bluuebunny/crossref_metadata_2025 huggingface dataset:
Solar-Powered Electric Vehicles: Enhancing Endurance and Sustainability through Photovoltaic Integration
Authors: Ogunrinola I. E. , Udechukwu C. J. , Akinyemi M. L. , Oladapo O. F.
Published: May 2024

The potential of solar photovoltaic (PV) technology as a transformative and sustainable energy solution in the context of global energy challenges is explored in this work. The advancements in solar PV technology, including innovative cell architectures like heterojunction and Passivated Emitter Rear Contact (PERC) cells, the emergence of perovskite solar cells, and the influence of roll-to-roll manufacturing processes are discussed in this paper. The paper also highlights the diversification of energy portfolios, enhanced energy system reliability, resilient energy infrastructure, energy security, and the profound environmental benefits associated with solar PV technology. The results of a performance study involving a prototype electric vehicle, both with and without integrating a solar panel as an alternative energy source are noted. The findings reveal a substantial increase in the vehicle’s endurance when the solar panel is incorporated, emphasizing the transformative potential of solar PV in reshaping energy systems, mitigating environmental hazards, and promoting responsible land use. The work underscores the ongoing journey towards a cleaner and more resilient energy future, empowered by the harnessing of solar energy.
Organellar phylogenomics at the epidendroid orchid base, with a focus on the mycoheterotrophic Wullschlaegelia
Authors: Barrett Craig F , Pace Matthew C , Corbett Cameron W , Kennedy Aaron H , Thixton-Nolan Hana L , Freudenstein John V
Published: May 2024

Background and Aims

Heterotrophic plants have long been a challenge for systematists, exemplified by the base of the orchid subfamily Epidendroideae, which contains numerous mycoheterotrophic species.

Methods

Here we address the utility of organellar genomes in resolving relationships at the epidendroid base, specifically employing models of heterotachy, or lineage-specific rate variation over time. We further conduct comparative analyses of plastid genome evolution in heterotrophs and structural variation in matK.

Key Results

We present the first complete plastid genomes (plastomes) of Wullschlaegelia, the sole genus of the tribe Wullschlaegelieae, revealing a highly reduced genome of 37 kb, which retains a fraction of the genes present in related autotrophs. Plastid phylogenomic analyses recovered a strongly supported clade composed exclusively of mycoheterotrophic species with long branches. We further analysed mitochondrial gene sets, which recovered similar relationships to those in other studies using nuclear data, but the placement of Wullschlaegelia remains uncertain. We conducted comparative plastome analyses among Wullschlaegelia and other heterotrophic orchids, revealing a suite of correlated substitutional and structural changes relative to autotrophic species. Lastly, we investigated evolutionary and structural variation in matK, which is retained in Wullschlaegelia and a few other ‘late stage’ heterotrophs and found evidence for structural conservation despite rapid substitution rates in both Wullschlaegelia and the leafless Gastrodia.

Conclusions

Our analyses reveal the limits of what the plastid genome can tell us on orchid relationships in this part of the tree, even when applying parameter-rich heterotachy models. Our study underscores the need for increased taxon sampling across all three genomes at the epidendroid base, and illustrates the need for further research on addressing heterotachy in phylogenomic analyses.
Discharging Care Orders in England and Wales: A New Typology of Applications and Outcomes
Authors: Roy Jessica , Staines Jo , Stone Beth , Macdonald Gillian
Published: May 2024

A care order represents one of the most significant state interventions in England and Wales. The end of a care order is equally important, often meaning a withdrawal of statutory support and monitoring, and children returning home to birth parent(s), living with kinship carers or living independently. Despite its importance, little is known about the discharge of care orders. This article reports on the findings of the first study of the discharge of care orders in England and Wales. Casefile data from 323 children’s records were analysed using descriptive and bivariate statistical analysis. Qualitative data from the same records were collected and analysed thematically. Interviews and focus groups were also held with forty-one professionals involved in discharge. Based on the findings, this article reports on a new typology of discharge applications. The typology represents six distinctly different types of application varying on: process and application outcome; length of proceedings; applicant motivation and age and views of the child. The typology developed indicates that differentiated legal and social work processes may be needed to better meet the needs of children and families. This article concludes by presenting recommendations for policy, practice and research in this field.
‘Something Mythic’:  The power of shared stories in Kamila Shamsie’s Home Fire
Authors: Hardy Clara Shaw
Published: May 2024

Kamila Shamsie’s (2017) novel Home Fire draws on Sophocles’ Antigone for its plot, but neither requires familiarity with, nor explicitly references, the tragedy. This article attempts to build a specific case for the effects of attending to the intertext by focusing on Shamsie’s complex treatment of Antigone’s punishment and its consequences in Sophocles. Reading the novel’s denouement in conversation with that of the tragedy suggests questions about higher authority and checks on political power in the world of the novel. I argue that shared stories in the novel exert a force analogous to that of Sophocles’ gods in that they authorize moral judgments; attention to the intertext enacts the same experience for readers of the novel that shared stories do for characters within the novel.
Joint ERS/EACTS/ESTS clinical practice guidelines on adults with spontaneous pneumothorax
Authors: Walker Steven , Hallifax Robert , Ricciardi Sara , Fitzgerald Deirdre , Keijzers Marlies , Lauk Olivia , Petersen Jesper , Bertolaccini Luca , Bodtger Uffe , Clive Amelia , Elia Stefano , Froudarakis Marios , Janssen Julius , Lee Y C Gary , Licht Peter , Massard Gilbert , Nagavci Blin , Neudecker Jens , Roessner Eric , Van Schil Paul , Waller David , Walles Thorsten , Cardillo Giuseppe , Maskell Nick , Rahman Najib
Published: May 2024

OBJECTIVES

The optimal management for spontaneous pneumothorax (SP) remains contentious, with various proposed approaches. This joint clinical practice guideline from the ERS, EACTS and ESTS societies provides evidence-based recommendations for the management of SP.

METHODS

This multidisciplinary Task Force addressed 12 key clinical questions on the management of pneumothorax, using ERS methodology for guideline development. Systematic searches were performed in MEDLINE and Embase. Evidence was synthesised by conducting meta-analyses, if possible, or narratively. Certainty of evidence was rated with GRADE (Grading, Recommendation, Assessment, Development and Evaluation). The Evidence to Decision framework was used to decide on the direction and strength of the recommendations.

RESULTS

The panel makes a conditional recommendation for conservative care of minimally symptomatic patients with primary spontaneous pneumothorax (PSP) who are clinically stable. We make a strong recommendation for needle aspiration over chest tube drain for initial PSP treatment. We make a conditional recommendation for ambulatory management for initial PSP treatment. We make a conditional recommendation for early surgical intervention for the initial treatment of PSP in patients who prioritise recurrence prevention. The panel makes a conditional recommendation for autologous blood patch in secondary SP patients with persistent air leak (PAL). The panel could not make recommendations for other interventions, including bronchial valves, suction, pleurodesis in addition to surgical resection or type of surgical pleurodesis.

CONCLUSIONS

With this international guideline, the ERS, EACTS and ESTS societies provide clinical practice recommendations for SP management. We highlight evidence gaps for the management of PAL and recurrence prevention, with research recommendations made.

Shareable Abstract

This update of an ERS Task Force statement from 2015 provides a concise comprehensive update of the literature base. 24 evidence-based recommendations were made for management of pneumothorax, balancing clinical priorities and patient views.https://bit.ly/3TKGp9e
A chromosome-level genome assembly of the disco clam, Ctenoides ales
Authors: McElroy Kyle E , Masonbrink Rick , Chudalayandi Sivanandan , Severin Andrew J , Serb Jeanne M
Published: May 2024

The bivalve subclass Pteriomorphia, which includes the economically important scallops, oysters, mussels, and ark clams, exhibits extreme ecological, morphological, and behavioral diversity. Among this diversity are five morphologically distinct eye types, making Pteriomorphia an excellent setting to explore the molecular basis for the evolution of novel traits. Of pteriomorphian bivalves, Limida is the only order lacking genomic resources, greatly limiting the potential phylogenomic analyses related to eyes and phototransduction. Here, we present a limid genome assembly, the disco clam, Ctenoides ales (C. ales), which is characterized by invaginated eyes, exceptionally long tentacles, and a flashing light display. This genome assembly was constructed with PacBio long reads and Dovetail Omni-CTM proximity-ligation sequencing. The final assembly is ∼2.3Gb and over 99% of the total length is contained in 18 pseudomolecule scaffolds. We annotated 41,064 protein coding genes and reported a BUSCO completeness of 91.9% for metazoa_obd10. Additionally, we report a complete and annotated mitochondrial genome, which also had been lacking from Limida. The ∼20Kb mitogenome has 12 protein coding genes, 22 tRNAs, 2 rRNA genes, and a 1,589 bp duplicated sequence containing the origin of replication. The C. ales nuclear genome size is substantially larger than other pteriomorphian genomes, mainly accounted for by transposable element sequences. We inventoried the genome for opsins, the signaling proteins that initiate phototransduction, and found that, unlike its closest eyed-relatives, the scallops, C. ales lacks duplication of the rhabdomeric Gq-protein-coupled opsin that is typically used for invertebrate vision. In fact, C. ales has uncharacteristically few opsins relative to the other pteriomorphian families, all of which have unique expansions of xenopsins, a recently discovered opsin subfamily. This chromosome-level assembly, along with the mitogenome, is a valuable resource for comparative genomics and phylogenetics in bivalves and particularly for the understudied but charismatic limids.
The RT M184V resistance mutation clearance in the reservoir is mainly related to CD4 nadir and viral load zenith independently of therapeutic regimen type
Authors: Teyssou Elisa , Soulie Cathia , Fauchois Antoine , Palich Romain , Nouchi Agathe , Sayon Sophie , Abdi Basma , Wirden Marc , Katlama Christine , Pourcher Valérie , Marcelin Anne-Geneviève , Calvez Vincent
Published: May 2024

Objectives

Resistance associated mutations (RAMs) are archived in the HIV reservoir and can re-emerge with an inappropriate ART use limiting treatment options. However, recent studies, using ultra-deep sequencing (UDS), showed a decrease of quasispecies harbouring RAMs, suggesting that recycling some antiretrovirals could be considered. The aim of this study was to characterize, in HIV treated PLWHIV, the M184V mutation decrease kinetics in proviral DNA and associated factors of M184V mutation clearance over time.

Methods

UDS was performed on HIV-DNA from blood cells at different time points to quantify the percentage of M184V positive quasispecies. The sequence reads were analysed with a minimum coverage set at 50 and an ambiguity filter at 5% or 2%.

Results

At 2.5 years after the first time point, the M184V lost was observed in 50% of PLWHIV. Moreover, univariate analyses highlight that a higher nadir CD4 count and a lower zenith HIV1 RNA viral load were correlated with a faster clearance of the mutation. In multivariate analysis, a higher zenith was negatively associated with the M184V clearance at the 5% threshold. Interestingly, lamivudine/emtricitabine presence in the ART therapy regiment during the 5 years was not associated with the persistence of the M184V.

Conclusions

Our study provides new information concerning the clearance speed of M184V mutation over time in PLWHIV with fully suppressed viremia, opens the discussion about the duration needed to consider a lamivudine/emtricitabine recycling and reinforces the association of the nadir and zenith values with the M184V mutation clearance.
The association of body composition phenotypes before chemotherapy with epithelial ovarian cancer mortality
Authors: Davis Evan W , Attwood Kristopher , Prunier Joseph , Paragh Gyorgy , Joseph Janine M , Klein André , Roche Charles , Barone Nancy , Etter John Lewis , Ray Andrew D , Trabert Britton , Schabath Matthew B , Peres Lauren C , Cannioto Rikki
Published: May 2024

Background

The association of body composition with epithelial ovarian carcinoma (EOC) mortality is poorly understood. To date, evidence suggests that high adiposity is associated with decreased mortality (an obesity paradox), but the impact of muscle on this association has not been investigated. Herein, we define associations of muscle and adiposity joint-exposure body composition phenotypes with EOC mortality.

Methods

Body composition from 500 women in the Body Composition and Epithelial Ovarian Cancer Survival Study was dichotomized as normal or low skeletal muscle index (SMI), a proxy for sarcopenia, and high or low adiposity. Four phenotypes were classified as fit (normal SMI and low adiposity; reference; 16.2%), overweight or obese (normal SMI and high adiposity; 51.2%), sarcopenia and overweight or obese (low SMI and high adiposity; 15.6%), and sarcopenia or cachexia (low SMI and low adiposity; 17%). We used multivariable Cox models to estimate associations of each phenotype with mortality for EOC overall and high-grade serous ovarian carcinoma (HGSOC).

Results

Overweight or obesity was associated with up to 51% and 104% increased mortality in EOC and HGSOC [Hazard Ratio (HR)] = 1.51, 95% CI = 1.05 to 2.19 and HR = 2.04, 95% CI = 1.29 to 3.21). Sarcopenia and overweight or obesity was associated with up to 66% and 67% increased mortality in EOC and HGSOC (HR = 1.66, 95% CI = 1.13 to 2.45 and HR = 1.67, 95% CI = 1.05 to 2.68). Sarcopenia or cachexia was associated with up to 73% and 109% increased mortality in EOC and HGSOC (HR = 1.73, 95% CI = 1.14 to 2.63 and HR = 2.09, 95% CI = 1.25 to 3.50).

Conclusions

Overweight or obesity, sarcopenia and overweight or obesity, and sarcopenia or cachexia phenotypes were each associated with increased mortality in EOC and HGSOC. Exercise and dietary interventions could be leveraged as ancillary treatment strategies for improving outcomes in the most fatal gynecological malignancy with no previously established modifiable prognostic factors.
TESS light-curve modelling and period study of four eclipsing binaries
Authors: Yang Yuangui , Wang Shuang
Published: May 2024

We reported the light curves (LCs) and orbital period variations of four short-period eclipsing binaries in the Southern hemisphere. From short-cadence time-series observations of the TESS, the intrinsic light changes rapidly with time. Δmmax and Δmmin exhibit random wave-like variations or quasi-periodicities. We deduced 14 sets of photometric solutions from the truncated LCs using the W-D programme. The results imply that V757 Cen and BC Gru are near-contact binaries, whose one or two components almost fill the Roche lobes with $f\gt 98{{\ \rm per\ cent}}$. Meanwhile, V535 Ara and AQ Tuc are A-subtype contact binaries. The asymmetric LCs were modelled by a cool spot assumed on a more massive component, which was used to track the stellar longitudes of star-spots. Based on all available eclipsing times (ETs), including 1495 ones from TESS LCs, the orbital period variations of four binaries were analysed. The (O − C) curves are coincidentally demonstrated by the light-time effect via the presence of the third bodies. The modulation periods approximate to 50 ∼ 60 yr. In the coplanar orbit with the central binaries, the third companions’ masses are 0.105 M⊙ for V757 Cen, 0.340 M⊙ for BC Gru, 0.238 M⊙ for V535 Ara, and 0.343 M⊙ for AQ Tuc, whose systems are stable according to Harrington’s criterion. Therefore, the four short-period eclipsing binaries, V757 Cen, BC Gru, V535 Ara, and AQ Tuc are hierarchical triple stellar systems.
Safety of sarilumab in a Japanese population with rheumatoid arthritis by age group: Data from an interim analysis of a postmarketing surveillance study
Authors: Kameda Hideto , Tasaka Sadatomo , Takahashi Toshiya , Suzuki Katsuhisa , Soeda Naoki , van Hoogstraten Hubert , Diab Remco , Tanaka Yoshiya
Published: May 2024

Objectives

Using data from a postmarketing surveillance, this interim subgroup analysis investigated the safety of sarilumab in younger (<65 years) and older patients (≥65 and ≥75 years) with rheumatoid arthritis.

Methods

During this interim analysis, patients who were treated with sarilumab in Japan were enrolled between June 2018 and 2021. Data collected by 12 January 2022 were analysed, with adverse drug events monitored over 52 weeks.

Results

Of 972 patients with available data, the proportion of patients aged <65 years, ≥65 years, and ≥75 years was 40.8%, 59.2%, and 27.8%, respectively. Most patients (95.5%) received the standard 200 mg dose of sarilumab as the initial dose. Adverse drug reactions were reported in 24.6% of patients, with serious events accounting for 6.4% of cases. No malignancy and low incidences of adverse drug reactions of special interest were reported across all age groups (<65 years, 7.8%; ≥65 years, 8.2%; ≥75 years, 8.5%). When stratified by absolute neutrophil count above and below the lower limit of normal, there were no numerical differences in incidences of serious and non-serious infections between age groups.

Conclusions

Regardless of age, sarilumab therapy was well tolerated by patients with rheumatoid arthritis, with no new safety signals reported in this study.
Clinical importance of anti-Ro52 antibody in polymyositis and dermatomyositis
Authors: Sugita Toshiki , Tsuboi Hiroto , Sugita Naoki , Akiyoshi Rai , Kuroda Yuki , Kawashima Akira , Kawashima Fumina , Tabuchi Daiki , Honda Fumika , Ohyama Ayako , Abe Saori , Kitada Ayako , Asashima Hiromitsu , Miki Haruka , Hagiwara Shinya , Kondo Yuya , Matsumoto Isao
Published: May 2024

Objectives

To clarify the clinical features of anti-Ro52 antibody (Ab)-positive polymyositis (PM)/dermatomyositis (DM).

Methods

We retrospectively examined the clinical features and status of anti-Ro52 Abs in patients with PM/DM admitted to the University of Tsukuba Hospital between January 2019 and February 2023. We compared the anti-Ro52 Ab-positive and anti-Ro52 Ab-negative groups.

Results

A total of 40 patients were selected and analysed. Twenty-three cases were PM, and 17 cases were DM (including six clinically amyopathic DM). Twenty-two cases were positive for anti-Ro52 Ab, 14 for anti-ARS Ab, and 6 for anti-MDA5 Ab. Interstitial lung disease was detected in 29 cases, nine of which were rapidly progressive. Glucocorticoid-resistant cardiomyopathy was detected in six cases. Of the 22 anti-Ro52 Ab-positive cases, only 3 were single-positive and the remaining 19 cases simultaneously had other autoantibodies. Comparing the anti-Ro52 Ab-positive and anti-Ro52 Ab-negative groups, the frequencies of anti-ARS Ab positivity (63.6% vs. 0%), interstitial lung disease (95.5% vs. 44.4%), glucocorticoid-resistant cardiomyopathy (27.3% vs. 0%), concomitant use of immunosuppressants (95.5% vs. 55.6%), and levels of C-reactive protein were significantly higher in the anti-Ro52 Ab-positive group (P < .05).

Conclusions

Anti-Ro52 Abs were frequently positive in PM/DM, and may be useful as a severity marker.
Novel binuclear copper(II) complexes with sulfanylpyrazole ligands: synthesis, crystal structure, fungicidal, cytostatic, and cytotoxic activity
Authors: Akhmetova Vnira R , Akhmadiev Nail S , Gubaidullin Aidar T , Samigullina Aida I , Glazyrin Andrey B , Sadykov Rais A , Ishmetova Diana V , Vakhitova Yulia V
Published: May 2024

New binuclear copper(II) [Cu(II)] tetraligand complexes (six examples) with sulfanylpyrazole ligands were synthesized. Electron spin resonance (ESR) studies have shown that in solution the complexes are transformed to the mononuclear one. Fungicidal properties against Candida albicans were found for the Cu complexes with benzyl and phenyl substituents. An in vitro evaluation of the cytotoxic properties of Cu chelates against HEK293, Jurkat, MCF-7, and THP-1 cells identified the Cu complex with the cyclohexylsulfanyl substituent in the pyrazole core as the lead compound, whereas the Cu complex without a sulfur atom in the pyrazole ligand had virtually no cytotoxic or fungicidal activity. The lead Cu(II) complex was more active than cisplatin. Effect of the S-containing Cu complex on apoptosis and cell cycle distribution has been investigated as well.
The open society and the future of political philosophy
Authors: Messina J P
Published: May 2024

This paper defends traditional political philosophy against the challenges Gaus leverages against it in The Open Society and Its Complexities. Granting Gaus that consensus on the principles of political philosophy is not forthcoming and that complexity undermines many of our most ambitious reform efforts, the paper argues that much work remains for political philosophy as it has been practiced for centuries. This is for three reasons. First, Gaus's own defense of the open society requires resources from the very traditions that he tends to dismiss. Secondly, the kinds of reform Gaus encourages us to focus on in light of complexity presuppose answers to philosophical questions, answers that philosophers have long attempted to provide. Thirdly, not all politically salient philosophical questions are aimed at action guidance. Despite the value in Gaus's analysis, I conclude that political philosophy's future will look, at least in part, like its storied past.
The gender (tax) gap in parental transfers. Evidence from administrative inheritance and gift tax data
Authors: Tisch Daria , Schechtl Manuel
Published: May 2024

This study examines how inheritance and gift taxation, in combination with gendered parental transfer behavior, exacerbate gender wealth inequalities. Tax systems can help reproduce gender differences if men and women benefit differently from tax exemptions. This might happen when men and women receive different types of assets, only some of which are tax exempt. To investigate gendered parental transfer behavior and gendered tax rates, we draw on German administrative data on inheritance and gift taxation. Women are less likely than men to receive parental transfers, the value of such transfers tend to be lower, and women tend to receive different types of asset. Moreover, we identify a gender tax gap of 2% for inheritances and 22% for gifts. Our analyses suggest that men benefit more from tax exemptions on business assets. This study adds the tax system as another factor implicated in the reproduction of gender wealth inequalities.
Prolactin receptor potentiates chemotherapy through miRNAs‐induced G6PD/TKT inhibition in pancreatic cancer
Authors: Liao Ying‐Na , Huang Pei‐Qi , Pan Hong , Gai Yan‐Zhi , Zhan Yun‐Fei , Li Shu‐Xin , Nie Hui‐Zhen
Published: May 2024

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a notoriously dismal prognosis. As a competitive inhibitor of DNA synthesis, gemcitabine is the cornerstone drug for treating PDAC at all stages. The therapeutic effect of gemcitabine, however, is often hindered by drug resistance, and the underlying mechanisms remain largely unknown. It is unclear whether their response to chemotherapeutics is regulated by endocrine regulators, despite the association between PDAC risk and endocrine deregulation. Here, we show that prolactin receptor (PRLR) synergizes with gemcitabine in both in vitro and in vivo treatment of PDAC. Interestingly, PRLR promotes the expression of miR‐4763‐3p and miR‐3663‐5p, two novel miRNAs whose functions are unknown. Furthermore, the analysis of transcriptome sequencing data of tumors from lactating mouse models enriches the PPP pathway, a multifunctional metabolic pathway. In addition to providing energy, the PPP pathway mainly provides a variety of raw materials for anabolism. We demonstrate that two key enzymes of the pentose phosphate pathway (PPP), G6PD and TKT, are directly targeted by miR‐4763‐3p and miR‐3663‐5p. Notably, miR‐4763‐3p and miR‐3663‐5p diminish the nucleotide synthesis of the PPP pathway, thereby increasing gemcitabine sensitivity. As a result, PRLR harnesses these two miRNAs to suppress PPP and nucleotide synthesis, subsequently elevating the gemcitabine sensitivity of PDAC cells. Also, PDAC tissues and tumors from LSL‐KrasG12D/+, LSL‐Trp53R172H/+, and PDX1‐cre (KPC) mice exhibit downregulation of PRLR. Bisulfite sequencing of PDAC tissues revealed that PRLR downregulation is due to epigenetic methylation. In this study, we show for the first time that the endocrine receptor PRLR improves the effects of gemcitabine by boosting two new miRNAs that block the PPP pathway and nucleotide synthesis by inhibiting two essential enzymes concurrently. The PRLR‐miRNAs‐PPP axis may serve as a possible therapeutic target to supplement chemotherapy advantages in PDAC.
Moving the Needle: Using Guidelines on Diversity, Equity, and Inclusion to Uplift a Stronger Medical Education Community
Authors: Buery-Joyner Samantha D. , Baecher-Lind Laura , Katz Nadine T.
Published: May 2024

The Association of Professors of Gynecology and Obstetrics created the Diversity, Equity, and Inclusion Guidelines Task Force to develop best practices to establish a diverse physician workforce and eliminate racism in medical education. Using the guidelines, educators are impacting their communities and, in some areas, leading their institutions toward greater diversity and inclusion. The guidelines are organized by 4 domains: learning environment, grading and assessment, pathway programs, and metrics. This manuscript uses that framework to highlight the work of individual educators who are moving the needle towards racism-free health care and aims to inspire others contemplating incorporation into their programs.
First Experience of Radionuclide Therapy With 177Lu-FAPI-2286 in a Patient With Metastatic Mediastinal Sarcoma
Authors: Banihashemian Seyedeh Somayyeh , Bayat Mohadese , Pirayesh Elahe , Divband Ghasemali , Abolhosseini Abdolghafar , Akbari Mohammad Esmaeel
Published: May 2024

Fibroblast activation protein (FAP) is a new promising molecular target for theragnostic approach. FAP inhibitors (FAPIs) labeled with 177Lu could be potentially a therapeutic radiopharmaceutical. Here, we presented the experience of 4 cycles of 177Lu-FAPI in a 67-year-old man with an unresectable mediastinal sarcoma.
Efficacy and Safety Evaluation of 177Lu-FAP-2286 in the Treatment of Advanced Lung Cancer
Authors: Xie Yang , Ma Jiao , Tang Wenxin , Zhang Yu , Zhang Chunyin , Chen Yue
Published: May 2024

Purpose

The aim of this study was to evaluate the efficacy and safety of peptide-targeted radionuclide therapy (PTRT) with 177Lu-FAP-2286 in advanced lung cancer.

Patients and Methods

This single-center prospective study included 9 patients diagnosed with advanced lung cancer. These patients met the inclusion criteria and received PTRT with 177Lu-FAP-2286. Short-term efficacy was assessed using RECIST 1.1 and PERCIST 1.0 criteria. Long-term efficacy was evaluated through overall survival, progression-free survival (PFS), overall response rate, EORTC QLQ-C30 v3.0, Eastern Cooperative Oncology Group, and Karnofsky Performance Status. Toxicity response was assessed using CTCAE v5.0.

Results

The results based on RECIST 1.1 and PERCIST 1.0 criteria were comparable, with 44% of patients showing a partial metabolic response, 33.3% with stable metabolic disease, and 22.22% with progressive metabolic disease. The highest metabolic response after treatment reached 66.89%, and the overall response rate could reach 77.78%. In the long-term efficacy assessment, the median overall survival and PFS were 10 months and 6 months, respectively. The 2 patients with the lowest PFS (3 months) started PTRT relatively late. EORTC QLQ-C30 v3.0, Eastern Cooperative Oncology Group, and Karnofsky Performance Status scores showed that the overall health status, symptom response, and quality of life of patients improved after 177Lu-FAP-2286 treatment. The most noticeable improvements in clinical symptoms were dyspnea and cancer-related pain. No grade III/IV toxicity events were observed during follow-up period, and fibrinogen decreased significantly after treatment.

Conclusions

177Lu-FAP-2286 has the potential to be a viable PTRT option for patients with advanced lung cancer.
Systematic review and network meta-analysis of agomelatine for the treatment of generalized anxiety disorder in adult patients
Authors: Hood Sean D , Odufowora-Sita Olatunji , Briere Jean-Baptiste , Lucchino Marco , Khrouf Fatma , Olewinska Elzbieta , Pierzchala Paulina , Mezghani Marwa , Nikodem Mateusz , Lévy Pierre
Published: May 2024

This systematic literature review aimed to assess the efficacy and tolerability of agomelatine versus approved medications for the treatment of generalized anxiety disorder (GAD) in adult patients. We selected randomized controlled trials on various medications used to treat GAD in adult patients. An existing systematic literature review (Kong et al., 2020) was used to identify relevant studies published before 2020. Outcomes of remission and discontinuation due to adverse events (AEs) were analyzed, following a random-effects network meta-analysis approach. Of 25 identified studies, 20 and 22 studies were included in the network meta-analysis for studying the remission and discontinuation (due to AEs) outcomes, respectively. A statistically significant difference in the remission rate was observed between agomelatine and pregabalin [odds ratio (OR), 2.22; 95% confidence interval (CI), 1.19–4.21]. For the other comparators, the results were nonsignificant; however, all the point estimates were in favor of agomelatine. Similarly, for discontinuation because of AEs, the point estimates leaned consistently toward agomelatine suggesting its higher tolerability. The probabilities of agomelatine having the highest remission rate and lowest discontinuation (due to AEs) rate were 67% and 68%, respectively. Based on its demonstrated effectiveness and tolerability, agomelatine can be considered as a drug of choice for the treatment of GAD.
Adapting Indirect Calorimetry to measure metabolic status of healthy and septic neonatal mice
Authors: Eynaud Adrien , Solomon Joan , Schoeman Elizna , Wu Ziyuan , Amenyogbe Nelly
Published: May 2024

Commercially available platforms to measure murine pulmonary gas exchange have long been used to measure metabolic status of adult animals, thus providing insights into metabolic disease, diabetes, and infection. Metabolic status is increasingly being recognized as an important modulator of neonatal immunity, and capturing pulmonary gas exchange in neonatal animals provides a non-invasive way to capture physiological information in health and disease and may reveal metabolic determinants of immune-mediated diseases unique to this life stage. We evaluated an indirect calorimetry (IC) system, the Promethion Core CGF system outfitted with Respirometry Chambers (RC3) as a tool to accurately capture pulmonary gas exchange from individual healthy and septic murine neonatal pups in the first week of life. We assessed the technical variance of the platform, impact of the procedure of animal welfare, compared measurements performed either at room temperature or at 30°C, and determined the platform’s sensitivity to measure gas exchange from pups with very small lung capacity or low respiratory rate. While gas exchange was not captured above background levels in all pups with either very small lung volume (pups less than 4 days old) or with very low respiratory rates (septic pups with the most depressed respiratory status), measurements did capture physiologically relevant changes in gas exchange across age and disease states. The impost associated with frequent handling of septic animals for IC did not negatively impact clinical outcomes among pups challenged with a polymicrobial slurry. Further, while performing the IC readings at 30°C successfully stabilized animal body temperature, the VO2 and VCO2 values differed across temperature states for older pups. In conclusion, the Promethion Core system outfitted with RC3 chambers is a viable platform to integrate IC into murine neonatal health research.
Loss of neutrophil Shp1 produces hemorrhagic and lethal acute lung injury
Authors: Moussavi-Harami SF , Cleary SJ , Magnen M , Seo Y , Conrad C , English BC , Qiu L , Wang KM , Abram CL , Lowell CA , Looney MR
Published: May 2024

The acute respiratory distress syndrome (ARDS) is associated with significant morbidity and mortality and neutrophils are critical to its pathogenesis. Neutrophil activation is closely regulated by inhibitory tyrosine phosphatases including Src homology region 2 domain containing phosphatase-1 (Shp1). Here, we report that loss of neutrophil Shp1 in mice produced hyperinflammation and lethal pulmonary hemorrhage in sterile inflammation and pathogen-induced models of acute lung injury (ALI) through a Syk kinase-dependent mechanism. We observed large intravascular neutrophil clusters, perivascular inflammation, and excessive neutrophil extracellular traps in neutrophil-specific Shp1 knockout mice suggesting an underlying mechanism for the observed pulmonary hemorrhage. Targeted immunomodulation through the administration of a Shp1 activator (SC43) reduced agonist-induced reactive oxygen speciesin vitroand ameliorated ALI-induced alveolar neutrophilia and NETsin vivo. We propose that the pharmacologic activation of Shp1 has the potential to fine-tune neutrophil hyperinflammation that is central to the pathogenesis of ARDS.
Mechanism-based design of DNA-nanoparticle motor with high speed and processivity comparable to motor proteins
Authors: Harashima Takanori , Otomo Akihiro , Iino Ryota
Published: May 2024

DNA-nanoparticle motor is a burnt-bridge Brownian ratchet moving on RNA-modified surface driven by Ribonuclease H (RNase H), and one of the fastest nanoscale artificial motors. However, its speed is still much lower than those of motor proteins. Here we resolve elementary processes of motion and reveal long pauses caused by slow RNase H binding are the bottleneck. As RNase H concentration ([RNase H]) increases, pause lengths shorten from ∼100 s to ∼0.1 s, while step sizes are constant (∼20 nm). At high [RNase H], speed reaches ∼100 nm s−1, however, processivity, run-length, and unidirectionality largely decrease. A geometry-based kinetic simulation reveals switching of bottleneck from RNase H binding to DNA/RNA hybridization at high [RNase H], and trade-off mechanism between speed and other performances. A mechanism-based newly-designed motor with 3.8-times larger DNA/RNA hybridization rate simultaneously achieves 30 nm s−1speed, 200 processivity, and 3 μm run-length comparable to motor proteins.
TIF1γ regulates stability of T regulatory cells during inflammation
Authors: Contreras-Castillo Eugenio , Zambrano-Romero Jesús Daniel , Pérez-Vázquez Diego , García-Patiño María Guadalupe , Tapia-Urzúa Gustavo , Candelario-Martínez Aurora , Ramos-Balderas Jose Luis , Licona-Limón Irma Ileana , Madera-Salcedo Iris , Rosetti-Scuitto Florencia , Crispin-Acuña Jose Carlos , Noriega-López Lilia , Nava Porfirio , Recillas-Targa Félix , Kaartinen Veesa , Henao-Mejía Jorge , Flavell Richard , Licona-Limón Paula
Published: May 2024

T regulatory cells are a suppressor population critical to control inflammation and maintain tissue homeostasis. The TGF-β pathway is a fundamental signal for T regulatory cell differentiation, yet the molecular determinants of how TGF-β signals regulate all these processes are not completely understood. TIF1γ was demonstrated to promote a noncanonical TGF-β/Smad pathway in HSC, however the role of TIF1γ in Treg function has been largely ignored. Here we showed that TIF1γ deficient Tregs lose stability and acquire an effector phenotype in the presence of an inflammatory stimuli or upon activation. TIF1γ deficient T regs gain a Th1-like Treg phenotype or become pro-inflammatory exTregs, by losing Foxp3 expression and acquiring IFNγ expression in an autoimmune model. Loss of TIF1γ in Tregs was cell-intrinsic and was also accompanied by increased proliferation and enhanced glycolytic capacity upon activation. Additionally, we demonstrated that in the absence of TIF1γ, there was an increased methylation status in the CNS2 enhancer region of the Foxp3 locus, further suggesting increased susceptibility for loss of Foxp3 expression. Mechanistically, TGF-β was in part responsible to inhibit the Th1-like bias a Treg has in the absence of TIF1γ, however, the proliferative phenotype observed in these cells was mostly independent of TGF-β signaling. Finally, we identified the beta-catenin pathway as the molecular mechanism driving both TIF1γ-dependent Treg stability and proliferation upon inflammation. Altogether, our data demonstrated that TIF1γ is required for the maintenance of a suppressor phenotype and stability of Treg lymphocytes during inflammatory conditionsin vivoand represents a new modulatory pathway to manipulate Treg cells for therapeutic purposes.
Molecular Sequestration Enhances Precision in Timing of Intracellular Events
Authors: Biswas Kuheli , Dey Supravat , Singh Abhyudai
Published: May 2024

Expressed gene products often interact ubiquitously with binding sites at nucleic acids and macromolecular complexes, known as decoys. Binding of transcription factors (TFs) to decoys is shown to be an indirect but crucial way to control the dynamics and stochasticity in gene regulation. Here, we explore how such decoys impact the timing of intracellular events, as captured by the time taken for the levels of a given TF to reach a critical threshold level, known as the first passage time (FPT). As binding introduces nonlinearity, an exact mathematical analysis is challenging. However, assuming quasi-static equilibrium (QSE) for binding/unbinding reactions, we can analytically discern the impact of decoys on FPT statistics by using small noise approximation (SNA) and reformulating the FPT question in terms of a suitable variable whose dynamics is linear. The stability of the decoy-bound TFs influences the impact of decoys on FPT statistics. The presence of decoys makes the mean FPT long and even longer for unstable bound TFs. Decoys reduce noise in FPT, and stable decoy-bound TFs offer greater timing precision with less expression cost than their unstable counterparts. Interestingly, when both bound and free TFs decay at the same rate, the noise in FPT is not directly influenced by the number of decoys or their binding affinities. We verify these results by performing exact stochastic simulations. These results have important implications for the precise temporal scheduling of events involved in the functioning of biomolecular clocks, development processes, cell-cycle control, and cell-size homeostasis.
SimpleMating: R-package for Prediction and Optimization of Breeding Crosses Using Genomic Selection
Authors: Peixoto Marco Antônio , Amadeu Rodrigo Rampazo , Bhering Leonardo Lopes , Ferrão Luís Felipe V. , Munoz Patrício R. , Resende Márcio F. R.
Published: May 2024

Selecting parents and crosses is a critical step for a successful breeding program. The ability to design crosses with high means that will maintain genetic variation in the population is the goal for long-term applications. Herein, we describe a new computational package for mate allocation in a breeding program. SimpleMating is a flexible and open-source R package originally designed to predict and optimize breeding crosses in crops with different reproductive systems and breeding designs. Divided into modules, SimpleMating first estimates the cross performance (criterion), such as mean parental average, cross total genetic value, and/or usefulness of a set of crosses. The second module implements an optimization algorithm to maximize a target criterion while minimizing next-generation inbreeding. The software is flexible, allowing users to specify the desired number of crosses, maximum/minimum number of crosses per parent, and the maximum value of the parent relationship for creating crosses. As an outcome, SimpleMating generates a mating plan from the target parental population using single or multi-trait criteria. As example, we implemented and tested SimpleMating in a simulated maize breeding program obtained through stochastic simulations. The crosses designed via SimpleMating showed large genetic mean over time (up to 22% more genetic gain than conventional genomic selection programs, with lower genetic diversity decrease over time), supporting the use of this tool, as well as the use of data-driven decisions in applied breeding programs.
Finding novel vulnerabilities of hypomorphic BRCA1 alleles
Authors: Schreuder Anne , de Lint Klaas , Góis Mariana M. , Kampen Rosalie A. , Martin Alonso Marta San , Nootenboom Ilse , Garzero Veronica , Wolthuis Rob M. F. , Noordermeer Sylvie M.
Published: May 2024

With the recent rise in CRISPR/Cas9-mediated genome-wide synthetic lethality screens, many new synthetic lethal targets have been identified for diseases with underlying genetic causes such as tumours withBRCA1mutations. Such screens often use full deficiency of a protein to identify novel vulnerabilities. However, patient-derived mutations not only result in loss of the protein but often also concern missense mutations with hypomorphic phenotypes. Here we study the genetic vulnerabilities of two previously described hypomorphic BRCA1 missense mutations and compare these to a BRCA1-depleted setting to study whether this affects screening for synthetic lethal interactions. Our research showed that BRCA1I26Amutated cells have very similar vulnerabilities to BRCA1 wildtype cells, confirming its low tumorigenic effect. In contrast, the BRCA1R1699Qmutation induced a more similar phenotype to BRCA1-deficient cells. For this mutation, we also unveiled a unique vulnerability to the loss of NDE1. Specifically in BRCA1R1699Qmutated cells, and not BRCA1-proficient or -deficient cells, NDE1 loss leads to increased genomic instability. Altogether our findings highlight the importance to differentiate between patient-derived mutations when assessing novel treatment targets.
Dating the origin of a viral domestication event in parasitoid wasps attacking Diptera
Authors: Guinet Benjamin , Vogel Jonathan , Peters Ralph S. , Hrcek Jan , Buffington Matthew L. , Varaldi Julien
Published: May 2024

Over the course of evolution, hymenopteran parasitoids have developed a close relationship with heritable viruses, sometimes even integrating viral genes into their chromosomes. For example, inDrosophilaparasitoids belonging to the Leptopilina genus, 13 viral genes from the Filamentoviridae family have been integrated and domesticated to deliver immunosuppressive factors to host immune cells, thereby protecting parasitoid offspring from host immune responses. The present study aims to comprehensively characterise this domestication event in terms of the viral genes involved, the wasp diversity affected by this event, and its chronology. Our genomic analysis of 41 Cynipoidea wasps from six subfamilies revealed 18 viral genes that were endogenised during the early radiation of the Eucoilini+Trichoplastini clade around 75 million years ago. Wasps from this highly diverse clade develop not only fromDrosophilabut also from a variety of Schizophora. This event coincides with the radiation of Schizophora, a highly speciose Diptera clade, suggesting that viral domestication facilitated wasp diversification in response to host diversification. Additionally, at least one viral gene was replaced by another Filamentovirus gene in one of the species, highlighting the dynamic nature of viral endogenisation. This study highlights the impact of viral domestication on the diversification of parasitoid wasps.
RUCova: Removal of Unwanted Covariance in mass cytometry data
Authors: Astaburuaga-García Rosario , Sell Thomas , Mutlu Samet , Sieber Anja , Lauber Kirsten , Blüthgen Nils
Published: May 2024

High dimensional mass cytometry is confounded by unwanted covariance due to variations in cell size and staining efficiency, making analysis and interpretation challenging.

We present RUCova, a novel method designed to address confounding factors in mass cytometry data. RUCova removes unwanted covariance using multivariate linear regression on Surrogates of Unwanted Covariance (SUCs), and Principal Component Analysis (PCA). We exemplify the use of RUCova and show that it effectively removes unwanted covariance while preserving genuine biological signals. Our results demonstrate the efficacy of RUCova in elucidating complex data patterns, facilitating the identification of activated signalling pathways, and improving the classification of important cell populations. By providing a robust framework for data normalization and interpretation, RUCova enhances the accuracy and reliability of mass cytometry analyses, contributing to advancements in our understanding of cellular biology and disease mechanisms. The R package is available onhttps://github.com/molsysbio/RUCova. Detailed documentation, data, and the code required to reproduce the results are available onhttps://doi.org/10.5281/zenodo.10913464. Supplementary material: Available at bioRxiv.
WITHDRAWN: Physiological modeling and biomechanical insights of cytokine modulation in COVID-19 and pulmonary fibrosis through a multi-dimensional graph-based approach
Authors: Ray Rajarshi , Bhowmik Ratul , Shyamal Sagar Singh , Manaithiya Ajay , Gong Wenping , Parkkila Seppo , Aspatwar Ashok
Published: May 2024

Withdrawal Statement

The authors have withdrawn their manuscript owing to the inability to complete the revisions or follow up on the manuscript at this time, due to personal circumstances. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.