bluuebunny/crossref_metadata_2025 huggingface dataset:
Real-world safety and effectiveness of mepolizumab for patients with eosinophilic granulomatosis with polyangiitis in Japan: Long-term observation of the MARS study
Authors: Ishii Tomonori , Kunishige Hideaki , Kobayashi Tamami , Hayashi Etsuko , Komatsubara Masaki , Alfonso-Cristancho Rafael , Tamaoki Jun , Howarth Peter
Published: November 2024

Objectives

To provide long-term, real-world safety and effectiveness data for mepolizumab treatment in eosinophilic granulomatosis with polyangiitis in Japan.

Methods

MARS (NCT04551989) was a real-world, observational study of patients who had previously completed the PMS study [NCT03557060; ≥96 weeks of mepolizumab treatment before study entry (baseline)] and continued receiving four-weekly mepolizumab 300 mg subcutaneously for a further 96 weeks. Safety outcomes were assessed from baseline to Week 96 (observation period); clinical outcomes were assessed pre-mepolizumab initiation (retrospective period) and during the observation period.

Results

Of 118 patients enrolled in the study, 58% (69/118) experienced adverse events and 22% (26/118) experienced serious adverse events over the observation period; none were mepolizumab-related. Over the study (pre-mepolizumab period, baseline, and end of observation period), the proportion of patients with no clinical symptoms increased (from 6% to 27% to 32%, respectively), median oral glucocorticoid dose decreased (from 6.9 to 3.0 to 2.0 mg/day, respectively), and the proportion of oral glucocorticoid-free patients increased (from 8% to 31% to 36%, respectively).

Conclusions

Long-term MARS study data are consistent with the known safety profile of mepolizumab. Over 192 weeks (pre-mepolizumab observation), mepolizumab was well tolerated, with improvements in eosinophilic granulomatosis with polyangiitis disease control and reductions in oral glucocorticoid use.
Background and emerging applications of acoustic metamaterials: a forum on classical waves
Authors: Zhu He
Published: November 2024

Acoustic metamaterials provide new dimensions over traditional materials to modulate sound wave. As a result, we observe new phenomenon and achieve new functions. This is a Forum article, please use the corresponding template.
The Context of the Emergency Department as a Location for a Smoking Cessation Intervention—Process Evaluation Findings From the Cessation of Smoking Trial in the Emergency Department Trial
Authors: Notley Caitlin , Belderson Pippa , Ward Emma , Clark Lucy V , Clark Allan , Stirling Susan , Parrott Steve , Li Jinshuo , Coats Timothy J , Bauld Linda , Holland Richard , Gentry Sarah , Agrawal Sanjay , Bloom Benjamin M , Boyle Adrian , Gray Alasdair , Morris M Geraint , Pope Ian
Published: November 2024

Introduction

Hospital emergency departments (ED) offer an opportunity to engage with large numbers of people who smoke to prompt cessation, although the acceptability of opportunistic intervention in this context has been questioned. This process evaluation study was embedded into the Cessation of Smoking Trial in the Emergency Department (COSTED) randomized controlled trial and sought to explore the context of intervention delivery within the ED.

Aims and Methods

Qualitative interviews were conducted with participants and staff across six EDs participating in the COSTED randomized controlled trial. Interview data were thematically analyzed specifically exploring contextual influences. Data were triangulated with ethnographic observations.

Results

In participant interviews (N = 34), it was acceptable overall to receive a brief opportunistic smoking cessation intervention in the ED. Contextual factors are impacted at a range of levels. At the micro level participant views and experiences combined with staff tailoring were important. Being given an e-cigarette starter kit by a “credible source” helped to legitimize vaping for smoking cessation and gave confidence in personal ability to switch away from tobacco. At the meso level, adaptations to intervention delivery were made in response to the context of the ED. Stop smoking advisors (N = 11) had to adapt and deliver the intervention flexibly depending on space and clinical need. At the macro level, hospital policies supportive of vaping legitimized the approach.

Conclusions

Smoking cessation outcomes reported in the main trial across sites were very similar because of the high credibility, acceptability, and flexible approach to delivering the COSTED intervention in the ED.

Implications

Attending a hospital ED is the right time and place to receive smoking cessation intervention, even for those not motivated to quit. People are willing to receive intervention, and clinical staff are willing to support intervention delivery. Despite challenges, overall the context is helpful in supporting people to switch away from tobacco. The intervention, with flexible and tailored implementation, is adaptable to different ED contexts. This suggests that wider implementation across NHS Trusts of the effective COSTED intervention is feasible and will ultimately support smoking cessation for people attending EDs, who may not otherwise have sought support.
Do Patients With Candidemia Need an Ophthalmologic Examination?
Authors: Lehman Alice , Tessier Katelyn M , Sattarova Victoria , Montezuma Sandra Rocio , Kline Susan , Erayil Serin Edwin
Published: November 2024

Background

The Infectious Diseases Society of America recommends a screening dilated retinal examination by an ophthalmologist for all patients with candidemia. Conversely, the American Academy of Ophthalmology recommends against routine screening in patients with candidemia without symptoms.

Methods

In a collaborative effort between infectious diseases and ophthalmology, we examined the incidence of ocular complications in 308 patients with candidemia and subsequently measured the rate of fundoscopic examinations, risk factors for ocular complications, management changes, and outcomes.

Results

Among those who received fundoscopic exams, findings suspicious for ocular candidiasis were found in 12 patients (8%, 12/148). After independent review by ophthalmology and infectious diseases, 3 patients were found to have alternate pathologies that explained their ocular findings. Nine patients (6%, 9/148) were adjudicated as having presumed Candida chorioretinitis. Of these 9 patients, 4 (44%) were asymptomatic, and 2 (22%) were unable to declare symptoms. No patients were definitively determined to have Candida endophthalmitis. Ocular candidiasis was not found to have a statistically significant association with symptoms or comorbidities. Ocular candidiasis was more likely to be found at ophthalmology exams >7 days from first positive Candida blood culture. The number needed to screen to detect presumed Candida chorioretinitis among asymptomatic patients was 20.

Conclusions

Based on the available evidence and high risk of morbidity of eye involvement, continued ophthalmological screens seem prudent, but a definitive consensus was found to be challenging given a lack of outcome data. Additional investigations are warranted. Ophthalmology screenings have a higher sensitivity at >7 days from positive blood culture.
Environmental DNA reveals a presence of Anser fabalis (Bean Goose) and an absence of Anser erythropus (Lesser White-fronted Goose) in Finnish Northern Lapland
Authors: Honka Johanna , Kvist Laura , Øien Ingar J , Aarvak Tomas , Siivonen Stefan , Aspi Jouni
Published: November 2024

Detecting rare and elusive species from vast wilderness areas poses significant challenges. The Fennoscandian population of Anser erythropus (Lesser White-fronted Goose) is among the most endangered bird populations in Europe, with only 25–30 breeding pairs remaining in Northern Norway. Historically, its former breeding range extended across the mountainous regions of Fennoscandia. Thanks to targeted conservation efforts during the 21st century, A. erythropus has started to recolonize some of its former breeding areas in Norway and possibly also in Finland. Anser serrirostris rossicus (Tundra Bean Goose) is classified as Endangered in Finland, with just a few breeding pairs in northernmost Finnish Lapland with a poorly known breeding range. It breeds in higher numbers in Finnmark Norway and is listed as Vulnerable in Norway. Anser fabalis fabalis (Taiga Bean Goose), classified as Endangered in Norway, can also breed in the same area in low numbers. To locate individuals of these elusive goose species during breeding seasons, we used environmental DNA (eDNA) extracted from filtered lake water from selected lakes in northern Finland. We amplified and sequenced a short region of the mitochondrial control region to identify the species. Additionally, for positive controls, we sampled eDNA from the water of a Finnish spring staging site and known Norwegian breeding sites of the A. erythropus, from which eDNA of the A. erythropus was identified. eDNA of the A. erythropus was not detected within the former Finnish breeding range. Based on this, the A. erythropus has either not recolonized its former breeding habitats in Finland, the correct lakes were not sampled, the eDNA concentration was below detection limits, or due to other methodological issues. Anser s. rossicus was detected in 3 lakes and A. f. fabalis in 10 lakes, providing new information about the breeding distribution of Bean Geese in Finnish Lapland.
Evolution of X-ray and optical rapid variability during the low/hard state in the 2018 outburst of MAXI J1820+070 = ASASSN-18ey
Authors: Kimura Mariko , Negoro Hitoshi , Yamada Shinya , Iwakiri Wataru , Sako Shigeyuki , Ohsawa Ryou
Published: November 2024

We performed shot analyses of X-ray and optical subsecond flares observed during the low/hard state of the 2018 outburst in MAXI J1820+070. Optical shots were less spread than X-ray shots. The amplitude of X-ray shots was highest at the onset of the outburst, and they faded at the transition to the intermediate state. The timescale of shots was ~0.2 s, and we detected abrupt spectral hardening synchronized with this steep flaring event. The time evolution of optical shots was not similar to that of X-ray shots. These results suggest that accreting gas blobs triggered a series of magnetic reconnections at the hot inner accretion flow in the vicinity of the black hole, which enhanced X-ray emission and generated flaring events. Rapid X-ray spectral hardening would be caused by this kind of magnetic activity. Also, synchrotron emission not only at the hot flow but also at the jet plasma would contribute to the optical rapid variability. We also found that the low/hard state exhibited six different phases in the hardness–intensity diagram and the correlation plot between the optical flux and the X-ray hardness. The amplitude and duration of X-ray shots varied in synchrony with these phases. This time variation may provide key information about the evolution of the hot flow, the low-temperature outer disk, and the jet-emitting plasma.
Implementing a resident-led transition-specific bootcamp curriculum during pediatric residency training: Our 3-year experience
Authors: Hadjinicolaou Aristides , Dandavino Mylène , D’Arienzo David , Kaspy Kimberley , Ruano Cea Elisa
Published: November 2024

Objectives

Postgraduate programs that use ‘bootcamps’ to help trainees transition into new clinical roles usually solely target entry to residency, failing to address other critical transition periods. We developed, implemented, and evaluated a resident-led transition-specific bootcamp curriculum in our Pediatrics program and described our first 3 years of experience.

Methods

Our bootcamp curriculum was developed around Kern’s framework. A needs assessment identified key transition periods (Incoming Resident [IR]; Night Float [NF]; Ward Senior [WS]). Teaching content and methods were informed by Residents-As-Teacher principles. Program evaluation included surveys exploring trainees’ satisfaction, and perceived knowledge and self-efficacy before and after bootcamp participation. For the IR bootcamp, knowledge and behaviour were objectively assessed through written examinations and Observed Structured Clinical Examinations (OSCEs).

Results

Twenty-seven pediatric residents participated in the IR bootcamp, 26 in the NF bootcamp, and 25 in the WS bootcamp. Trainees’ baseline self-reported knowledge and confidence around clinical skills taught showed an improving trend post-bootcamp in all transition periods. Strengths identified included the level-appropriate teaching content and residents’ engagement as teachers.

Conclusions

Bootcamps can help residents adapt to new roles and should target all key transitions within the training continuum. Capitalizing on resident leadership for bootcamp curriculum development and implementation is instrumental to its success.
Relativistic BEC extracted from a complex FRG flow equation
Authors: Terazaki Fumio , Mameda Kazuya , Suzuki Katsuhiko
Published: November 2024

Based on the functional renormalization group (FRG) under the local potential approximation, we analyze the Bose–Einstein condensation (BEC) in the relativistic complex scalar theory. This framework leads to a complex flow equation of the effective potential, even with the well-known Litim regulator. In order to evaluate the condensate from such a complex effective potential, we impose a condition between chemical potential and mass, analogously to those in the free theory or the mean field theory. We elucidate that for the strongly (weakly) coupled theory, the phase diagrams computed from the FRG are more (less) deviated from that under the mean field approximation. This result implies that quantum fluctuations strongly affect the nonperturbative formation of the BEC.
Rethinking the missions and functions of public research institutes: evidence from Iranian PRIs
Authors: Safdari Ranjbar Mostafa , Karimmian Zohreh , Nesari Mohammad
Published: November 2024

Public research institutes (PRIs) are pivotal in national and sectoral innovation systems and the transition to a knowledge-based economy. So, the current study has reassessed these institutes’ functions and suggested policy recommendations to augment their influence in moving toward a knowledge-based economy. The findings of this research reveal that functions such as innovation hub and specialized accelerator; strategic and problem-oriented research management platform; standard and regulatory reference; specialized technical service center; center for cooperation, transfer, and dissemination of technology; and the hub of technology and policy intelligence in a specific industrial sector are crucial functions of PRIs in transitioning to a knowledge-based economy. Additionally, to foster a conducive environment for the influence of PRIs in actualizing a knowledge-based economy, policies related to governance and division of responsibilities, stimulation of both supply and demand sides, strengthening the linkage between the supply and demand sides, and provisioning supportive environment and infrastructure are recommended.
Physical therapy approach and non-invasive modalities in treatment of vaginal laxity: a literature review
Authors: Eid Lama , George Mina , Abdel Hady Doaa A
Published: November 2024

Introduction

Pelvic floor physical therapy (PFPT) and noninvasive modalities can be more safe and available treatments for vaginal laxity (VL) with less risk of postsurgical complications.

Objectives

The purpose of this review is to define the concepts of PFPT and noninvasive modalities, examine the evidence supporting those modalities as a treatment for VL, and evaluate their effectiveness.

Methods

Between 2002 and 2023, clinical studies including women diagnosed with VL were examined in the Web of Science, Cochrane Library, Scopus, and PubMed databases. Exclusion criteria included studies with no outcomes or inadequate data, procedures, suggestions, editorials, book chapters, letters to editors, reviews, meta-analyses, animal research, and articles in languages other than English.

Result

Only seventeen studies have been identified. Four studies have demonstrated the impact of PFPT (low- and medium-energy radiofrequency (RF), ultrasound, low-energy laser treatment, par sacral stimulation, the knack method, and pelvic floor exercises), and thirteen studies have discussed the impact of noninvasive modalities (RF, combined multipolar RF with pulsed electromagnetic, combined RF and pulsed electromagnetic field, high-intensity focused ultrasound, CO2 laser, combining multipolar RF and hybrid fractional laser, microfocused ultrasound, and the VIVEVE surface-cooled RF) on vaginal laxity.

Conclusion

This review indicates many knowledge areas that must be attempted in order to understand the influence of nonstrengthening physical therapy and noninvasive methods on vaginal laxity. In addition to the mechanisms behind their impacts. In addition, we strongly recommend that more clinical trials of high methodological and interventional quality are required to investigate the efficacy of various physical therapy approaches, including electrical stimulation, biofeedback exertion, acupressure, manual therapy, neuromodulation, core exercise therapy, hydrotherapy, well-designed ultrasound therapy protocols, and vaginal weight training.
The circadian clock participates in seasonal growth in Norway spruce (Picea abies)
Authors: Lázaro-Gimeno David , Ferrari Camilla , Delhomme Nico , Johansson Mikael , Sjölander Johan , Singh Rajesh Kumar , Mutwil Marek , Eriksson Maria E
Published: November 2024

The boreal forest ecosystems of the northern hemisphere are dominated by conifers, of which Norway spruce (Picea abies [L.] H. Karst.) is one of the most common species. Due to its economic interest to the agroforestry industry, as well as its ecological significance, it is important to understand seasonal growth and biomass production in Norway spruce. Solid evidence that the circadian clock regulates growth in conifers has proved elusive, however, resulting in significant gaps in our knowledge of clock function in these trees. Here, we reassess the impact of the circadian clock on growth in Norway spruce. Using a combination of approaches monitoring the physiology of vegetative growth, transcriptomics and bioinformatics, we determined that the clock could be playing a decisive role in enabling growth, acting in specific developmental processes influenced by season and geographical location to guide bud burst and growth. Thus, the evidence indicates that there is time for spruce.
Vagus Nerve Stimulation for Neurologic Recovery
Authors: Malik Maarij , Ali Rushna , Keser Zafer , Esterov Dmitry , Khan Muhib
Published: November 2024

Neural plasticity, a potential mode of managing various neurologic diseases, can be modulated via bursts of neurotransmitter release, including norepinephrine and acetylcholine. One method to do so is by electrically stimulating the vagus nerve while performing a specific task. Vagus nerve stimulation (VNS) has proven to be a viable intervention for conditions, including treatment-resistant epilepsy, depression, and, more recently, motor recovery after ischemic stroke. This article aims to explain the neurobiologic mechanism of VNS-induced cortical plasticity. It highlights both animal and human studies of VNS therapy, with a primary focus on recovery after stroke, traumatic brain injury, and spinal cord injury recovery. Furthermore, we discuss the long-term effects of VNS therapy, suggest potential solutions to overcome challenges encountered in previous studies, and elaborate on future directions in the field.
The clinico-epidemiological, diagnostic, and therapeutic aspects of methadone poisoning: a registry-based clinical study
Authors: Hosseininejad Seyed M. , Sharifpour Ali , Akbarnezhad Fatemeh , Veisi Hossein , Zakariaei Zakaria
Published: November 2024

Objectives:

Methadone is a long-acting synthetic agonist of opioid receptors, which is used as an analgesic and as an alternative treatment in opioid-dependent patients. Clinical manifestations of methadone poisoning include miotic pupils, low levels of consciousness (LOC), respiratory depression or apnea, and coma and death. Considering the high consumption of methadone in society and the prevalent instances of overdose and poisoning, whether accidental or intentional, the authors decided to investigate the clinico-epidemiological, diagnostic, and therapeutic characteristics of methadone poisoning in the Mazandaran province, northern Iran, from 2020 to 2022.

Methods:

This study was a retrospective and descriptive cross-sectional registry-based study, wherein data was collected from the Mazandaran Registry Center of Opioids Poisoning (MRCOP), on patients with methadone poisoning. Data based on various parameters such as individual characteristics, ingestion motivation, and clinical outcomes were collected in a checklist.

Results:

Of the 385 patients, who entered the study, 264 were men and 121 were women. The mean age of the patients was 29.02 years. Two hundred forty-four patients had intentionally consumed methadone. The most common symptoms observed among individuals with methadone poisoning were decreased arterial blood oxygen (225 patients) and decreased LOC (173 patients). The length of hospitalization for most patients was less than 1 week. Except for seven of them who died, most of them were discharged in good general condition.

Conclusion:

The study identified sex, age, marital and employment status, and suicidal intent as the most significant factors influencing methadone poisoning, which should be considered in the design and implementation of public education and prevention programs.
Seaweed and Seaweed-Based Products As Plant-Based Sources of Dietary Iodine
Authors: Pawlak Roman
Published: November 2024

Vegans have lower risks of some health problems such as ischemic heart disease, type 2 diabetes, and some cancers. However, they are at high risk of some nutrient deficiencies, including iodine, because plant foods are poor sources of the nutrient, except for seaweed. Also, some vegans refuse to use iodized salt or dietary supplements containing iodine. Urinary iodine concentration among vegans, indicative of mild, moderate, or severe deficiency, is common among a large percentage of vegans in many countries. Similarly, there is a high incidence of inadequate iodine concentration in the breast milk of vegan mothers. This article provides information on the iodine content of brown, red, and green algae. Some seaweed types, especially brown algae, contain very high amounts of iodine, and so, soaking and blanching are necessary to reduce the iodine content to safe levels to prevent iodine toxicity. This article focuses on seaweed and its use as a source of iodine. Because some vegans do not use iodized salt or iodine-containing supplements and because plant foods are poor sources of iodine, seaweed is a potential source of the nutrient, but to reduce the risk of toxicity, soaking and blanching are needed to dispose of excess iodine.
Evaluation of Oropharyngeal Structure and DISE Findings for Successful Soft Palatal Webbing Flap Pharyngoplasty
Authors: Jin Siyeon , Kim Minju , Kim Hyun Jung , Han Doo Hee , Won Tae-Bin , Kim Dong-Young , Rhee Chae-Seo , Kim Hyun Jik
Published: November 2024

Purpose:

Lateral pharyngeal wall collapse, linked to weak pharyngeal wall stability, is characteristic of severe obstructive sleep apnea (OSA) patients. Soft palate webbing flap palatopharyngoplasty (SPWFPP) has been introduced to enhance the stability of the lateral pharyngeal wall with minimal postoperative complications by eliminating the need for tonsillectomy. This study analyzed the anatomic findings of oropharynx for determination of outcome in OSA patients requiring SPWFPP.

Methods:

Twenty-eight OSA patients who underwent SPWFPP combined with septoturbinoplasty were included in this study. Patient medical records, including endoscopic findings, polysomnography (PSG) data, and drug-induced sleep endoscopy (DISE), were analyzed.

Results:

PSG data revealed that SPWFPP provided significant improvements of AHI scores in severe OSA patients with lateral pharyngeal wall collapse, whereas AHI scores of mild and moderate OSA cases minimally declined after SPWFPP. Notably, among the patients who underwent SPWFPP, some experienced abrupt increases in AHI levels after surgery, particularly in mild OSA cases, and those patients showed collapse of the epiglottis before surgery according to DISE findings. The outcome of SPWFPP was successful in severe OSA patients whose epiglottis was not collapsible on preoperative DISE findings and in patients with palatal collapse of grade III or higher.

Conclusion:

SPWFPP provides good surgical outcomes even in severe OSA patients with lateral pharyngeal wall collapse. However, the surgical results may be worse in certain patients depending on epiglottis collapsibility. A close analysis of DISE findings before SPWFPP reveals important indicators for predicting better surgical results and selecting OSA patients suitable for SPWFPP.
Complications of Submentonian and Cervical Liposuction Surgery Associated With Platysmaplasty
Authors: das Chagas Rachel Santos , Machado Vanessa Fonseca , Grillo Ricardo
Published: November 2024

The aim of this study was to report a series of 3 cases of complications following submentonian and cervical liposuction associated with platysmaplasty. The complications include hemorrhage, Ludwig’s angina, and paralysis caused by injury to the marginal mandibular nerve. The procedure was performed by the same operator using the same technique, and the patients were informed of the risks. It is important to emphasize that the surgeon must be prepared to manage any of these complications, and treatment should be immediate and appropriate. The management of complications following submentonian and cervical liposuction associated with platysmaplasty must be prompt and effective to prevent further risks and damage. The approaches are discussed and referenced by the authors. Submentonian and cervical liposuction surgery associated with platysmaplasty is a valuable tool for reducing neck fat and enhancing esthetic outcomes, but there is a possibility of postoperative complications, which, although rare, can occur. Proper patient selection and thorough explanation of risks are crucial to preventing some of these situations.
Non-local impact of distal airway constrictions on patterns of inhaled particle deposition
Authors: Shemilt James D. , Horsley Alex , Wild Jim M. , Jensen Oliver E. , Thompson Alice B. , Whitfield Carl A.
Published: November 2024

Airway constriction and blockage in obstructive lung diseases cause ventilation heterogeneity and create barriers to effective drug deposition. Established computational particle-deposition models have not accounted for these impacts of disease. We present a new particle-deposition model that calculates ventilation based on the resistance of each airway, such that ventilation responds to airway constriction. The model incorporates distal airway constrictions representative of cystic fibrosis, allowing us to investigate the resulting impact on patterns of deposition. Unlike previous models, our model predicts how constrictions affect deposition in airways throughout the lungs, not just in the constricted airways. Deposition is reduced in airways directly distal and proximal to constrictions. When constrictions are clustered together, central-airways deposition can increase significantly in regions away from constrictions, but distal-airways deposition in those regions remains largely unchanged. We use our model to calculate lung clearance index (LCI), a clinical measure of ventilation heterogeneity, after applying constrictions of varying severities in one lobe. We find an increase in LCI coinciding with significantly reduced deposition in the affected lobe. Our results show how the model provides a framework for development of computational tools that capture the impacts of airway disease, which could significantly affect predictions of regional dosing.
Diversity of HBV genotypes and their association with precore/basal core mutations among HBsAg-positive patients in Ibadan, Nigeria
Authors: Faneye Adedayo Omotayo , Motayo Babatunde Olanrewaju , Mustafa Aisha , Odiabo Georgina
Published: November 2024

Background. Hepatitis B virus (HBV) is the most implicated cause of severe liver disease and hepatocellular carcinoma worldwide. Studies have shown that the basal core protein (BCP) and precore protein (PC) of HBV play a significant role in HBV-related carcinogenesis. There is a paucity of data on the type and effect of BCP and PC mutations in Nigeria. This study aims to genotype HBV and investigate any mutations within the BCP and PC among HBV patients in Ibadan, Nigeria.

Methods. Forty HBV-DNA-positive patients were recruited into this study, and the viral load assay and genotyping by nested multiplex PCR were done. The partial X gene region was amplified and Sanger sequenced. The BPC and PC genomic regions were then analysed using bioinformatics.

Results. Twenty-three participants recorded HBV DNA viral load of >20 000 IU, while 17 had <20 000 IU and 28 samples were genotyped. Five genotypes (A, B, C, D and E) and four mixed genotypes (AC, AD ACD and ABCD) were detected. Genotype AC was the most frequently encountered, while genotypes E and B were the least encountered. Mutation was highest in ages 34–45 years. Double mutation A1762T and G1764A within the BCP region was the most encountered mutation.

Conclusions. We report a diverse HBV genetic landscape, with mixed infections between genotypes with BCP double-mutation A1762T/G1764A, signalling the likelihood of poor HBV-related liver disease prognosis. Our findings contribute to our understanding of the molecular characteristics of HBV and its potential implications for disease progression and management among HBV-infected Nigerians.
Targeting of PTP4A3 overexpression sensitises HGSOC cells towards chemotherapeutic drugs
Authors: López-Garza Ana , James David , Creagh Emma , Murray James T.
Published: November 2024

Of all the gynecologic malignancies, Ovarian cancer (OC) has the highest mortality rate, partly attributable to its propensity for chemotherapy resistance. The most common sub-type of OC is serous, of which High-Grade Serous Ovarian Cancer (HGSOC) is the most lethal sub-type. Elevated expression of Protein Tyrosine Phosphatase 4 A3 (PTP4A3) is implicated in tumour cell invasion and metastasis, by upregulating the PI3K/Akt/mTORC1 axis. Previously we reported PTP4A3 increased the survival of non-serous OC cellsin vitroby activating the autophagy pathway.

The present study focused on understanding the impact of PTP4A3 on cell growth, proliferation, and autophagy in HGSOC cells. In particular, we sought to understand whether targeting PTP4A3 in cancer cells that overexpress this phosphatase would sensitise HGSOC cells to existing chemotherapeutic drugs. We report that shRNA-mediated gene silencing of PTP4A3 resulted in the upregulation of compensatory mechanisms that may render PTP4A3 targeting redundant as a monotherapy. However, pan-PTP4A inhibition with JMS-053 overcame this. Finally, silencing of PTP4A3 expression sensitized HGSOC cells to clinically relevant chemotherapeutic drugs.

Since mAb therapies targeting PTP4A3 are already in clinical trials, therapeutic targeting of PTP4A3 may have significant value in improving outcomes for those patients with HGSOC, in the clinical setting.
Early regional lymph node activation drives influenza vaccine responses in an ancestrally diverse cohort
Authors: Siu Jacqueline HY , Coelho Sofia , Palomeras Aime , Belij-Rammerstorfer Sandra , Lee Chloe H , Strobel Tamara , Thorpe Christopher , Kaur Charandeep , Cole Tom , Remmert Nico , Fowler Jamie , Pledger Sam , Dooley Kyla B , Opoka Daniel , Szommer Tamas , Vanderslott Samantha , Kaleebu Pontiano , Milicic Anita , Palmer Donald B , Lambe Teresa , Marsden Brian D , Koohey Hashem , Coles Mark , Dendrou Calliope A , Pollock Katrina M
Published: November 2024

Earlyin vivodynamics of human immune-cell activation across regionally activated lymphoid tissue sites upon immunisation are poorly characterised in ancestrally diverse individuals. Here, we profiled draining and non-draining axillary lymph nodes (dLNs and ndLNs) by ultrasound-guided fine-needle aspiration (FNA) in 13 Black and Asian ancestry individuals, before and 3-7 days after vaccination with adjuvanted influenza vaccine. Draining but not ndLNs rapidly increased in size post-vaccination, by day 3, with distinct cellular dynamics determined through single cell multiomics. Dissecting LN cellular diversity into 42 lymphoid and non-lymphoid cell states, post-vaccination cell abundance changes were observed across all LNs, but dLNs were specifically characterised by CD4+T follicular helper (CD4+Tfh) cell expansion. Gene expression analysis revealed a dLN post-vaccination hub of multicellular activity defined by CD4+Tfh signalling, cross-compartmental activation, translation, and enhanced antigen-presentation capacity. Thus, robust responses to intramuscular immunisation transcending ancestral inter-individual variation are elicited through temporal, anatomical and cellular lymphatic co-ordination with implications for vaccine design in ancestrally diverse populations.

In this study of ancestrally diverse young adults, the temporarily co-ordinated response to an adjuvanted influenza vaccine at lymph nodes local to (draining) and distal from (non-draining) the injection site, reveals early regulation of cellular kinetics and anatomical hierarchy of the innate and adaptive immune responses.
BC-Design: A Biochemistry-Aware Framework for Highly Accurate Inverse Protein Folding
Authors: Tang Xiangru , Ye Xinwu , Wu Fang , Shao Daniel , Fang Yin , Chen Siming , Xu Dong , Gerstein Mark
Published: November 2024

Inverse protein folding, which aims to design amino acid sequences for desired protein structures, is fundamental to protein engineering and therapeutic development. While recent deep-learning approaches have made remarkable progress in addressing this challenge, they typically represent biochemical properties as discrete features associated with individual residues. Here, we present BC-Design, an approach that explicitly represents these properties as decorations on randomly sampled points on exterior surfaces and within internally bound regions representing the complete molecular extent of the protein. This provides a more natural way to capture the spatial distribution of properties. We demonstrate that BC-Designsignificantly outperforms all current methods, improving sequence recovery from 67% to88.37%over the state-of-the-art methods (a21.32%absolute improvement) and reducing perplexity from 2.4 to1.47(a39.51%relative improvement) on the CATH 4.2 benchmark. Notably, our model exhibits robust generalization across diverse protein characteristics, achieving consistently high performance on proteins of varying sizes (50-500 residues), structural complexity (measured by contact order), and all major CATH fold classes. Through ablation tests, we compare the relative contribution of both structure encoding information and the encoded property information, and we show that both substantially contribute equally to this strong performance. Overall, this opens new avenues for computational protein engineering and drug discovery.
Pathophysiological Implications of Nucleotide Self-Assembly: Adenine-Derived Nucleotides Aggregation in Disease Mechanisms
Authors: Dave Raj , Singh Ankur , Pandey Kshipra , Patel Ritu , Gour Nidhi , Bhatia Dhiraj
Published: November 2024

Adenine nucleotides, including adenosine monophosphate, adenosine diphosphate, and adenosine triphosphate, play pivotal roles in cellular bioenergetics, nucleic acid metabolism, and signal transduction. However, their propensity to undergo self-assembly and form supramolecular aggregates under certain conditions is not well-characterized. In this study, we examined the self-assembly, aggregation, and cytotoxicity of AMP, ADP, and ATP in both fresh and aged conditions. Utilizing advanced microscopy techniques, Thioflavin T (ThT) fluorescence assays, and cross-seeding experiments, we identified oligomer formation in freshly prepared nucleotide solutions, which progressed to larger, more stable aggregates over time. The cytotoxic potential of these nucleotide aggregates was assessed using in vitro models, including human retinal pigment epithelial (RPE-1) and colorectal carcinoma (HCT-116) cell lines. Our findings demonstrate that nucleotide aggregation induces significant cytotoxic effects, particularly in aged conditions. Further investigations into bacterial toxicity models revealed similar deleterious impacts, indicating a broad-spectrum biological stress response to nucleotide aggregates. These results suggest that nucleotide self-assembly and aggregation may contribute to cellular dysfunction, offering new insights into their non-canonical roles in disease pathophysiology, potentially analogous to protein misfolding disorders.
RvD1 and LXA4 inhibitory effects on cardiac voltage-gated potassium channels
Authors: De la Cruz Alicia , Ronchi Carlotta , Bartolucci Chiara , Socuéllamos Paula G , Benito-Bueno Angela de , Severi Stefano , Zaza Antonio , Valenzuela Carmen
Published: November 2024

Aims

The resolution of inflammation is modulated by specialized pro-resolving lipid mediators (SPMs), which can be modified in some cardiovascular diseases. Among them, RvD1 and LXA4prevent atrial fibrillation (AF) remodeling in the atria and cardiac hypertrophy, respectively in animal models. However, little is known about their electrophysiological effects on cardiac voltage-gated (VG) ion channels.

Methods and results

We used the patch-clamp technique in heterologous systems and cardiomyocytes to assess the acute effect of RvD1, and LXA4, on VG potassium currents.In silicosimulations were used to predict the effect of current modulation on the atrial and ventricular action potentials (AP). RvD1 and LXA4reducedIKs(channel KV7.1/KCNE1) in COS-7 cells and guinea-pig cardiomyocytes without modifying its voltage dependence; RvD1 was more potent than LXA4. In heterologous systems, RvD1 was also tested onIKur(channel KV1.5),Ito(channel KV4.3/KChIP2),IKr(channel KV11.1), andIK1(channel Kir2.1) with the largest inhibitory effect onIKsandIKr. In simulations RvD1 prolonged repolarization significantly in both atrial and ventricular myocytes.

Conclusion

The results provide a comprehensive evaluation of RvD1 and LXA4on cardiac human potassium channels, at pathophysiological relevant concentrations, being RvD1 more potent than LXA4. The predicted effects on the action potential suggest that, along with their antiinflammatory action, RvD1 may reverse AF-induced electrical remodeling in the atria by direct modulation of K+currents. The same action might instead contribute to ventricular functional remodeling; however, direct evidence for this is missing.
Intestinal stem cells enhance local mucosal immunity through apoptotic body phagocytosis
Authors: Zhou Julie Y. , Lu Qiuhe , Hu Yujia , Fujii Satoru , Espenschied Scott T. , Engelhart Morgan J. , Lewis Kelsey J. , Karell Paul E. , Han Yi , Shin Heaji , Schmidt Robert E. , Silver Daniel J. , Ivanov Andrei I. , Yilmaz Omer H. , Stappenbeck Thaddeus S.
Published: November 2024

Modulation of immune tone at mucosal surfaces is critical to maintain homeostasis while facilitating the handling of emerging threats. One dynamic component of immune modulation is the phagocytosis and clearance of apoptotic bodies known as efferocytosis that inhibits inflammation by promoting its resolution. Here, we evaluated the effects of apoptotic body phagocytosis by intestinal epithelial stem and progenitor cells (ISCs). Unexpectedly, instead of immunomodulation through efferocytosis, this process elevated local immune system activity. To achieve this result, ISCs actively engaged apoptotic bodies in a unique fashion, leading to their engulfment and ultimate delivery to lysosomes for processing. We found that ISCs were capable of actively recruiting inert material such as apoptotic bodies by using actin-based intrinsic biomechanical processes. Uptake of apoptotic bodies was facilitated by complement factor C3 produced by apoptotic bodies themselves. ISCs in turn generated signals heightening T cell activity that was driven in part by ISC-generated TNF. Taken together, uptake of apoptotic bodies by ISCs produced a local inflammatory alert to specific immune cells. This altered paradigm for the response to phagocytosed apoptotic bodies fits the needs of active mucosal surfaces and demonstrates that efferocytosis as currently defined is not a universal response of all cell types.
Drosophila melanogasteremploys nuclear architecture for recruitment of dosage compensation
Authors: Sneideman Maggie P. Lauria , Meller Victoria H.
Published: November 2024

Drosophila melanogastermales increase expression from their single X chromosome to match the expression from two female X chromosomes. Increased expression involves recruitment of the Male Specific Lethal (MSL) complex to X-linked genes and modification of chromatin by this complex. How X-linked genes are selectively identified remains unclear, butcis-acting recruiting elements are involved. Chromatin Entry Sites (CES) bind an adapter protein that directly recruits the MSL complex. In addition, a class of AT-rich satellites, the 1.688Xrepeats, are enriched on the X and facilitate compensation of nearby genes. How these elements cooperate to identify the X is unknown. Nuclear architecture influences dosage compensation in many organisms. In this study we test the idea that factors involved in nuclear architecture participate in recruitment by the CES and 1.688Xrepeats. We find genetic interactions between mutations that reduce X recognition and factors that govern chromatin structure, silencing, remodeling and insulation, suggesting roles in X recognition. A reporter for recruitment revealed that Heterochromatin Protein 2 (HP2) and Scaffold Attachment Factor-A (SAF-A) disrupt compensation but do not selectively influence recruitment by either element. In contrast, Imitation switch (ISWI), D1 and Nucleoporin 153kD (Nup153) contribute to recruitment by the CES and Centrosomal protein 190kD (Cp190) exerts a striking influence on recruitment by 1.688Xrepeats. These findings reveal that recruitment by the CES and 1.688Xrepeats involves nuclear organization. We propose that the use ofcis-acting elements that engage complementary aspects of nuclear organization ensures robust X recognition.
Genomic prediction by modelling genotype by environment interaction for yield in groundnut
Authors: Lubanga Nelson , Okaron Velma , Gimode Davis M. , Persa Reyna , Mwololo James , Okello David K. , Ssemakula Mildred Ochwo , Odong Thomas L. , Odeny Damaris A. , Jarquin Diego
Published: November 2024

Multi-environment trials (METs) are routinely conducted in plant breeding to capture the genotype-by-environment (G×E) interaction effects. We assessed the potential of using genomic prediction (GP) in four groundnut traits (pod yield[PY], shelling percentage[SP], seed weight[SW] and seed weight of 100 seeds[SW100]) observed in four environments. Three prediction models (M1: Environment + Line, M2: Environment + Line + Genomic, and M3: Environment + Line + Genomic + Genomic × Environment) were evaluated under four cross-validation (CV) schemes that simulate realistic problems that breeders face at different stages of their programs. CV2 predicts lines tested in sparse multi-location trials; CV1 predicts newly developed lines; CV0 predicts tested lines in unobserved environments by leaving one environment out; CV00 predicts untested lines in unobserved environments. Under CV2, the average predictive ability (PA) range was 0.6-0.68 (PY), -0.26-0.05 (SP), 0.5-0.59 (SW) and 0.79-0.86 (SW100). For CV1, the PA range was -0.12-0.51 (PY), -0.08-0.35 (SP), -0.10-0.47 (SW) and -0.05-0.47 (SW100). In CV0, the PA range was 0.27-0.35 (PY), -0.18--0.17 (SP), 0.24-0.32 (SW) and 0.59-0.66 (SW100). In CV00, the PA range was 0.01-0.23 (PY), -0.03-0.07 (SP), 0.01-0.19 (SW) and -0.02-0.38 (SW100). In all the four CV schemes, including marker data improved the PA. Incorporating G×E in M3 model improved PA in CV2 and CV1 schemes and also reduced the residual and environment variances. The high PA in CV2 imply that sparse testing could be implemented. The low PA recorded in CV00 shows that it is difficult to predict untested lines in new environments.
The Xanthophyll Cycle balances Photoprotection and Efficiency in the seawater alga Nannochloropsis oceanica
Authors: Michelberger Tim , Mezzadrelli Eleonora , Bellan Alessandra , Perin Giorgio , Morosinotto Tomas
Published: November 2024

Photosynthetic reactions require continuous modulation to respond to highly dynamic environmental conditions. Regulation of photosynthesis involves various mechanisms, which differ across phylogenetic groups. One such mechanism, found widespread in photosynthetic eukaryotes, is the xanthophyll cycle, which involves the reversible light-dependent conversion between the carotenoids violaxanthin, antheraxanthin, and zeaxanthin.

In this study, we investigated the impact of the xanthophyll cycle inNannochloropsis oceanica, a seawater microalga member of Eustigmatophyta that features a peculiarly high content of xanthophylls. We generated and characterized lines with increased levels of the enzymes involved in the xanthophyll cycle, i.e. violaxanthin de-epoxidase (VDE) and zeaxanthin epoxidase (ZEP) and demonstrated that their content is a main factor in controlling the overall reaction rates and the dynamics of the xanthophyll cycle. Subsequent differences in the xanthophyll profile affect the activation of photoprotection mechanisms such as non-photochemical quenching and tolerance to reactive oxygen species. Interestingly, overexpression of VDE expands the limits of high light tolerance, whereas the increased content of ZEP facilitates faster recovery after exposure to light but also heightened photosensitivity under some conditions.

These findings underscore the critical role of the xanthophyll cycle in the regulation of photosynthesis inNannochloropsis,where it is not simply a mechanism to respond to excess illumination, but plays a central role in modulating photosynthesis, fulfilling the complex task of balancing photoprotection and light-use efficiency under different environmental conditions.
Development of an ELISA assay for EV quantification to assist the large-scale EV manufacture
Authors: Zhou Xin , Wang Wenli , Zhang Lei , Yang Shiyi , Peng Xincheng , Zhang Xin , Zhao Jinxiu , He Xinjun , Xu Ke
Published: November 2024

Accurate EV quantitation is essential for ensuring quality, consistency, and safety during large-scale extracellular vesicle (EV) manufacturing. In the upstream phase, EV quantitation allows for the monitoring of cell culture conditions that impact EV yield and quality, while in the downstream phase, it helps to control the efficiency and purity of EV purification. Nanoparticle Tracking Analysis is the most commonly used method for EV quantification, while it faces significant limitations due to interference from nanosize contaminants like protein aggregates, especially in crude samples (e.g. cell culture media). To address this issue, we developed a highly specific and accurate ELISA assay that quantifies EVs even in crude samples. With ultra-pure EV standard samples, this assay showed reliable quantitative result of EV detection to support method development as well as in-process control of large-scale EV manufacture. The detection range of this assay is from 4.1E7 to 3E10 EVs/mL, with an LOD of 1.04E7 EVs/mL and an LOQ of 3.21E7 EVs/mL. We therefore developed this assay into a testing kit and demonstrated that this EV quantification ELISA kit is capable of ensuring minimal interference from impurities and supporting the process development and in-process control in EV production.