutic intervention and the development of more accurate diagnostic and prognostic to improve patient outcomes.
What is true for plants may not be true forPhaeodactylum tricornutum: The case ofVanilla planifoliavanillin synthase (VpVAN) targeted to four subcellular compartments of the diatom
Authors: Diaz-Garza Aracely Maribel , Lavoie-Marchand Félix , Merindol Natacha , Diamond Andrew , Desgagné-Penix Isabel
Published: October 2024

Vanillin is the major organoleptic compound of the vanilla flavor. Since the extraction process from its natural source (Vanilla planifolia) is limited by a low yield, the market demand for vanillin is met by producing it through chemical synthesis or biotechnologically using microorganisms to convert ferulic acid, lignin, and guaiacol into vanillin. Our aim was to use the diatomPhaeodactylum tricornutum, a photosynthetic model organism already used to produce eukaryotic proteins and high-value compounds, to characterizeV. planifoliavanillin synthase (VpVAN). This enzyme is the subject of conflicting results and was reported to be localized in the plastid ofV. planifoliacells, which may play a role in its activity. For this purpose, we targetedVpVAN linked by anin vitrocleavable sequence (Xa) to the enhanced green fluorescent protein (eGFP) to the cytoplasm, peroxisomes, plastid, and Golgi apparatus. We used an episomal expression system transformingP. tricornutumwithVpVAN:Xa:eGFPby bacterial conjugation. Positive cell lines were selected by fluorescence and characterized by sequencing the episomes, confirming stable replication in the diatom, as well as assessing the subcellular localization in the targeted cell compartments. Strategies such as enriching GFP-positive cells by cell sorting, protein purification, and organelle isolation did not yield detectable levels of the fusion protein. A better understanding of the diatom expression system is needed to complete the characterization of this enzyme and reveal whether the subcellular localization could be a missing aspect ofVpVAN expression in microorganisms.
SETD2 promotes PAF1C interactions with the elongating RNA Pol II and is required for neuronal differentiation
Authors: Ambrosi Christina , Pfaendler Ramon , Butz Stefan , Recchia Davide , Bao Xue , Schmolka Nina , Baubec Tuncay
Published: October 2024

Chromatin modifications are relevant for mammalian development and their aberrant deposition is associated with human disease. While the mechanisms that deposit and remove these modifications have been largely elucidated, their role in regulating gene activity during cellular differentiation have yet to be completely understood. By differentiating a panel of mouse embryonic stem cells lacking major chromatin regulators towards neuronal cells, we identified their requirement at different stages of cellular differentiation. We show that the H3K36me3 methyltransferase SETD2 is important for the establishment of neuronal gene expression during late stages of differentiation, but is dispensable once the cells have fully differentiated. This function is largely independent of the histone methyltransferase activity. By measuring the protein interaction network of elongating RNA Pol II, we identify a novel role for SETD2 in mediating interactions between the PAF1 complex and the elongating RNA Pol II, which is required to ensure optimal transcriptional processivity of neuronal genes.
Imaging of live bacterial whole-cell biosensors illuminates spatial sialic acid availability within the inflamed mammalian gut
Authors: Carreño David , Robinson Clare M , Jackson Raphaella , Li Peirong , Nunes Vanessa , Palma-Duran Susana A. , Nye Emma , MacRae James I. , Riglar David T.
Published: October 2024

Host mucin-derived sialic acids are key drivers of microbial colonisation, growth and pathogenicity within the mammalian gut. However, their study is hindered by complex spatiotemporal dynamics, with availability driven by the interplay of microbial sialidase enzyme activity and microbial utilisation. Here, we demonstrate regional increases in the bioavailability of sialic acid in the inflamed mouse gut. We monitor metabolite availabilityin situusing an engineered bacterial whole-cell biosensor colonised within the gut. Through organ-scale imaging of cleared tissues at single bacterial resolution we observe strong correlations between global inflammation status and biosensor response. Profiling along the length of the gut uncovers regional variations between the peak sialic acid sensing and the peak inflammatory response within host tissues. These data illuminate the complex spatial dynamics involved in shared host-microbiome metabolism and demonstrate the broader power of using engineered bacterial biosensors to monitor bioavailabilityin situwithin the gut.
Enhanced Fear Extinction Through Infralimbic Perineuronal Net Digestion: The Modulatory Role of Adolescent Alcohol Exposure
Authors: Obray J. Daniel , Denton Adam R. , Carroll-Deaton Jayda , Marquardt Kristin , Chandler L. Judson , Scofield Michael D.
Published: October 2024

Perineuronal nets (PNNs) are specialized components of the extracellular matrix that play a critical role in learning and memory. In a Pavlovian fear conditioning paradigm, degradation of PNNs affects the formation and storage of fear memories. This study examined the impact of adolescent intermittent ethanol (AIE) exposure by vapor inhalation on the expression of PNNs in the adult rat prelimbic (PrL) and infralimbic (IfL) subregions of the medial prefrontal cortex. Results indicated that following AIE, the total number of PNN positive cells in the PrL cortex increased in layer II/III but did not change in layer V. Conversely, in the IfL cortex, the number of PNN positive cells decreased in layer V, with no change in layer II/III. In addition, the intensity of PNN staining was significantly altered by AIE exposure, which narrowed the distribution of signal intensity, reducing the number of high and low intensity PNNs. Given these changes in PNNs, the next experiment assessed the effects of AIE and PNN digestion on extinction of a conditioned fear memory. In Air control rats, digestion of PNNs by bilateral infusion of Chondroitinase ABC (ChABC) into the IfL cortex enhanced fear extinction and reduced contextual fear renewal. In contrast, both fear extinction learning and contextual fear renewal remained unchanged following PNN digestion in AIE exposed rats. These results highlight the sensitivity of prefrontal PNNs to adolescent alcohol exposure and suggest that ChABC-induced plasticity is reduced in the IfL cortex following AIE exposure.