bluuebunny/crossref_metadata_2025 huggingface dataset:
Screening for resistance alleles to Cry1 proteins through targeted sequencing in the native and invasive range of Spodoptera frugiperda (Lepidoptera: Noctuidae)
Authors: Tandy Peter , Lamour Kurt , Placidi de Bortoli Caroline , Nagoshi Rodney , Emrich Scott J , Jurat-Fuentes Juan Luis
Published: June 2023

The fall armyworm, Spodoptera frugiperda (J. E. Smith), is a highly polyphagous pest native to the tropical Americas that has recently spread to become a global super-pest threatening food and fiber production. Transgenic crops producing insecticidal Cry and Vip3Aa proteins from Bacillus thuringiensis (Bt) are used for control of this pest in its native range. The evolution of practical resistance represents the greatest threat to sustainability of this technology and its potential efficacy in the S. frugiperda invasive range. Monitoring for resistance is vital to management approaches delaying S. frugiperda resistance to Bt crops. DNA-based resistance screening provides higher sensitivity and cost-effectiveness than currently used bioassay-based monitoring. So far, practical S. frugiperda resistance to Bt corn-producing Cry1F has been genetically linked to mutations in the SfABCC2 gene, providing a model to develop and test monitoring tools. In this study, we performed targeted SfABCC2 sequencing followed by Sanger sequencing to confirm the detection of known and candidate resistance alleles to Cry1F corn in field-collected S. frugiperda from continental USA, Puerto Rico, Africa (Ghana, Togo, and South Africa), and Southeast Asia (Myanmar). Results confirm that the distribution of a previously characterized resistance allele (SfABCC2mut) is limited to Puerto Rico and identify 2 new candidate SfABCC2 alleles for resistance to Cry1F, one of them potentially spreading along the S. frugiperda migratory route in North America. No candidate resistance alleles were found in samples from the invasive S. frugiperda range. These results provide support for the potential use of targeted sequencing in Bt resistance monitoring programs.
The first case of human infection with H5N1 avian Influenza A virus in Chile
Authors: Castillo Andrés , Fasce Rodrigo , Parra Barbara , Andrade Winston , Covarrubias Paulo , Hueche Andrea , Campano Constanza , Tambley Carolina , Rojas Marcelo , Araya Maykol , Hernández Felipe , Bustos Patricia , Fernández Jorge
Published: June 2023

Highlights Here we present the first human case of Influenza A H5N1 infection in Chile, and the fifth worldwide in 2023.The patient is a 53-year-old man who lives in the north region of Chile, near the seashore.The Chilean sample was subtyped in the clade 2.3.4.4b.
Neural responses underlying extraordinary altruists’ generosity for socially distant others
Authors: Rhoads Shawn A , O'Connell Katherine , Berluti Kathryn , Ploe Montana L , Elizabeth Hannah S , Amormino Paige , Li Joanna L , Dutton Mary Ann , VanMeter Ashley Skye , Marsh Abigail A
Published: June 2023

Most people are much less generous toward strangers than close others, a bias termed social discounting. But people who engage in extraordinary real-world altruism, like altruistic kidney donors, show dramatically reduced social discounting. Why they do so is unclear. Some prior research suggests reduced social discounting requires effortfully overcoming selfishness via recruitment of the temporoparietal junction. Alternatively, reduced social discounting may reflect genuinely valuing strangers’ welfare more due to how the subjective value of their outcomes is encoded in regions such as rostral anterior cingulate cortex (ACC) and amygdala. We tested both hypotheses in this pre-registered study. We also tested the hypothesis that a loving-kindness meditation (LKM) training intervention would cause typical adults’ neural and behavioral patterns to resemble altruists. Altruists and matched controls (N = 77) completed a social discounting task during functional magnetic resonance imaging; 25 controls were randomized to complete LKM training. Neither behavioral nor imaging analyses supported the hypothesis that altruists’ reduced social discounting reflects effortfully overcoming selfishness. Instead, group differences emerged in social value encoding regions, including rostral ACC and amygdala. Activation in these regions corresponded to the subjective valuation of others’ welfare predicted by the social discounting model. LKM training did not result in more generous behavioral or neural patterns, but only greater perceived difficulty during social discounting. Our results indicate extraordinary altruists’ generosity results from the way regions involved in social decision-making encode the subjective value of others’ welfare. Interventions aimed at promoting generosity may thus succeed to the degree they can increase the subjective valuation of others’ welfare.
West Virginia v. EPA: Major Questions for the Future of the Administrative State and American Federalism
Authors: Dishman Elysa M
Published: June 2023

State attorney general (AG) lawsuits have led to judicial limitations on federal agencies’ powers, including the Supreme Court’s formal adoption of the major questions doctrine in the West Virginia v. EPA case in 2022. These limitations empower states to further challenge federal agencies and shape national policy while correspondingly weakening agencies’ ability to defend such lawsuits and aggressively regulate important issues of the day. AG lawsuits against the Biden administration regularly asserted the major questions doctrine leading up to the West Virginia decision, setting the stage for the Court’s adoption of the doctrine, and states continue to rely on the doctrine in the aftermath of the opinion. The major questions doctrine has important implications for relationships between the federal government and the states and among the states, exposing patterns of cooperation and conflict. Such conflict and cooperation will likely be heavily influenced by ideology and policy outcomes, further exacerbating political partisanship and polarization.
Thomas Elyot and the Translation of Galen
Authors: Colley John
Published: June 2023

Galen’s reception in Renaissance literature is usually studied as the reception of Galenic anatomy or humoral physiology, rather than the reception of actual texts that Galen wrote. Revising that orthodoxy, this article analyses fragmentary vernacular translations from Galen’s works by Thomas Elyot, many of which are filtered through intermediary Latin translations by Thomas Linacre. This approach foregrounds the often highly literary nature of Galen’s treatises, as well as the extent to which Elyot responds to Galen with a concern for style as well as content. The results contribute to scholarship on Greek translation in sixteenth-century England, which to date has neglected scientific works. New conclusions are also reached about the scale and nature of Linacre’s early Tudor reception. Ultimately, Elyot’s Galen translations shed new light on the burgeoning status of English as a classically validated language in the sixteenth century, and offer a case study in the value of linking medical humanities with scholarship in translation studies and classical reception.
ZIC1 Dictates Osteogenesis Versus Adipogenesis in Human Mesenchymal Progenitor Cells Via a Hedgehog Dependent Mechanism
Authors: Thottappillil Neelima , Gomez-Salazar Mario A , Xu Mingxin , Qin Qizhi , Xing Xin , Xu Jiajia , Broderick Kristen , Yea Ji-Hye , Archer Mary , Ching-Yun Hsu Ginny , Péault Bruno , James Aaron W
Published: June 2023

Numerous intrinsic factors regulate mesenchymal progenitor commitment to a specific cell fate, such as osteogenic or adipogenic lineages. Identification and modulation of novel intrinsic regulatory factors represent an opportunity to harness the regenerative potential of mesenchymal progenitors. In the present study, the transcription factor (TF) ZIC1 was identified to be differentially expressed among adipose compared with skeletal-derived mesenchymal progenitor cells. We observed that ZIC1 overexpression in human mesenchymal progenitors promotes osteogenesis and prevents adipogenesis. ZIC1 knockdown demonstrated the converse effects on cell differentiation. ZIC1 misexpression was associated with altered Hedgehog signaling, and the Hedgehog antagonist cyclopamine reversed the osteo/adipogenic differentiation alterations associated with ZIC1 overexpression. Finally, human mesenchymal progenitor cells with or without ZIC1 overexpression were implanted in an ossicle assay in NOD-SCID gamma mice. ZIC1 overexpression led to significantly increased ossicle formation in comparison to the control, as assessed by radiographic and histologic measures. Together, these data suggest that ZIC1 represents a TF at the center of osteo/adipogenic cell fate determinations—findings that have relevance in the fields of stem cell biology and therapeutic regenerative medicine.
The Hairdresser Blues: British Women and the Secondary Modern School, 1946–72
Authors: Carter Laura
Published: June 2023

Between the late 1940s and the early 1970s, the majority of teenage girls in Britain attended secondary modern schools. Yet, histories of the meaning and experience of postwar education continue to neglect this constituent of postwar women, favouring grammar-school leavers. This article draws upon a set of fifty-eight newly mined life histories from two postwar birth cohort studies to recapture the perspectives of ordinary women who attended secondary modern schools in England, Wales, and Scotland between c.1957 and c.1963. The longitudinal sources show that these women developed their attitudes to education gradually, across their lifecourses. Hairdressing, which stood for a desire for clean, creative, and autonomous paid work that could be balanced with domesticity, is identified as a reoccurring theme in the testimonies of secondary modern women. The article diagnoses secondary modern women with the hairdresser blues, a formulation that encapsulates their collective expectations, disappointments, and regrets born out of their closely interlinked experiences of schooling and paid work across the 1960s and early 1970s. These women’s educational attitudes were defined by the cumulative realization that a secondary modern education might not even be able to make you into a hairdresser. The article ultimately suggests that it was more often the hairdresser blues rather than ‘missing out’ on the prestigious grammar school that politicized secondary modern schools for the ordinary women who attended them.
Molecular and phylogenetic characterization of zoonotic Trichostrongylus species from goats for the first time in Bangladesh
Authors: Ahmed Nurnabi , Roy Babul Chandra , Hasan Mohammad Manjurul , Zim Md Makshuder Rahman , Biswas Hiranmoy , Talukder Md Hasanuzzaman
Published: June 2023

Background

Trichostrongylus is one of the most important nematodes infecting animals and humans. The current study was designed to identify the Trichostrongylus species infecting goats by multiplex PCR and phylogenetic analysis.

Methods

A total of 124 goats’ viscera were collected from different abattoirs of Mymensingh division. Trichostrongylus species were isolated and characterized based on morphometry, multiplex PCR and phylogenetic analysis.

Results

Among 124 viscera of goats, 39 were positive with two species, Trichostrongylus colubriformis and Trichostrongylus vitrinus, revealing an overall 31.45% prevalence. Morphological identification of Trichostrongylus species was confirmed by multiplex PCR amplification of the ITS2 gene and sequencing. Partial sequencing of the ITS2 gene of two species revealed seven single nucleotide polymorphisms (three transitions and four transversions) in this study. The neighbor-joining phylogenetic tree demonstrated that T. colubriformis and T. vitrinus isolates were clustered together with the reference sequences that belong to the clade A and B without any geographical boundaries.

Conclusions

This is the first report on molecular and phylogenetic analysis of Trichostrongylus species from ruminants in Bangladesh. These results provide the baseline data for understanding the zoonosis and epidemiology of this parasite in Bangladesh and global perspectives.
Mast cell activation and degranulation in acute artery injury: A target for post‐operative therapy
Authors: Harper Rebecca L. , Fang Fang , San Hong , Negro Alejandra , St. Hilaire Cynthia , Yang Dan , Chen Guibin , Yu Zhen , Dmitrieva Natalia I. , Lanzer Jan , Davaine Jean‐Michel , Schwartzbeck Robin , Walts Avram D. , Kovacic Jason C. , Boehm Manfred
Published: June 2023

The increasing incidence of cardiovascular disease (CVD) has led to a significant ongoing need to address this surgically through coronary artery bypass grafting (CABG) and percutaneous coronary interventions (PCI). From this, there continues to be a substantial burden of mortality and morbidity due to complications arising from endothelial damage, resulting in restenosis. Whilst mast cells (MC) have been shown to have a causative role in atherosclerosis and other vascular diseases, including restenosis due to vein engraftment; here, we demonstrate their rapid response to arterial wire injury, recapitulating the endothelial damage seen in PCI procedures. Using wild‐type mice, we demonstrate accumulation of MC in the femoral artery post‐acute wire injury, with rapid activation and degranulation, resulting in neointimal hyperplasia, which was not observed in MC‐deficient KitW‐sh/W‐sh mice. Furthermore, neutrophils, macrophages, and T cells were abundant in the wild‐type mice area of injury but reduced in the KitW‐sh/W‐sh mice. Following bone‐marrow‐derived MC (BMMC) transplantation into KitW‐sh/W‐sh mice, not only was the neointimal hyperplasia induced, but the neutrophil, macrophage, and T‐cell populations were also present in these transplanted mice. To demonstrate the utility of MC as a target for therapy, we administered the MC stabilizing drug, disodium cromoglycate (DSCG) immediately following arterial injury and were able to show a reduction in neointimal hyperplasia in wild‐type mice. These studies suggest a critical role for MC in inducing the conditions and coordinating the detrimental inflammatory response seen post‐endothelial injury in arteries undergoing revascularization procedures, and by targeting the rapid MC degranulation immediately post‐surgery with DSCG, this restenosis may become a preventable clinical complication.
Exposing Undergraduate Nursing Students to Older Adults
Authors: Pariseault Christine A. , Whitehouse Christina R. , O’Connor Melissa
Published: June 2023

Care of the older adult can be complex and influenced by ageism. The purpose of this pilot study was to expose nursing students to older adults earlier in the undergraduate curriculum. This study examined the experiences of student participation in caring for older adults. Qualitative analysis of student logs was conducted. Themes that emerged included age-related changes, environmental considerations, psychosocial needs and changes, consideration of gerontology as a career choice, and existing bias. Early experiences are vital in the curriculum and provide enhanced engagement in gerontology.
Disparities in employment outcomes among critical care graduates with different training backgrounds
Authors: Eisinger Greg J. , Sylvester Patrick J. , Duggineni Dheeraj , Way David P. , Peng Jing , Ma Jiang , McCallister Jennifer W. , Exline Matthew C.
Published: June 2023

Background

We sought to characterize the impact of critical care training pathways on subsequent employment opportunities.

Methods

A survey assessing the postfellowship work environment and barriers to employment in a preferred setting was electronically distributed on September 16, 2019, to program directors and coordinators at all US adult critical care fellowships with instructions to forward it to the prior year’s graduates.

Results

Data collection was interrupted by the coronavirus disease 2019 pandemic. Fifty-nine participants were included, reflecting a low rate of return. Most worked in urban areas (76.6%) at academic hospitals (81.7%). Graduates of internal medicine critical care (IMCC) were more likely than pulmonary critical care (PCC) to report their fellowship as a barrier to employment (50% vs 0%; P < 0.05). Emergency medicine graduates were more likely than internal medicine to report their residency as a barrier to employment (83.3% vs 4.6%; P < 0.05). Inability to find a desired position at an academic center (50% vs 5.9%; P < 0.05) and in the preferred metropolitan setting (37.5% vs 0%; P < 0.05) were more common among IMCC than PCC.

Conclusion

In this survey of critical care graduates, residency in emergency medicine and fellowship in IMCC were associated with increased barriers to finding desired employment.
Distinguishing Glaucoma, Cataract, and Glaucoma Suspect Based on Visual Symptoms
Authors: Quintero Michael , Mihailovic Aleksandra , Sikder Shameema , Jun Albert S. , Daoud Yassine , Ramulu Pradeep Y.
Published: June 2023

Précis:

Cataract, glaucoma, and glaucoma suspect patients report differing visual symptoms. Asking patients about their visual symptoms may provide useful diagnostic information and inform decision-making in patients with comorbid conditions.

Purpose:

To compare visual symptoms in glaucoma, glaucoma suspect (controls), and cataract patients.

Methods:

Glaucoma, cataract, and glaucoma suspect patients at Wilmer Eye Institute responded to a questionnaire rating the frequency and severity of 28 symptoms. Univariate and multivariable logistic regression determined the symptoms that best differentiate each disease pair.

Results:

In all, 257 patients (mean age: 67.4 ± 13.4 y; 57.2% female; 41.2% employed), including 79 glaucoma, 84 cataract, and 94 glaucoma suspect patients, participated. Compared with glaucoma suspects, glaucoma patients were more likely to report poor peripheral vision (OR 11.29, 95% CI: 3.73–34.16), better vision in 1 eye (OR 5.48, 95% CI: 1.33–22.64), and light sensitivity (OR 4.85, 95% CI: 1.78–13.24), explaining 40% of the variance in diagnosis (ie, glaucoma vs. glaucoma suspect). Compared with controls, cataract patients were more likely to report light sensitivity (OR 3.33, 95% CI: 1.56–7.10) and worsening vision (OR 12.20, 95% CI: 5.33–27.89), explaining 26% of the variance in diagnosis (ie, cataract vs. glaucoma suspect). Compared with cataract patients, glaucoma patients were more likely to report poor peripheral vision (OR 7.24, 95% CI: 2.53–20.72) and missing patches (OR 4.91, 95% CI: 1.52–15.84), but less likely to report worsening vision (OR 0.08, 95% CI 0.03–0.22), explaining 33% of the variance in diagnosis (ie, glaucoma vs. cataract).

Conclusions:

Visual symptoms distinguish disease state to a moderate degree in glaucoma, cataract, and glaucoma suspect patients. Asking about visual symptoms may serve as a useful diagnostic adjunct and inform decision-making, for example, in glaucoma patients considering cataract surgery.
Zonulopathy Identified During Cataract Extraction in Patients With Primary Angle Closure Disease
Authors: Zhang Hui , Zhang Ye , Zhang Shuo , Cao Kai , Li Dongjun , Liu Mugen , Liang Jing , Song Jing , Wang Ningli , Qiao Chunyan
Published: June 2023

Précis:

The proportion, clinical characteristics, and risk factors of zonulopathy in primary angle closure disease (PACD) were analyzed. Zonulopathy is an underrecognized common finding in PACD, especially in patients with acute angle closure (AAC).

Purpose:

To examine the proportion and risk factors associated with intraoperative zonulopathy in PACD.

Patients and Methods:

This is a retrospective analysis of 88 consecutive patients with PACD who underwent bilateral cataract extraction at Beijing Tongren Hospital from August 1, 2020 to August 1, 2022. Zonulopathy was diagnosed based on intraoperative findings including the presence of a lens equator, radial folds of the anterior capsule while making capsulorhexis, and other signs of the unstable capsular bag. The subjects were grouped based on their PACD subtype diagnoses: AAC, primary angle closure glaucoma (PACG), primary angle closure (PAC), or primary angle closure suspect (PACS). Multivariate logistic regression was performed to identify risk factors associated with zonulopathy. The proportion and the risk factors of zonulopathy were estimated in patients with PACD and in PACD subtypes.

Results:

Of 88 patients with PACD (67.3 ± 6.9 y old, 19 males and 69 females), the overall proportion of zonulopathy was 45.5% of patients (40/88) and 30.1% of eyes (53/176). Among the PACD subtypes, the proportion of zonulopathy was highest (69.0%) in AAC, followed by 39.1% in PACG, and 15.3% in PAC and PACS combined. AAC was an independent risk factor associated with zonulopathy (P = 0.015, AAC vs PACG, PAC, and PACS combined; odds ratio: 0.340, CI: 0.142–0.814). Shallower anterior chamber depth (P = 0.031) and greater lens thickness (P = 0.036), but not laser iridotomy, were associated with an increased proportion of zonulopathy.

Conclusions:

Zonulopathy is common in PACD, especially in patients with AAC. Shallow anterior chamber depth and thick lens thickness were associated with an increased proportion of zonulopathy.
Use of Carbon Nanoparticles to Improve the Efficiency of Harvesting Lymph Nodes in Rectal Cancer
Authors: Ji Hongli , Hu Yaowen , Cheng Jiaxin , Lu Jianping , Zhu Weifeng , Li Qingping , Li Zhiming , Liu Xiumin , Wang Shijie , Wu Xiufeng , Yan Jun
Published: June 2023

Background:

The accurate determination of lymph node status in patients with rectal cancer requires harvesting a certain number of lymph nodes. This study investigated whether using carbon nanoparticles (CNs) could improve the efficiency of harvesting lymph nodes in rectal cancer patients.

Materials and Methods:

Data from patients with rectal cancer treated with radical resection were collected from Nanfang Hospital between January 2014 and June 2021. Patients in the CN group received a CN suspension 1 day before surgery, which was endoscopically injected around the tumor. A 1:1 case-matched study was performed using the propensity score. The efficiency of harvesting lymph nodes was investigated by comparing the number of total nodes, total time, and percentage of nodes <5 mm in size between the CN and non-CN groups.

Results:

A total of 768 patients were included, with 246 patients who underwent CN injection and 522 patients who did not. After matching, 246 pairs of patients were analyzed. After matching, the number of total nodes of each sample was significantly higher in the CN group than in the non-CN group (P<0.001). The total time for node detection (P<0.001) was significantly shorter in the CN group. The percentage of nodes <5 mm in size was increased significantly in the CN group (P<0.001). Among patients with clinical staging I/II, the difference in positive LNs was significant (21.79% vs. 11.95%, P=0.029).

Conclusions:

The application of CNs improved the efficiency of harvesting lymph nodes during rectal cancer surgery.
Current Advances in Graft-Versus-Host Disease After Intestinal Transplantation
Authors: Oza Kesha , Kang Jiman , Patil Digvijay , Owen Kathryn L. , Cui Wanxing , Khan Khalid , Kaufman Stuart S. , Kroemer Alexander
Published: June 2023

Graft-versus-host disease (GvHD) remains a potentially fatal complication following intestinal transplant (ITx). Over the past decade, advances in the understanding of the pathophysiology of this complex immunological phenomenon have led to the reassessment of the host systemic immune response and have created a gateway for novel preventive and therapeutic strategies. Although sufficient evidence dictates the use of corticosteroids as a first-line option, the treatment for refractory disease remains contentious and lacks a standardized therapeutic approach. Timely diagnosis remains crucial, and the advent of chimerism detection and immunological biomarkers have transformed the identification, prognostication, and potential for survival after GvHD in ITx. The objectives of the following review aim to discuss the clinical and diagnostic features, pathophysiology, advances in immune biomarkers, as well as therapeutic opportunities in the prevention and treatment of GvHD in ITx.
Robotic Enhanced-View Totally Extraperitoneal vs Intraperitoneal Onlay Mesh Evaluation: 1-Year Exploratory Outcomes of the REVEAL Randomized Clinical Trial
Authors: Petro Clayton C , Maskal Sara M , Renton David B , Yunis Jonathan P , Meara Michael P , Diaz Kayla , Wilber Melanie , McKenzie Kristen , Tu Chao , Phillips Sharon E , Miller Benjamin T , Beffa Lucas R , Rosen Michael J , Prabhu Ajita S
Published: June 2023

Background:

Patients with small to medium-sized ventral hernias randomized to robotic enhanced-view totally extraperitoneal (eTEP) or robotic intraperitoneal onlay mesh (rIPOM) previously demonstrated comparable 30-day patient-reported outcomes. Here we report 1-year exploratory outcomes for this multi-center, patient-blinded randomized clinical trial.

Methods:

Patients with midline ventral hernias ≤7cm wide undergoing mesh repair were randomized to robotic eTEP or rIPOM. Planned exploratory 1-year outcomes include pain intensity (Patient-Reported Outcomes Measurement Information System [PROMIS 3a]), hernia-specific quality of life (HerQLes), pragmatic hernia recurrence, and reoperation.

Results:

One hundred randomized patients (51 eTEP, 49 rIPOM) reached a median 12 months follow-up [interquartile range 11-13] with 7% lost. Following regression analysis adjusting for baseline scores, there was no difference in postoperative pain intensity at 1-year for eTEP compared to rIPOM (OR 2.1, 95% CI 0.85-5.1, p=0.11). HerQLes scores were on average 15 points lower (i.e. less improved) at 1 year following eTEP repairs compared to rIPOM, a difference maintained after regression analysis (OR 0.31, 95% CI 0.15-0.67, p=0.003). Pragmatic hernia recurrence was 12.2% (6 of 49) for eTEP and 15.9% (7 of 44) for rIPOM (p = 0.834). Two eTEP and one rIPOM patients required reoperations related to their index repair in the first year (p=0.82).

Conclusion:

Exploratory analyses showed similar outcomes at 1 year in regards to pain, hernia recurrence, and reoperation. Abdominal wall quality of life at 1 year appears to favor rIPOM, and the possibility that an eTEP dissection is less advantageous in that regard should be the subject of future investigation.
Estimated mortality of the highly pathogenic avian influenza pandemic on northern gannets (Morus bassanus) in southwest Ireland
Authors: Giralt Paradell Oriol , Goh Tiffany , Popov Dimitar , Rogan Emer , Jessopp Mark
Published: June 2023

The 2022 highly pathogenic avian influenza (HPAI) outbreak that occurred in many European countries affected several seabird species. Among them, northern gannets (Morus bassanus) were particularly impacted. We conducted aerial surveys in waters around the two largest gannet colonies in southwest Ireland (Little Skellig and Bull Rock, together representing 87% of the national population) in September 2022. During surveys dead and alive northern gannets were counted on survey effort. A total of 184 dead gannets were recorded on survey effort, representing 3.74% of the total number of gannets recorded. We estimated the abundance of dead gannets in the surveyed area at 1526 (95% confidence intervals (CIs) 1450–1605) individuals. The percentage of dead gannets observed was used to estimate a minimum local population mortality of 3126 (95% CIs 2993–3260) individuals across both colonies. Aerial surveys provided key information on gannet mortality from HPAI at sea. The study provides the first estimate of gannet mortality in the two largest gannetries in Ireland.
Structure and its transformation of elliptical nege-like virus Tanay virus
Authors: Okamoto Kenta , Song Chihong , Wang Han , Sakaguchi Miako , Chalkiadaki Christina , Miyazaki Naoyuki , Nabeshima Takeshi , Morita Kouichi , Inoue Shingo , Murata Kazuyoshi
Published: June 2023

Negeviruses that infect insects are recently identified virus species that are phylogenetically related to several plant viruses. They exhibit a unique virion structure, an elliptical core with a short projection. Negeviruses encode two structural proteins, a glycoprotein that forms a short projection, and an envelope protein that forms an elliptical core. The glycoprotein has been reported only in the negeviruses’ genes, and not in phylogenetically related plant viruses’ genes. In this report, we first describe the three-dimensional electron cryo-microscopy (cryo-EM) structure of Tanay virus (TANAV), one of the nege-like viruses. TANAV particle demonstrates a periodical envelope structure consisting of three layers surrounding the centred viral RNA. The elliptical core dynamically changes its shape under acidic and even low detergent conditions to form bullet-like or tubular shapes. The further cryo-EM studies on these transformed TANAV particles reveal their overall structural rearrangement. These findings suggest putative geometries of TANAV and its transformation in the life cycle, and the potential importance of the short projection for enabling cell entry to the insect hosts.
PF-431396 hydrate inhibition of kinase phosphorylation during adherent-invasive Escherichia coli infection inhibits intra-macrophage replication and inflammatory cytokine release
Authors: Li Xiang , Ormsby Michael J. , Fallata Ghaith , Meikle Lynsey M. , Walker Daniel , Xu Damo , Wall Daniel M.
Published: June 2023

Adherent-invasive

Escherichia coli

(AIEC) have been implicated in the aetiology of Crohn’s disease (CD). They are characterized by an ability to adhere to and invade intestinal epithelial cells, and to replicate intracellularly in macrophages resulting in inflammation. Proline-rich tyrosine kinase 2 (PYK2) has previously been identified as a risk locus for inflammatory bowel disease and a regulator of intestinal inflammation. It is overexpressed in patients with colorectal cancer, a major long-term complication of CD. Here we show that Pyk2 levels are significantly increased during AIEC infection of murine macrophages while the inhibitor PF-431396 hydrate, which blocks Pyk2 activation, significantly decreased intramacrophage AIEC numbers. Imaging flow cytometry indicated that Pyk2 inhibition blocked intramacrophage replication of AIEC with no change in the overall number of infected cells, but a significant reduction in bacterial burden per cell. This reduction in intracellular bacteria resulted in a 20-fold decrease in tumour necrosis factor α secretion by cells post-AIEC infection. These data demonstrate a key role for Pyk2 in modulating AIEC intracellular replication and associated inflammation and may provide a new avenue for future therapeutic intervention in CD.
Quantitative and geometric motor unit analysis using magnetomyography
Authors: Broser Philip J. , Middelmann Thomas , Noury Nima , Siegel Markus , Hartwig Stefan , Klotz Thomas , Marquetand Justus
Published: June 2023

Objective

Magnetomyography (MMG) is currently a rather unexplored neurophysiological modality and it is not known to which extent the number of motor units have an influence on the amplitude and the direction of the MMG-signal.

Methods

A simultaneous invasive electromyography (iEMG), surface EMG (sEMG) and MMG using optically pumped magnetometer (OPM-MMG) of the right abductor digiti minimi muscle (ADM) of two healthy participants was recorded during a stepwise increasing electrical stimulation of the ADM innervating ulnar nerve. Then, the number of electrically evoked motor units was estimated (MUNE), the magnetic field vectors were reconstructed and aligned to the muscular anatomy. In addition, a finite element simulation of the ADM muscle was performed and compared to the experimental data.

Results

The more motor units were activated by increasing electrical stimulation, the stronger the MMG signal became, which was the same for iEMG&sEMG (r>0.96). The finite element simulation showed the same relation between the magnetic and electric signal. Further, based on the simulation the number of activated muscular fibers and neuromuscular units could be estimated the ratio of signal to fibers determined.

In addition, the precise vector direction of the magnetomyography (MMG) signal can reliably be recorded following the electric stimulation of the ulnar nerve and followed the muscle fiber direction.

Conclusion

The MMG signal can be used to determine the amount of activated motor units, but also analysis of the magnetic field vector corresponds to the muscle fiber direction, offering a functional as well as structural characterization of muscles. The modelling and simulation is especially helpful to understand the magnetic muscular signal in detail.

Significance

Next to establishing MUNE in MMG, our results provide the first quantitative comparison between MMG vs. iEMG&sEMG and highlight the possibilities of the vector component analysis in MMG.

Highlights

- Comparative study of MMG, iEMG&sEMG using electrically induced activation of motor units.

- MUNE in MMG is possible and is potentially superior to surface EMG.

- The vector components of the MMG-signal correspond to the muscle fiber direction of the muscle.

- Finite element simulation of the muscular magnetic and electric signal
Polygenic risk of idiopathic pulmonary fibrosis and COVID-19 severity
Authors: Guillen-Guio Beatriz , Marcelino-Rodriguez Itahisa , Lorenzo-Salazar Jose Miguel , Leavy Olivia C , Allen Richard J ,   Scourge Cohort Group, Riancho José A. , Rojas Augusto , Lapunzina Pablo , Carracedo Ángel , Wain Louise V , Flores Carlos
Published: June 2023

Introduction

Coronavirus disease 2019 (COVID-19) survivors can develop residual lung abnormalities consistent with lung fibrosis. A shared genetic component between COVID-19 and idiopathic pulmonary fibrosis (IPF) has been shown. However, genetic overlap studies of IPF and COVID-19 have primarily concentrated on the IPF genome-wide significant risk variants that have been previously identified, rather than combined into a genome-wide polygenic risk. Here we used IPF genome-wide association study (GWAS) results to calculate polygenic risk scores (PRSs) and study their association with COVID-19 severity.

Methods

We used results from the largest meta-GWAS of clinically defined IPF risk (base dataset; n=24,589) and individual-level imputed data from the SCOURGE study of patients with COVID-19 (target dataset; n=15,024). We calculated IPF PRSs using PRSice-2 and assessed their association with COVID-19 hospitalisation, severe illness, and critical illness. We also evaluated the effect of age and sex stratification. Results were validated using an independent PRS method. Enrichment analyses and pathway-specific PRSs were performed to study biological pathways associated with COVID-19 severity.

Results

IPF PRSs were significantly associated with COVID-19 hospitalisation and severe illness. The strongest association was found in patients aged <60 years, especially among younger males (OR=1.16; 95%CI=1.08-1.25; p=6.39×10−5). A pathway enrichment analysis of the variants included in the best model fit and subsequent pathway-specific PRSs analyses supported the link of Cadherin and Integrin signalling pathways to COVID-19 severity when stratified by age and sex.

Conclusion

Our results suggest that there is genome-wide genetic overlap between IPF and severe COVID-19 that is dependent on age and sex and adds further support that the pathogenesis of both IPF and severe COVID-19 share underlying biological mechanisms. This could imply that individuals with a high IPF genetic risk are at an overall increased risk of developing lung sequelae resulting from severe COVID-19.
A pilot study of the quality of care of atrial fibrillation in Irish general practice
Authors: McErlean Sarah , Broughan John , McCombe Geoff , Fawsitt Ronan , Ledwidge Mark , Cullen Walter , Gallagher Joe
Published: June 2023

Aim

The aim of this pilot study is to develop and test a quality of care score for patients with permanent atrial fibrillation (AF) in general practice, and identify the patterns of quality of care using this score.

We developed a quality of care score based on the Atrial Fibrillation Better Care pathway recommended by the European Society of Cardiology and the European Heart Rhythm Association guidelines. This is a 14-point score that we have termed the MAGIC score(Management of Atrial Fibrillation in Integrated Care and General Practice).

Methods & Results

An observational cross-sectional pilot study was undertaken. Proportionate sampling was used across 11 practices from the Ireland East practice-based research network. The GPs completed a report form on each patient provided by the research team by undertaking a retrospective chart review.

11 practices participated with a total number of 1855 patients with AF. We received data on 153 patients.

The main findings were that:

No patient met all 14 guideline based recommendations Mean MAGIC score was 11.3

Points were most commonly deducted because the creatinine-clearance and HAS-BLED score were not recorded and the patient was not on the correct dose of oral anti-coagulation.

Conclusion

This study demonstrates the feasibility of using a quality of care score to measure quality of AF management in general practice. This scoring system; which is based on internationally recognised quality of care markers, highlights key areas that can be targeted with intervention to improve care.
Large-scale blood mitochondrial genome-wide study provides novel insights into mitochondrial disease-related traits
Authors: Cannon S , Hall T , Hawkes G , Colclough K , Boggan RM , Wright CF , Pickett SJ , Hattersley AT , Weedon MN , Patel KA
Published: June 2023

Background/Objectives

Whole genome sequencing (WGS) from large cohorts enables the study of mitochondrial DNA (mtDNA) variation on human health. We aimed to investigate the influence of common, rare, and pathogenic mtDNA variants on 15 mitochondrial disease-related phenotypes.

Methods

Using WGS from 179,862 individuals from in the UK Biobank, we identified mtDNA variants using MitoHPC. We performed extensive association analyses with 15 mitochondrial disease-relevant phenotypes. We compared the results for the m.3243A>G variant with those from a clinically referred patient cohort.

Results

Of 15,881 mtDNA variants, 12 homoplasmic and one heteroplasmic variant had genome-wide significant associations. All homoplasmic variants increased aspartate aminotransferase level and three were novel, low frequency, variants (MAF∼0.002 and beta∼0.3 SD). Only m.3243A>G (MAF=0.0002) associated with diabetes (OR=5.6, 95%CI [3.2-9.9]), deafness (OR=12.3, 95%CI [6.2-24.4]) and heart failure (OR=39.5, 95%CI [9.76-160.1]). Multi-system disease risk and penetrance of all three traits increased with m.3243A>G level. Diabetes risk was further influenced by common nuclear genome variation. The penetrance of diabetes with m.3243A>G in the UK Biobank was lower than clinically referred patients, partly attributed to lower heteroplasmy. Of 73 pathogenic mitochondrial disease variants, most were rare in the population with low penetrance.

Conclusion

Our study highlights the utility of WGS for investigating mitochondrial genetics within a large, unselected population. We identified novel associations and demonstrated that pathogenic mitochondrial variants have lower penetrance in clinically unselected than clinically referred settings. m.3243A>G associated with mitochondrial-related phenotypes at higher heteroplasmy. Our findings suggest potential benefits of reporting incidentally identified m.3243A>G at high heteroplasmy levels.
Spatial proteomics reveals heterogeneity in neural markers underpinning high-fat diet-induced myopathy in male mice
Authors: Hardowar Lydia , Vadakekolathu Jayakumar , Rutella Sergio , Hulse Richard P. , Doig Craig L.
Published: June 2023

Metabolic dysfunction in skeletal muscle disturbs its contractile response as well as its innervation and vascular networks. The molecular drivers responsible for affecting decline in function remain poorly defined. To provide insight and locate these, we mapped changes in the spatial proteome occurring as a result of impaired metabolic health. We exposed male mice (C57/BL6J) to diet induced obesity to investigate the impairment of muscle metabolic function and myopathy. We conducted digital spatial profiling using the NanoString GeoMx® platform on recovered skeletal muscle (tibialis anterior) comparing it to standard fed controls. Digital spatial profiling revealed areas with shifts in the contractile protein desmin and CD31 expression, a marker of tissue stress and cellular maladaptation. We find increased expression of proinflammatory markers were identified in areas of elevated Desmin in obese samples compared to controls. Our data suggest a dietary-driven relationship between the spatial abundance of the sarcomere protein desmin and the influx of neural and inflammatory mediators to muscle. This supports the concept of pro-inflammatory events underpinning the muscle metabolic dysfunction associated with chronic non-communicative diseases such as type 2 diabetes, metabolic syndrome, and chronic obstructive pulmonary disorder.
Zfp697 is an RNA-binding protein that regulates skeletal muscle inflammation and regeneration
Authors: Correia Jorge C. , Jannig Paulo R. , Gosztyla Maya L. , Cervenka Igor , Ducommun Serge , Præstholm Stine M. , Dumont Kyle , Liu Zhengye , Liang Qishan , Edsgärd Daniel , Emanuelsson Olof , Gregorevic Paul , Westerblad Håkan , Venckunas Tomas , Brazaitis Marius , Kamandulis Sigitas , Lanner Johanna T. , Yeo Gene W. , Ruas Jorge L.
Published: June 2023

Muscular atrophy is a mortality risk factor that happens with disuse, chronic disease, and aging. Recovery from atrophy requires changes in several cell types including muscle fibers, and satellite and immune cells. Here we show that Zfp697/ZNF697 is a damage-induced regulator of muscle regeneration, during which its expression is transiently elevated. Conversely, sustained Zfp697 expression in mouse muscle leads to a gene expression signature of chemokine secretion, immune cell recruitment, and extracellular matrix remodeling. Myofiber-specific Zfp697 ablation hinders the inflammatory and regenerative response to muscle injury, compromising functional recovery. We uncover Zfp697 as an essential interferon gamma mediator in muscle cells, interacting primarily with ncRNAs such as the pro-regenerative miR-206. In sum, we identify Zfp697 as an integrator of cell-cell communication necessary for tissue regeneration.

One Sentence Summary

Zfp697 is necessary for interferon gamma signaling and muscle regeneration.
Targeting Fibroblast-Endothelial Interactions in LAM Pathogenesis: 3D Spheroid and Spatial Transcriptomic Insights for Therapeutic Innovation
Authors: Koc-Gunel Sinem , Liu Emily C. , Gautam Lalit K. , Calvert Ben A. , Murthy Shubha , Harriott Noa C. , Nawroth Janna C. , Zhou Beiyun , Krymskaya Vera P. , Ryan Amy L.
Published: June 2023

Lymphangioleiomyomatosis (LAM) is a progressive lung disease with limited treatments, largely due to an incomplete understanding of its pathogenesis. Lymphatic endothelial cells (LECs) invade LAM cell clusters, which include HMB-45-positive epithelioid cells and smooth muscle α-actin-expressing LAM-associated fibroblasts (LAMFs). Recent evidence shows that LAMFs resemble cancer-associated fibroblasts, with LAMF-LEC interactions contributing to disease progression. To explore these mechanisms, we used spatial transcriptomics on LAM lung tissues and identified a gene cluster enriched in kinase signaling pathways linked to myofibroblasts and co-expressed with LEC markers. Kinase arrays revealed elevated PDGFR and FGFR in LAMFs. Using a 3D co-culture spheroid model of primary LAMFs and LECs, we observed increased invasion in LAMF-LEC spheroids compared to non-LAM fibroblasts. Treatment with sorafenib, a multikinase inhibitor, significantly reduced invasion, outperforming Rapamycin. We also confirmed TSC2-null AML cells as key VEGF-A secretors, which was suppressed by sorafenib in both AML cells and LAMFs. These findings highlight VEGF-A and bFGF as potential therapeutic targets and suggest multikinase inhibition as a promising strategy for LAM.

One Sentence Summary

Using 3D spheroids and spatial transcriptomics, we identified LAMFs and LECs as key contributors to LAM, with bFGF and VEGF-A as potential therapeutic targets
Combination EZH2 inhibition and retinoic acid treatment promotes differentiation and apoptosis in rhabdomyosarcoma cells
Authors: O’Brien Eleanor , Tse Carmen , Tracy Ian , Reddin Ian , Selfe Joanna , Gibson Jane , Tapper William , Pengelly Reuben J , Gao Jinhui , Aladowicz Ewa , Petts Gemma , Thway Khin , Popov Sergey , Kelsey Anna , Underwood Timothy J , Shipley Janet , Walters Zoë S
Published: June 2023

Rhabdomyosarcomas (RMS) are predominantly pediatric sarcomas thought to originate from muscle precursor cells due to impaired myogenic differentiation. Despite intensive treatment, 5-year survival for patients with advanced disease remains low (<30%), highlighting a need for novel therapies to improve outcomes. Differentiation therapeutics are agents that induce differentiation of cancer cells from malignant to benign. The histone methyltransferase, Enhancer of Zeste Homolog 2 (EZH2) suppresses normal skeletal muscle differentiation and is highly expressed in RMS tumors. We demonstrate combining EZH2 inhibition with the differentiating agent retinoic acid (RA) is more effective at reducing cell proliferation in RMS cell lines than single agents alone. In PAX3 -FOXO1 positive RMS cells this is due to an RA-driven induction of the interferon pathway resulting in apoptosis. In fusion negative RMS, combination therapy led to an EZH2i-driven upregulation of myogenic signaling resulting in differentiation. These results provide insight into the mechanism that drives the anti-cancer effect of the EZH2/RA single agent and combination treatment and indicate that the reduction of EZH2 activity combined with the induction of RA signalling represents a potential novel therapeutic strategy to treat both subtypes of RMS.

Highlights

EZH2 expression is upregulated fusion positive (FPRMS) and fusion negative (FNRMS) rhabdomyosarcomas

EZH2 inhibition combined with retinoic acid treatment was investigated RMS cell models.

Combination treatment reduced cell proliferation and tumor spheroid volume.

Combination treatment in FPRMS resulted in apoptosis in FPRMS via interferon signaling.

Conversely, combination treatment in fusion negative RMS resulted in myogenic differentiation.
The effect of parental age on the quantity and quality of offspring inSyngnathus typhle, a species with male pregnancy
Authors: Pappert Freya Adele , Kolbe Daniel , Dubin Arseny , Roth Olivia
Published: June 2023

Offspring quantity and quality are known to vary according to parental age, with most studies focusing on the mother’s age, who produces costly eggs and often carries out pregnancy, hampering to distinction between trans-generational age effects due to egg quality or physiological deterioration. We investigated the ramification of parental age on the offspring in the broad-nosed pipefishSyngnathus typhle, a fish species with male pregnancy, allowing us to separate these two female traits. By mating parents of different sizes we examined the impact of parental age on offspring number, size and gene expression. Our results show that older parents produced more and larger-sized offspring. However, we revealed intriguing insights into the differential gene expression patterns in offspring, strongly influenced by the paternal lineage but minimally affected by maternal age. Offspring from old fathers exhibited notable changes in gene expression profiles, particularly related to cell cycle regulation, metabolism, protein synthesis, stress response, DNA repair and neurogenesis. Our findings provide valuable insights into the role of pregnancy in shaping offspring physiology. Moreover, we recognize the value of assessing a broader range of species that have evolved with sex-specific differences in parental investment vs. gamete provisioning, as the age of either the mother or father may hold greater significance than the other in influencing offspring fitness.